In this paper, we look at how Artificial Swarm Intelligence can evolve using evolutionary algorithms that try to minimize the sensory surprise of the system. We will show how to apply the free-energy principle, borrowed from statistical physics, to quantitatively describe the optimization method (sensory surprise minimization), which can be used to support lifelong learning. We provide our ideas about how to combine this optimization method with evolutionary algorithms in order to boost the development of specialized Artificial Neural Networks, which define the proprioceptive configuration of particular robotic units that are part of a swarm. We consider how optimization of the free-energy can promote the homeostasis of the swarm system, i.e. ensures that the system remains within its sensory boundaries throughout its active lifetime. We will show how complex distributed cognitive systems can be build in the form of hierarchical modular system, which consists of specialized micro-intelligent agents connected through information channels. We will also consider the co-evolution of various robotic swarm units, which can result in development of proprioception and a comprehensive awareness of the properties of the environment. And finally, we will give a brief outline of how this system can be implemented in practice and of our progress in this area.

The cerebellum is an encephalic region classically known for its central role in the control of movement, although recent research has revealed its involvement in other cognitive and affective tasks. Several different pathologies are known to affect this structure, causing a wide range of behavioral and gait impairments. Intriguingly, although the neurodegenerative factors affect all Purkinje cells of the cerebellum uniformly, certain neurodegeneration patterns can be distinguished, in which some Purkinje cells persist longer than other cell types. Precisely, there is a cerebellar region, lobe X, which is more resistant to different types of neurodegeneration regardless of the injury. This work will review the main models of cerebellar degeneration, with special emphasis on this region, and aims to reveal a common origin for its resistance to neuronal death.

Neuro-rehabilitation services are essential in reducing post-stroke impairments, enhancing independence, and improving recovery in hospital and post-discharge. However these services are therapist-dependent and resource intensive. Patients’ disengagement and boredom in stroke units are common which adversely affect functional and psychological outcomes. Novel techniques such as use of iPads™ are increasingly researched to overcome such challenges. The aim of this review is to determine the feasibility, effectiveness, acceptability, and barriers to the use of iPads™ in stroke neuro-rehabilitation. Four databases and manual literature search were used to identify published studies using the terms “iPad”, “Stroke”, and “neuro-rehabilitation”. Studies were included in accordance with the review selection criteria. A total of 16 articles were included in the review. The majority of the studies focused on iPads use in speech and language therapy. Although of small scale, the studies highlighted that iPads are feasible, have the potential to improve rehabilitation outcomes, and can improve patient’s social isolation. Patients’ stroke severity and financial limitations are some of the barriers highlighted in this review. This review presents preliminary data supportive for the use of iPad technology in stroke neuro-rehabilitation. However, further research is needed to determine impact on rehabilitation goals acquisition, clinical efficacy, and cost-efficiency.

A novel hypothesis concerning language evolution is advanced. It posits that languages have evolved as a means of binding individuals to a group, as well as for defining those groups. This means that language evolution has to be considered on the level of groups and not only on the level of individuals. This hypothesis helps to explain the huge diversity of human languages, as well as their complexity. Perhaps more importantly, it explains why adults lose the ability to learn languages with the ease that children possess.

Reptilians or reptoids are staple characters of Hollywood cinema, science fiction literature, ufology and conspiracy theories. Despite its popularity, the reptoid has been dismissed by the scientific community as a figment of the imagination; born out of a speculation, paranoia and wanton anthropocentricism. In this paper, however, the Life Sequence Conjecture is advanced as a supportive framework for the notion of reptilian extraterrestrials. This paper is not an argument in support of the existence of extraterrestrials. Rather, it proposes that if extraterrestrials do exist, then a reptilian morphology is not untenable.

Background: Post-operative delirium in elderly with hip fracture is associated with various adverse clinical outcomes. Nevertheless, the pathophysiological processes underpinning delirium have remained elusive. The aim of this study is to explore the associations between delirium and its features and immune-inflammatory and blood gas biomarkers.Methods: In this prospective study we examined 65 patients who underwent a hip fracture surgery and assessed the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), Richmond Agitation-Sedation Scale (RASS), and Delirium Rating Scale Revised-98 (DRS-R-98) before and during 4 days after the surgery. Complete Blood Count (CBC) and venous blood gas markers were obtained at the same time points.Results: Delirium was observed in 19 patients and was accompanied by significantly increased pO2, number of white blood cells, neutrophil percentage, and neutrophil/lymphocyte ratio, and lower mean platelet volume (MPV) (after adjusting for age, central nervous system (CNS) disease, blood loss during surgery, sleep disorders, and body mass index. The severity of delirium was associated with lowered number of platelets and MPV. Psychomotor disorders were associated with lower bicarbonate levels. The requirement of physical restraint of the patients was predicted by increased percentages of neutrophils and lymphocytes. Prior CNS disease was together with these biomarkers a significant predictor of delirium and severity of delirium. Conclusion: Delirium and psychomotor disorders following hip fracture and surgery may be caused by immune-inflammatory and oxidative stress pathways probably attributable to an aseptic inflammatory process. Oxygen administration may aggravate these pathways.

Objective: To examine associations between chemokines and menstrual cycle associated symptoms (MCAS). Methods: Forty-one women completed the Daily Record of Severity of Problems (DRSP) rating scale during 28 consecutive days of the menstrual cycle. MCAS is diagnosed when the total daily DRSP score during the menstrual cycle is > 0.666 percentile. We assayed plasma CCL2, CCL5, CCL11, CXCL8, CXCL10, EGF, IGF-1, and PAI-1 at days 7, 14, 21 and 28 of the menstrual cycle. Results: CCL2, CCL5, CCL11 and EGF are significantly higher in women with MCAS than in those without. Increased CCL2, CXCL10, CXCL8, CCL11 and CCL5 levels are significantly associated with DRSP scores while CCL2 is the most significant predictor explaining 39.6% of the variance. The sum of the neurotoxic chemokines CCL2, CCL11 and CCL5 is significantly associated with the DRSP score and depression, physiosomatic, breast-craving and anxiety symptoms. The impact of chemokines on MCAS symptoms may differ between consecutive weeks of the menstrual cycle with CCL2 being the most important predictor of increased DRSP levels during the first two weeks, and CXCL10 or a combination of CCL2, CCL11 and CCL5 being the best predictors during week 3 and 4, respectively. Discussion: The novel case definition “MCAS” is externally validated by increased levels of uterus-associated chemokines and EGF. Those chemokines are involved in MCAS and are regulated by sex hormones and modulate endometrium functions and brain neuro-immune responses, which may underpin MCAS symptoms. As such, uterine-related chemokines may link the uterus with brain functions via a putative uterine-chemokine-brain axis.

There is now evidence that major depression is accompanied by lowered serum zinc, an immune-inflammatory biomarker. However, the effect of anti-inflammatory drugs as adjuvant to antidepressants on serum zinc and copper in relation to pro- and anti-inflammatory cytokines are not studied. The aim of the present work is to examine the effects of treatment with sertraline with and without ketoprofen on serum levels of zinc and copper in association with immune-inflammatory biomarkers in drug-naïve major depressed patients. We measured serum zinc and copper, interleukin (IL)-1β, IL-4, IL-6, IL-18, interferon (IFN)-γ, and transforming growth factor (TGF)-β1 in 40 controls and 133 depressed patients. The clinical efficacy of the treatment was measured using the Beck Depression Inventory-II (BDI-II) at baseline and 8 weeks later. In drug-naïve major depressed patients we found significantly reduced baseline levels of serum zinc and copper in association with upregulation of all cytokines, indicating activation of the immune-inflammatory responses system (IRS) as well as the compensatory immune regulatory system (CIRS). Treatment with sertraline significantly increased zinc and decreased copper levels, while ketoprofen did not have a significant add-on effect on zinc but attenuated the suppressant effects of sertraline on copper levels. During treatment, there was a significant inverse association between serum zinc and activation of the IRS/CIRS. The improvement in the BDI-II during treatment was significantly associated with increments in serum zinc coupled with attenuation of the IRS/CIRS. In conclusion, lower serum zinc is a hallmark of depression, while increments in serum zinc and attenuation of the immune-inflammatory response during treatment appear to play a role in the clinical efficacy of sertraline. Intertwined changes in zinc levels and the immune response play a role in the pathophysiology of major depression and participate in the mechanisms underpinning the clinical efficacy of antidepressants.

Monitoring complex electro-mechanical processes is not straightforward despite the arsenal of techniques nowadays availanle. This paper presents a method based on Adaptive-Network-based Fuzzy Inference System (ANFIS) to estimate eccentricity of its spinning axis. The method is experimentally tested on an ultra-precision rotating device commonly used for micro-scale turning. The developed model has three inputs, two obtained from a frequency domain analysis of a vibration signal and the third, which is the device rotation frequency. A comparative study demonstrates that an adaptive neural-fuzzy inference system model provides better error-based performance indices for detecting imbalance than a non-linear regression model. This simple, fast, and non-intrusive imbalance detection strategy is proposed to counteract eventual deterioration in the performance of ultra-high precision rotating machines due to vibrations.

BACKGROUND: Glioblastoma (GBM) is driven by various genomic alterations. Next generation sequencing (NGS) could yield targetable alterations that may impact outcomes. The goal of this study was to describe how NGS can inform targeted therapy (TT) in this patient population. METHODS: The medical records of patients (pts) with a diagnosis of GBM from 2017-2019 were reviewed. Records of patients with recurrent GBM and genomic alterations were evaluated. Objective response rates and disease control rates were deter-mined. RESULTS: A total of 87 pts with GBM underwent NGS. Forty percent (n = 35) were considered to have actionable alterations. Of the 35, 40% (n=14) pts had their treatment changed due to an alteration. The objective response rate (ORR) of this population was 43%. The disease control rate (DCR) was 100%. The absolute mean decrease in contrast enhancing disease was 50.7% (95% CI 34.8 – 66.6). CONCLUSION: NGS for GBM, particularly in the recurrent setting, yields a high rate of actionable alterations. We observed a high ORR and DCR, reflecting the value of NGS in deciding on TT to match alterations that are likely to respond. In conclusion, patient selection and availability of NGS may impact outcomes in select pts with recurrent GBM.

Structure - function interdependence is a universal phenomenon in biological systems. Any alteration in structural features may result in change in functions–leading to natural selection of a particular trait, or dysfunctions thereof. Many such alterations arise during the course of evolution of a species and may meticulously be traced during embryonic development of an organism. Through the theoretical construct of morphological integration, a set of phenotypic traits alter in a coordinated and integrated manner during evolution and embryonic development of an organism yielding efficient environmentally adapted physiological functions pertinent to those structures. Such integration may go awry sometimes, setting the basis for genesis of diseases. Morphological integration in human skull has been established through various methods. The brain-skull co-development is handcuffed through evolution and development, and the very basis of a neuro-psychiatric disorder could be underlying in dysmorphogenesis of the skull, its consequent effect on structures, and thus functions of the pertinent brain components. Here we propose that morphological integration in human skull may be mechanistically implied in etiogenesis of certain neuro-psychiatric disorders and should be borne in mind during clinical diagnosis and therapeutic interventions.

Background: CCL11 (eotaxin) is a chemokine with an important role in allergic conditions. Recent evidence indicates that CCL11 plays a role in brain disorders as well. Aims: This paper reviews the associations between CCL11 and aging, neurodegenerative, neuroinflammatory and neuropsychiatric disorders.Methods: Electronic databases were searched for original articles examining CCL11 in neuropsychiatric disorders.Results: CCL11 is rapidly transported from the blood to the brain through the brain-blood barrier. Age-related increases in CCL11 are associated with cognitive impairments in executive functions, episodic and semantic memory and, therefore, this chemokine was described as an “endogenous cognition deteriorating chemokine” (ECDC) or “accelerated brain-aging chemokine” (ABAC). In schizophrenia, increased CCL11 is not only associated with impairments in cognitive functions, but also with key symptoms including formal thought disorders. Some patients with mood disorders and premenstrual syndrome show increased plasma CCL11 levels. In diseases of old age, CCL11 is associated with lowered neurogenesis and neurodegenerative processes and, as a consequence, increased CCL11 increases risk towards Alzheimer's Disease. Polymorphisms in the CCL11 gene are associated with stroke. Increased CCL11 also plays a role in neuroinflammatory disease including multiple sclerosis. In animal models, neutralization of CCL11 may protect against nigrostriatal neurodegeneration. Increased production of CCL11 may be attenuated by glucocorticoids, minocycline, resveratrol and anti-CCL11 antibodies.Conclusion: Increased CCL11 production during inflammatory conditions may play a role in human disease including age-related cognitive decline, schizophrenia, mood disorders and neurodegenerative disorders. Increased CCL11 production is a new drug target in the treatment and prevention of those disorders.

Background: Schizophrenia and treatment-resistant schizophrenia (TRS) are associated with aberrations in immune-inflammatory pathways. Increased High Mobility Group Protein 1 (HMGB1), an inflammatory mediator, and Dickkopf-Related Protein (DKK1), a Wnt/β-catenin signaling antagonist, affect the blood-brain-barrier and induce neurotoxic effects and neurocognitive deficits.Aim of the study: The present study aims to examine HMGB1 and DDK1 in non-responders to treatments with antipsychotics (NRTT, n=60), partial RTT (PRTT, n=55) and healthy controls (n=43) in relation to established markers of schizophrenia including IL-6, IL-10 and CLL11 (eotaxin); and to delineate whether these proteins are associated with the schizophrenia symptom subdomains and neurocognitive impairments.Results: HMGB1, DKK1, IL-6 and CCL11 were significantly higher in schizophrenia patients than in controls. DKK1 and IL-6 were significantly higher in NRTT than in PRTT and controls while IL-10 was higher in NRTT than in controls. Binary logistic regression analysis showed that schizophrenia was best predicted by increased DDK1 and HMGB1 while NRTT (versus PRTT) was best predicted by increased IL-6 and CCL11 levels. A large part of the variance in psychosis, hostility, excitation, mannerism and negative (PHEMN) symptoms, and formal thought disorders was explained by HMGB1, IL-6, and CCL11 while most neurocognitive functions were predicted by HMGB1, DDK1 and CCL11. Conclusion: The neurotoxic effects of HMGB1, DKK1, IL-6 and CCL11 including effects on the blood-brain-barrier and the Wnt/β-catenin signaling pathway may cause impairments in executive functions, and working, episodic and semantic memory and explain, in part, PHEMN symptoms and a non-response to treatment with antipsychotic drugs.

Premenstrual syndrome (PMS) frequently occurs in women of childbearing age. There are different case definitions of PMS, one proposed by the American College of Obstetricians and Gynecologists (ACOG) and another based on the Daily Record of Severity of Problems (DRSP) scores. Here we review our recent papers indicating that the discovery of biomarkers of menstrual cycle-related symptoms is strongly dependent on the case definitions used and that the gold standard methods used to asses PMS, including the ACOG case definition, induce a high degree of false-negative findings. We propose a new case definition of the menstrual cycle-associated syndrome (MCAS), which is characterized by increased DRSP scores during the menstrual cycle and additionally by an exaggerated increase in symptoms the week prior to the menses. This case definition performed well and was externally validated by diverse biomarkers including plasma levels of progesterone and estradiol, chemokines (e.g. CCL2, CCL5 and CCL11), epidermal growth factor, hydroperoxides, paraoxonase 1 activity and complement C4. In conclusion, when evaluating menstrual cycle-related symptoms and their associations with biomarkers, we propose to assess daily measurements of the DRSP and based on those scores to a) use the diagnosis of MCAS as an indicant of menstrual cycle-related symptoms; and b) examine the associations of the time series in the DRSP and its subdomains (e.g. depression, physio-somatic, anxiety) and those in biomarkers including distributed lag models.

Beta-thalassemia major (β-TM) patients are treated with repeated blood transfusions, which may cause iron overload (IO), which in turn may induce immune aberrations. Patients with β-TM have an increased risk of major depressive disorder (MDD). The aims of the present study are to examine whether repeated blood transfusions, IO and immune-inflammatory responses are associated with MDD in children (6-12 years) with β-TM. The Children’s Depression Inventory (CDI), iron status (serum iron, ferritin, transferrin, TS%) and serum levels of CCL11, IL-1β, IL-10, and TNF-α were measured in β-TM with (n=54) and without (n=57) MDD and in healthy children (n=55). The results show that MDD in β-TM is associated with a greater number of blood transfusions, increased IO and IL-1β levels. Partial Least Squares path analysis shows that 68.8% of the variance in the CDI score is explained by the number of blood transfusions, IO, and increased levels of IL-1β and TNF-α. The latter two cytokines partly mediate the effects of IO on the CDI score, while the effects of blood transfusions on the CDI score are partly mediated by IO and the path from IO to immune activation. IO is also associated with increased IL-10 and lower CCL11 levels but these alterations are not significantly associated with MDD. In conclusion, blood transfusions may be causally related to MDD in β-TM children and their effects are in part mediated by increased IO and the consequent immune-inflammatory response. The results suggest that not only IO and its consequences including inflammation and ferroptosis, but also other factors related to the number of transfusions may cause MDD including psychosocial stressors. Current treatment modalities with folic acid and vitamin C are insufficient to attenuate IO and immune-inflammatory responses and to prevent MDD is children with β-TM undergoing blood transfusions.

Chronic fatigue and fibromyalgia symptoms frequently occur in major depressive disorder (MDD). The pathophysiology of these symptoms may in part, be ascribed to activated immune pathways, although it is unclear whether muscular factors play a role in their onset. The aim of the present study is to examine the role of muscle proteins in major depression in association with symptoms of chronic fatigue and fibromyalgia. We measured serum levels of agrin, talin-2, titin, and creatine phosphokinase (CPK) as well as the FibroFatigue (FF), the Hamilton Depression Rating Scale (HAM-D) and the Beck Depression Inventory (BDI-II) in 60 MDD patients and 30 healthy controls. The results show a significant increase in agrin and talin-2 in MDD patients as compared with controls. There were highly significant correlations between agrin and HAM-D, BDI-II and FF scores. Agrin, but not talin or titin, was significantly and positively associated with all 12 items of the FF scale. We found that a large part of the variance in HAM-D (47.4%), BDI-II (43.4%) and FF (43.5%) scores was explained by the regression on agrin, smoking, female sex (positively associated) and education (inversely associated). CPK was significantly and inversely associated with the total FF score and with muscle and gastro-intestinal symptoms, fatigue, a flu-like malaise, headache and memory, autonomic and sleep disturbances. These results suggest that aberrations in neuromuscular (NMJs) and myotendinous junctions may play a role in MDD and that the aberrations in NMJs coupled with lowered CPK may play a role in symptoms of chronic fatigue and fibromyalgia in MDD. Moreover, the increase of agrin in MDD probably functions as part of the compensatory immune-regulatory system (CIRS).

Objective: To examine associations between IgA responses to Gram-negative gut-commensal bacteria and peri-menstrual symptoms and sex hormone levels during the menstrual cycle in women with and without premenstrual symptoms. Methods: Forty women aged 18-45 years completed the Daily Record of Severity of Problems (DRSP) during all 28 consecutive days of the menstrual cycle. We assayed, in plasma,, IgA responses to 6 Gram-negative bacteria, i.e. Hafnei alvei, Pseudomonas aeruginosa, Morganella morganii, Klebsiella pneumoniae, Pseudomonas putida and Citrobacter pylori, progesterone and oestradiol at days 7, 14, 21 and 28 of the menstrual cycle. Results: Significant changes in Δ (actual minus one week earlier) IgA to LPS of the 6 Gram-negative bacteria during the menstrual cycle were observed with peak IgA levels at T4 (day 28) and lows at T1 or T2 (day 7 or 14). The Δ IgA changes in H. alvei, M. Morganii, P. putida during the menstrual cycle were significantly and positively associated with changes in the total DRSP score, and severity of physio-somatic, anxiety and breast-craving, but not depressive, symptoms. The changes in IgA responses to LPS were largely predicted by changes in progesterone and steady-state levels of progesterone averaged over the luteal phase. Discussion: Menstrual cycle-associated changes in IgA directed against LPS and by inference bacterial translocation may be driven by effects of progesterone on transcellular, paracellular and vascular pathways thereby contributing to the severity of physio-somatic and anxiety symptoms as well as fatigue, breast swelling and food cravings.

Major depressive disorder (MDD) is associated with changes in the levels of the cations calcium (Ca) and magnesium (Mg) as well as circulating pro- and anti-inflammatory cytokines. The immune-inflammatory nature of MDD has encouraged researchers to use anti-inflammatory drugs as an adjuvant treatment for MDD. However, the effect of this treatment on cation levels has not been studied. The present study examined a) differences in both cations between drug-naïve MDD patients and controls, and b) the effects of a combination of sertraline and ketoprofen, an anti-inflammatory drug, on Ca and Mg (both total and ionized). In the same patients we also examined the associations between both cations and IL-1β, IL-4, IL-6, IL-18, IFN-γ, TGF-β1, zinc and indoleamine 2,3-dioxygenase (IDO). Clinical improvement was estimated using the Beck Depression Inventory-II (BDI-II) at baseline and after follow up for two months. Serum Ca and Mg (total and ionized) were significantly lower in MDD patients as compared with controls, while treatment significantly increased calcium but decreased magnesium levels. There were significant and inverse correlations between the BDI-II scores from baseline to endpoint and Ca (both total and ionized), but not Mg, levels. The effects of calcium on the BDI-II score remained significant after considering the effects of zinc, IDO and an immune activation z unit weighted composite score based on the sum of all cytokines. There was a significant and inverse association between this immune activation index and calcium levels from baseline to endpoint. In conclusion, reduced levels of both cations play a role in the pathophysiology of major depression. Increased calcium levels are coupled to the clinical efficacy of antidepressants and attenuation of immune activation. The suppressant effect of antidepressants on Mg levels may be a side effect of those drugs. New antidepressant treatments should be developed that increase the levels both Ca and Mg.

This paper presents the design of a new neuro-generator of pseudorandom number type PRNG Pseudorandom Number Generator, which produces complex sequences with an adequate bit distri-bution. The circuit is connected to a neuronal module with six impulse neurons with different be-haviors: spike frequency adaptation, phasic spiking, mixed mode, phasic bursting, tonic bursting and tonic spiking. This module aims to generate a non-periodic signal that becomes the clock sig-nal for one of the LFSRs Linear Feedback Shift Register that the neuro-generator has. To verify its correct operation, the neuro-generator was subjected to a series of tests where the frequencies of the impulse neurons were modified. This modification allows generating a greater number of pulses at the output of the neuronal module, to obtain sequences with different characteristics that pass different NIST statistical tests National Institute of Standards and Technology of U.S. The results show that the new neuro-generator maintains pseudo-randomness in the sequences obtained with different frequencies and it can be implemented on reconfigurable FPGA Field Programmable Gate Array Virtex 7 xc7vx85t-2ffg1761 device. Therefore, it can be used for applications such as biologi-cal systems.

This study aims to systematically review and meta-analyze the nitro-oxidative stress (O&NS)/antioxidant (ANTIOX) ratio in the peripheral blood of people with mild cognitive impairment (MCI). We searched PubMed, Scopus, Google Scholar, and Web of Science for articles published from inception until July 31, 2021. Forty-six studies on 3.798 MCI individuals and 6.063 healthy controls were included. The O&NS/ANTIOX ratio was significantly higher in MCI than in controls with a Standardized Mean Difference (SMD)=0.378 (95% CI: 0.250; 0.506). MCI individuals showed increased lipid peroxidation (SMD=0.774, 95%CI: 4.416; 1.132) and O&NS-associated toxicity (SMD=0.621, CI: 0.377; 0.865) and reduced glutathione (GSH) defenses (SMD=0.725, 95%CI: 0.269; 1.182) as compared with controls. MCI was also accompanied by significantly increased homocysteine (SMD=0.320, CI: 0.059; 0.581), but not protein oxidation, and lowered non-vitamin (SMD=0.347, CI: 0.168; 0.527) and vitamin (SMD=0.564, CI: 0.129; 0.999) antioxidant defenses. The results show that MCI is at least in part due to increased neuro-oxidative toxicity and suggest that treatments targeting lipid peroxidation and the GSH system may be used to treat or prevent MCI.

Background. The aim of this study is to examine whether biomarkers of the immune-inflammatory response (IRS) and endogenous opioid (EOS) systems are associated with affective symptoms in schizophrenia. Methods. We recruited 115 schizophrenia patients and 43 healthy controls and assessed the Hamilton Depression (HDRS) and Anxiety (HAM-A) rating Scale scores as well as serum levels of interleukin (IL)-6, IL-10, eotaxin (CCL11), high mobility group box 1 (HMGB1), Dickkopf-related protein 1 (DKK1), and mu (MOR) and kappa (KOR) opioid receptors.Results. The HDRS and HAM-A scores are significantly and positively correlated with a) psychosis, hostility, excitation, mannerism, negative symptoms, psychomotor retardation, and formal thought disorders; and b) lowered scores on semantic and episodic memory, executive functions, and attention tests as measured with the Brief Assessment of Cognition in Psychiatry. Both HDRS and HAM-A are significantly increased in non-responders to treatment as compared with partial responders. Both affective scores are strongly associated with latent vectors extracted from all symptoms, reflecting overall severity of psychosis (OSOS), and neurocognitive test scores, reflecting a generalized cognitive decline (G-CoDe). The HDRS score was strongly and positively associated with IL-6, HMGB1, KOR, and MOR levels, and the HAM-A score with IL-6, IL-10, CCL11, HMGB1, KOR, and MOR levels. A single latent trait may be extracted from OSOS, G-CoDe, and the HDRS and HAMA scores, and this latent vector score is strongly predicted by HMGB1, MOR, and DKK1.Conclusion. Immune-inflammatory and EOS pathways contribute to the phenome of schizophrenia, which comprises OSOS, affective, and physiosomatic symptoms, and G-CoDe.

Accumulating evidence suggests that TNF-α-mediated immune-neurotoxicity contributes to cognitive impairments and the overall severity of schizophrenia (OSOS). There are no data whether peripheral IL-6 and IL-4 may affect the phenome of schizophrenia above and beyond the effects of TNF-α and whether those cytokines are regulated by lowered natural IgM to malondialdehyde (MDA) and paraoxonase 1 enzyme activity. We assessed the aforementioned biomarkers in schizophrenia patients with (n=40) and without (n=40) deficit schizophrenia and 40 healthy controls. Deficit schizophrenia was best predicted by a combination of increased IL-6 and PON1 status (QQ genotype and lowered CMPAase activity) and lowered IgM to MDA. Partial Least Squares bootstrapping shows that 41.0% of the variance in negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation, and formal thought disorders was explained by increased TNF-α and PON1 status (QQ genotype and lowered CMPAase activity), lowered IL-4 and IgM to MDA as well as male sex and lowered education. We found that 47.9% of the variance in verbal fluency, word list memory, true recall, Mini-Mental State Examination, and executive functions was predicted by increased TNF-α and lowered IL-4, IgM to MDA and education. In addition, both TNF-α and IL-4 levels were significantly associated with lowered IgM to MDA, while TNF-α was correlated with PON1 status. These data provide evidence that the symptomatic (both the deficit subtype and OSOS) and cognitive impairments in schizophrenia are to a large extent mediated by the effects of immune-mediated neurotoxicity as well as lowered regulation by the innate immune system.

In Schizophrenia, pathway-genotypes may be constructed by combining interrelated immune biomarkers with changes in specific neurocognitive functions that represent aberrations in brain neuronal circuits. These constructs provide insight on the phenome of schizophrenia and show how pathway-phenotypes mediate the effects of genome X environmentome interactions on the symptomatology/phenomenology of schizophrenia. Nevertheless, there is a lack of knowledge how to construct pathway-phenotypes using Partial Least Squares (PLS) path modeling and Soft Independent Modeling of Class Analogy (SIMCA). This paper aims to provide a step-by-step utilization guide for the construction of pathway-phenotypes that reflect aberrations in the neuroimmune - brain circuit axis (NIBCA) in deficit schizophrenia. This NIBCA index is constructed using immune biomarkers (CCL-2, CCL-11, IL-1β, sIL-1RA, TNF-α, sTNFR1, sTNFR2) and neurocognitive tests (Brief Assessment of Cognition in Schizophrenia) predicting overall severity of schizophrenia (OSOS) in 120 deficit SCZ and 54 healthy participants. Using SmartPLS path analysis, a latent vector is extracted from those biomarkers and cognitive tests, which shows a good construct reliability (Cronbach alpha and composite reliability) and replicability and which is reflectively measured through its NIBCA manifestations. This NIBCA pathway-phenotype explains 75.0% of the variance in PHEMN (psychotic, hostility, excitation, mannerism and negative) symptoms. Using SIMCA, we constructed a NIBCA pathway-class that defines deficit schizophrenia as a qualitatively distinct nosological entity and which allows patients with deficit schizophrenia to be authenticated as belonging to the deficit schizophrenia class. In conclusion, our nomothetic approach to develop a nomological network combining neuro-immune and neurocognitive phenome markers to predict OSOS and cross-validate a diagnostic class generated replicable models reflecting the key phenome of the illness, which may mediate the effects of genome X environmentome interactions on the final outcome phenome features, namely symptomatology and phenomenology.

In schizophrenia, a single latent trait underlies psychosis, hostility, excitation, mannerism, negative (PHEMN) symptoms, formal thought disorders (FTD) and psychomotor retardation (PMR). Schizophrenia is accompanied by a breakdown of gut and blood-brain-barrier (BBB) pathways, increased tryptophan catabolite (TRYCAT) levels, bacterial translocation, and lowered natural IgM and paraoxonase (PON)1 activity. The aim of this study was to examine the factor structure of schizophrenia symptom domains and the biomarker correlates of these factors. We recruited 80 patients with schizophrenia and 40 healthy subjects and assessed the IgA/IgM responses to paracellular/transcellular (PARA/TRANS) ratios, IgA responses to TRYCATs, natural IgM to malondialdehyde and Gram-negative bacteria, and PON1 enzymatic activity.Direct Hierarchical Exploratory Factor Analysis showed a bifactorial oblique model with a) a general factor which loaded highly on all symptom domains, named overall severity of schizophrenia (“OSOS”); and b) a single-group factor (SGF) loading on negative symptoms and PMR. We found that 40% of the variance in the OSOS score was explained by IgA/IgM to PARA/TRANS ratio, male sex and education while 36.9% of the variance in SGF score was explained by IgA to PARA/TRANS, IgM to Gram-negative bacteria, female sex (positively associated) and IgM to MDA, and PON1 activity (negatively associated). Schizophrenia phenomenology comprises two biologically-validated dimensions, namely a general OSOS dimension and a single-group negative symptom dimension, which are associated with a breakdown of gut/BBB barriers, increased bacterial translocation and lowered protection against oxidation, inflammation and bacterial infections through lowered PON1 and natural IgM.

Schizophrenia comprises various symptom domains, including positive and negative symptoms. Machine learning showed that a) negative symptoms are significantly interrelated with PHEM (psychosis, hostility, excitation, and mannerism) symptoms, formal thought disorders (FTD) and psychomotor retardation (PMR); and b) stable phase schizophrenia comprises two distinct classes, namely Major Neuro-Cognitive Psychosis (MNP, largely overlapping with deficit schizophrenia) and Simple NP (SNP). In this study, we recruited 120 MNP patients and 54 healthy subjects and measured the above-mentioned symptom domains. In MNP, there were significant associations between negative and PHEM symptoms, FTD and PMR. A single latent trait, which is essentially unidimensional, underlies these key domains of schizophrenia and MNP and additionally shows excellent internal consistency reliability, convergent validity, and predictive relevance. Confirmatory Tedrad Analysis indicates that this latent vector fits a reflective model. The lack of discriminant validity shows that PHEM and negative symptoms greatly overlap and probably measure the same construct. Soft Independent Modeling of Class Analogy (SIMCA) shows that MNP (diagnosis based on negative symptoms) is better modeled using PHEM symptoms, FTD, and PMR than negative symptoms. In conclusion, in stable phase MNP, a restricted sample of the schizophrenia population, negative and PHEM symptoms, FTD and PMR belong to one underlying latent vector reflecting overall severity of schizophrenia (OSOS). The bi-dimensional concept of “positive” and “negative” symptoms cannot be validated and, therefore, future research in stable phase schizophrenia should consider that the latent phenomenon OSOS as well as its 8 reflective manifestations are the key factors of schizophrenia phenomenology.

Rationale: Major depressive disorder (MDD) is characterized by signaling aberrations in interleukin (IL)-6, IL-10, beta-endorphins as well as mu (MOR) and kappa (KOR) opioid receptors. Here we examined whether these biomarkers may aid in the classification of unknown subjects into the target class MDD.Methods: The aforementioned biomarkers were assayed in 60 first-episode, drug-naïve depressed patients and 30 controls. We analyzed the data using joint principal component analysis (PCA) performed on all subjects to check whether subjects cluster by classes; support vector machine (SVM) with 10-fold validation; and linear discriminant analysis (LDA) and SIMCA performed on calibration and validation sets and we computed the figures of merit and learnt from the data. Results: PCA shows that both groups were well separated using the first three PCs, while correlation loadings show that all 5 biomarkers have discriminatory value. SVM and LDA yielded an accuracy of 100% in validation samples. Using SIMCA there was a highly significant discrimination of both groups (model-to-model distance=87.5); all biomarkers showed a significant discrimination and modeling power, while 10% of the patients were identified as outsiders and no aliens could be identified.Discussion: We have delineated that MDD is a distinct class with respect to neuro-immune and opioid biomarkers and that future unknown subjects can be authenticated as having MDD using this SIMCA fingerprint. Precision psychiatry should employ SIMCA a) to authenticate patients as belonging to the claimed target class and identify other subjects as outsiders, members of another class or aliens; and b) to acquire knowledge through learning from the data by constructing a biomarker fingerprint of the target class.

Deficit schizophrenia is characterized by leaky tight and adherens junctions and bacterial translocation. Here we examine whether (deficit) schizophrenia is accompanied by leaky paracellular, transcellular and vascular barriers in the gut and blood brain barriers. We measured IgA responses to occludin, claudin-5, E-cadherin and β-catenin (paracellular pathway, PARA), talin, actin, vinculin and epithelial intermediate filament (transcellular pathway, TRANS) and plasmalemma vesicle-associated protein (PLVAP, vascular pathway) in 78 schizophrenia patients and 40 controls. IgA responses to claudin-5, E-cadherin and β-catenin, the sum of the four PARA proteins and the ratio PARA/TRANS were significantly higher in deficit schizophrenia than in non-deficit schizophrenia and controls. A large part of the variance in PHEMN (psychosis, hostility, excitation, mannerism and negative) symptoms, psychomotor retardation, formal thought disorders, verbal fluency, word list memory, word list recall and executive functions was explained by the PARA/TRANS ratio coupled with plasma IgA responses to Gram-negative bacteria, IgM to malondialdehyde, CCL-11 (eotaxin), IgA levels of the ratio of noxious to more protective tryptophan catabolites (NOX/PRO TRYCATs) and a plasma immune activation index. Moreover, IgA levels to Gram-negative bacteria were significantly associated with IgA to E-cadherin, β-catenin and PLVAP, while IgA levels to claudin-5 were significantly predicted by IgA to E-cadherin, NOX/PRO TRYCAT ratio, Gram-negative bacteria and CCL11. The phenomenology of the deficit syndrome is to a large extent explained by the cumulative effects of lowered natural IgM, breakdown of the paracellular and vascular pathways, increased bacterial translocation, peripheral immune-inflammatory responses and indices of BBB breakdown.

Understanding the evolutionary role of environmentally-induced phenotypic variation (i.e., environmental plasticity) is an important issue in developmental evolution. One of the major physiological responses to environmental changes is cellular stress, which is counteracted by a generic stress reaction that detoxifies the cell, refolds proteins, and repairs DNA damage. In this paper, we elaborate on a previous finding suggesting that the cell differentiation cascade of human decidual stromal cells, a cell type critical for embryo implantation and the maintenance of pregnancy, evolved from a cellular stress reaction. We hypothesize that the stress reaction in these cells was elicited ancestrally through the inflammation caused by embryo attachment and invasion. We describe a model, Stress-Induced Evolutionary Innovation (SIEI), whereby ancestral stress reactions and their corresponding pathways can be transformed into novel structural components of body plans, such as new cell types. After reviewing similarities and differences between SIEI and the “plasticity first hypothesis” (PFH) of evolution, we argue that SIEI is a distinct form of plasticity-based evolutionary change because it leads to the origin of novel structures rather than the adaptive transformation of a pre-existing character.

The factors that determine the relative rates of amino acid substitution during protein evolution are complex and they are known to vary among taxa. We estimated relative exchangeabilities for pairs of amino acids from clades spread across the tree of life and assessed the historical signal in the distances among these clade-specific models. We trained these models separately on collections of arbitrarily selected protein alignments and on ribosomal protein alignments. In both cases we found a clear separation between the models trained using multiple sequence alignments from bacterial clades and the models trained on archaeal and eukaryotic data. We assessed the predictive power of our novel clade-specific models of sequence evolution by asking whether fit to the models could be used to identify the source of multiple sequence alignments. Model fit was generally able to classify protein alignments correctly at the level of domain (bacterial versus archaeal), but the accuracy of classification at finer scales was much lower. The only exceptions to this were the relatively high classification accuracy for two archaeal lineages: Halobacteriaceae and Thermoprotei. Genomic GC content had a modest impact on relative exchangeabilities despite having a large impact on amino acid frequencies. Relative exchangeabilities involving aromatic residues exhibited the largest differences among models. There were a small number of exchangeabilities that exhibited large differences in comparisons among major clades and between generalized models and ribosomal protein models. Taken as a whole, these results reveal that a small number of relative exchangeabilities are responsible for much of the structure of the “model space” for protein sequence evolution. If we look beyond the information that these clade-specific models reveal about protein evolution the models themselves are likely to be useful tools for phylogenomic inference across the tree of life.

Background: It is known that Preeclampsia affects the lactogenesis. However, data on effects of this pathology on the human milk neurobiomarkers composition are not available. The aim of this study is to investigate the effects of this gestational pathology on Activin A levels, a neurobi-omarker known to play an important role in the development and protection of the central nerv-ous system. Methods: The women recruited were divided in two different study groups: preeclamptic or normotensive women. All the human milk samples were collected using the same procedure. Activin A was quantified using an ELISA test. To investigate the effect of Preeclampsia on the Activin A concentration in the 3 lactation phases, mixed linear model with unistructural covariance structure, mother as random effect, and fixed effects were performed. Results: Activin A was detected in all samples. There were no significant differences between Preeclamptic and Normotensive women. The only significant effect is related to the lactation phase: it is significant the difference between colostrum and mature milk (p<0.01). In conclusion these results allow us to affirm that breast milk beneficial properties are maintained even if preeclampsia occurs.

This study used established biomarkers of death due to ischemic stroke (IS) and performed network, enrichment, and annotation analysis. Protein-protein interaction (PPI) network analysis revealed that the backbone of the highly connective network of IS death consisted of IL6, ALB, TNF, SERPINE1, VWF, VCAM1, TGFB1, and SELE. Cluster analysis revealed immune and hemostasis subnetworks, which were strongly interconnected through the major switches ALB and VWF. Enrichment analysis revealed that the PPI immune subnetwork of death due to IS was highly associated with TLR2/4, TNF, JAK-STAT, NOD, IL10, IL13, IL4, and TGF-β1/SMAD pathways. The top biological and molecular functions and pathways enriched in the hemostasis network of death due IS were platelet degranulation and activation, the intrinsic pathway of fibrin clot formation, the urokinase-type plasminogen activator pathway, post-translational protein phosphorylation, integrin cell surface interactions, and the proteoglycan-integrin-extra cellular matrix complex (ECM). Regulation Explorer analysis of transcriptional factors shows: a) that NFKB1, RELA and SP1 were the major regulating actors of the PPI network; and b) hsa-mir-26-5p and hsa-16-5p were the major regulating microRNA actors. In conclusion, prevention of death due to IS should consider that current IS treatments may be improved by targeting VWF, VEGFA, proteoglycan-integrin-ECM complex, NFKB/RELA and SP1.

There is evidence that schizophrenia is characterized by activation of the immune-inflammatory response (IRS) and compensatory immune-regulatory (CIRS) systems and lowered neuroprotection. Studies performed on antipsychotic-naïve first episode psychosis (AF-FEP) and schizophrenia (FES) patients are important as they may disclose the pathogenesis of the disease. However, the interactome of FEP/FES is not well delineated. The aim of the current study was to delineate the characteristics of the protein-protein interaction (PPI) network of AN-FEP and its transition to FES and the biological functions, pathways, and molecular patterns, which are over-represented in FEP/FES. PPI network analysis shows that FEP and FEP/FES are strongly associated with a response to a bacterium, TNF, NFκB, RELA, SP1, JAK-STAT, death receptor and TLR4 signaling, and tyrosine phosphorylation of STAT proteins. Specific molecular complexes of the peripheral immune response are associated with microglial activation, neuroinflammation and gliogenesis. FEP/FES is accompanied by lowered protection against inflammation in part attributable to dysfunctional miRNA maturation, deficits in neurotrophin/Trk, RTK and Wnt/catenin signaling and adherens junction organization. Lowered neuroprotection due to reduced neurotrophin/Trk and Wnt/catenin signaling, and DISC1 expression and multiple interactions between lowered BDNF, CDH1, CTNNB, and DISC1 expression, increase the vulnerability to the neurotoxic effects of immune products including cytokines and complement factors. All pathways or molecular patterns enriched in the interactome of FEP/FES are directly or indirectly affected by LPS. In summary: FEP appears to be triggered by a biotic stimulus (e.g. Gram-negative bacteria) which may induce neuro-immune toxicity cascades especially when anti-inflammatory and neurotrophic protections are deficient.

Background: COVID-19 is associated with neuropsychiatric symptoms including increased depressive, anxiety and chronic fatigue-syndrome (CFS)-like physiosomatic (previously known as psychosomatic) symptoms.Aims: To delineate the associations between affective and CFS-like symptoms in COVID-19 and chest CT-scan anomalies (CCTAs), oxygen saturation (SpO₂), interleukin (IL)-6, IL-10, C-Reactive Protein (CRP), albumin, calcium, magnesium, soluble angiotensin converting enzyme (ACE2) and soluble advanced glycation products (sRAGEs).Method: The above biomarkers were assessed in 60 COVID-19 patients and 30 heathy controls who had measurements of the Hamilton Depression (HDRS) and Anxiety (HAM-A) and the Fibromyalgia and Chronic Fatigue (FF) Rating Scales. Results: Partial Least Squares-SEM analysis showed that reliable latent vectors could be extracted from a) key depressive and anxiety and physiosomatic symptoms (the physio-affective or PA-core), b) IL-6, IL-10, CRP, albumin, calcium, and sRAGEs (the immune response core); and c) different CCTAs (including ground glass opacities, consolidation, and crazy paving) and lowered SpO2% (lung lesions). PLS showed that 70.0% of the variance in the PA-core was explained by the regression on the immune response and lung lesions latent vectors. Moreover, one common “infection-immune-inflammatory (III) core” underpins pneumonia-associated CCTAs, lowered SpO2 and immune activation, and this III core explains 70% of the variance in the PA core, and a relevant part of the variance in melancholia, insomnia, and neurocognitive symptoms.Discussion: Acute SARS-CoV-2 infection is accompanied by lung lesions and lowered SpO2 which both may cause activated immune-inflammatory pathways, which mediate the effects of the former on the PA-core and other neuropsychiatric symptoms due to SARS-CoV-2 infection.

Current case definitions of schizophrenia (DSM-5, ICD), made through a consensus among experts, are not cross-validated and lack construct reliability validity. The aim of this paper is to explain how to use bottom-up pattern recognition approaches to construct a reliable and replicable nomothetic network reflecting the direct effects of risk resilience (RR) factors, and direct and mediated effects of both RR and adverse outcome pathways (AOPs) on the schizophrenia phenome. This study was conducted using data of 40 healthy controls and 80 patients with schizophrenia. Using partial least Squares (PLS) analysis, we found that 39.7% of the variance in the phenomenome (lowered self-reported quality of life) was explained by the unified effects of AOPs (IgA to tryptophan catabolites, LPS, and the paracellular pathway, cytokines, and oxidative stress biomarkers), the cognitome (memory and executive deficits), and symptomatome (negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation, formal thought disorders); 55.8% of the variance in the symptomatome was explained by a single trait extracted from AOPs and the cognitome; and 22.0% of the variance in the latter was explained by the RR (Q192R polymorphism and CMPAaase activity, natural IgM, and IgM levels to zonulin). There were significant total effects (direct + mediated) of RR and AOPs on the symptomatome and phenomenome. In the current study, we built a reliable nomothetic network that reflects the associations between RR, AOPs, and the phenome of schizophrenia and discovered new diagnostic subclasses of schizophrenia based on unified RR, AOPs, and phenome scores.

Transfusion dependent thalassemia (TDT) patients are treated with continued blood transfusions and show a higher prevalence of depression. TDT with consequent iron overload and inflammation is associated with increased severity of depressive symptoms in TDT children.Aim of the study: To construct a pathway-phenotype which combines iron overload and neuro-immune biomarkers with depressive symptom subdomains in TDT children.Methods: We measured iron status parameters (iron, ferritin, transferrin saturation percentage) and inflammatory (interleukin-1β and tumour necrosis factor-α) biomarkers in TDT (n=111) and healthy (n=53) children and analyzed the results using machine learning.Results: Cluster analysis separated TDT children with depression from those without depression and revealed two depressive subgroups one with low self-esteem and another with increased social-irritability scores. Exploratory factor analysis validated four depressive symptom dimensions as reliable constructs, namely key depressive, physiosomatic, lowered self-esteem and social-irritability dimensions. Partial Least Squares showed that 73.0% of the variance in a latent vector extracted from those four clinical subdomains, immune-inflammatory and iron overload biomarkers was explained by exposure variables including the number of blood transfusions and hospitalizations and use of deferoxamine. The exposure data, iron and immune biomarkers, and symptom subdomains are reflective manifestations of a single latent trait, which shows internal consistency reliability and predictive relevance.Conclusions: The nomological network combining exposure, pathways and behavioral phenome manifestations provides an index of overall severity and disease risk and, therefore, constitutes a new drug target, indicating that iron overload and immune activation should be targeted to treat depression due to TDT.

Background: There is now evidence that schizophrenia and deficit schizophrenia are neuro-immune conditions and that oxidative stress toxicity (OSTOX) may play a pathophysiological role. Aims of the study: To compare OSTOX biomarkers and antioxidant (ANTIOX) defenses in deficit versus non-deficit schizophrenia. Methods: We examined lipid hydroperoxides (LOOH), malondialdehyde (MDA), advanced oxidation protein products (AOPP), sulfhydryl (-SH) groups, paraoxonase 1 (PON1) activity and PON1 Q192R genotypes, total radical-trapping antioxidant parameter (TRAP) as well as immune biomarkers in patients with deficit (n=40) and non-deficit (n=40) schizophrenia and healthy controls (n=40). Results: Deficit schizophrenia is characterized by significantly increased levels of AOPP and lowered -SH, and PON1 activity, while no changes in the OSTOX/ANTIOX biomarkers were found in non-deficit schizophrenia. An increased OSTOX/ANTIOX ratio was significantly associated with deficit versus non-deficit schizophrenia (Odds ratio=3.15, p<0.001). Partial least squares analysis showed that 47.6% of the variance in a latent vector extracted from psychosis, excitation, hostility, mannerism, negative symptoms, psychomotor retardation, formal thought disorders, and neurocognitive test scores was explained by LOOH+AOPP, PON1 genotype + activity, CCL11, tumor necrosis factor (TNF)-α, IgA responses to neurotoxic tryptophan catabolites (TRYCATs), whereas -SH groups and IgM responses to MDA showed indirect effects mediated by OSTOX and neuro-immune biomarkers. Discussion: Our findings indicate that with increasing overall severity of schizophrenia, neuro-immune and neuro-oxidative (especially protein oxidation indicating chlorinative stress) toxicities become more prominent and together with lowered antioxidant defenses and impairments in innate immunity-associated resilience against neurotoxic processes shape a distinct nosological entity, namely deficit schizophrenia.

Objective: To examine whether 1) immune and nitro-oxidative stress (IO&NS) biomarkers are associated with premenstrual syndrome (PMS); and 2) changes in IO&NS biomarkers during the menstrual cycle (MC) are associated with PMS symptoms and plasma estradiol and progesterone. Methods: Forty-one women completed the Daily Record of Severity of Problems (DRSP) rating scale during 28 consecutive days and MC Associated Syndrome (MCAS) was diagnosed when the summed DRSP score during the MC is > 0.666 percentile. We assayed plasma levels of complement C3 and C4, highly sensitive C-reactive protein (hsCRP), haptoglobin (Hp), advanced oxidation protein products (AOPP), lipid hydroperoxides (LOOH), nitric oxide metabolites (NOx), total radical-trapping antioxidant parameter (TRAP), sulfhydryl (-SH) groups and the activity of paraoxonase (PON)1 at days 7 (D7), 14 (D14), 21 (D21) and 28 (D28) of the MC. Results: All biomarkers, except hsCRP, showed significant alterations during the MC. Arylesterase (AREase) was lowered at D28, while LOOH increased at D14 and C4 at D21 in women with MCAS. The total DRSP score was predicted by the combined effects of C4 (positively) and AREase and malondialdehyde (MDA) (both inversely associated). Progesterone lowered levels of LOOH, AOPP and C3 and estradiol lowered levels of Hp while both sex hormones increased 4-(chloromethyl)phenyl acetate (CMPA)ase and AREase activities and levels of -SH groups. Conclusion: PMS/MCAS is not accompanied by a peripheral inflammatory response. Lowered MDA and antioxidant defenses and increased C4 may play a role in MC-associated symptoms while sex hormones may have a protective effect against oxidative stress toxicity.

A subset of patients with schizophrenia experience physio-somatic symptoms reminiscent of chronic fatigue and fibromyalgia. In schizophrenia, these symptoms contribute to impaired quality of life, and are strongly related to neuro-cognitive deficits, and increased IgA responses to tryptophan catabolites. Negative and PHEM (psychosis, hostility, excitation, mannerism) symptoms, psychomotor retardation (PMR) and formal thought disorders, appear to be manifestations of a single trait reflecting overall severity of schizophrenia (OSOS). In this study, 120 patients with deficit schizophrenia (DEFSCZ) and 54 healthy subjects were assessed with the FibroFatigue (FF) rating scale, and the above-mentioned symptom domains as well as neuro-cognitive tests and biomarkers were measured. In DEFSCZ, there were robust associations between the FF score and all above-mentioned symptom domains, and impairments in semantic and episodic memory and executive functions. Furthermore, the FF score loaded highly on an OSOS latent vector (LV), which showed adequate convergent validity, internal consistency reliability and predictive relevance and fitted a reflective model. Soft Independent Modelling of Class Analogy (SIMCA) showed that the FF items discriminated DEFSCZ from controls with an overall accuracy of 100%. Interleukin IL-1β, IL-1 receptor antagonist (sIL-1RA), tumour necrosis factor (TNF)-α and CCL-11 (eotaxin) explained 66.8% of the variance in the FF score and 59.4% of the variance in OSOS. In conclusion, these data show that physio-somatic symptoms are a core component of the phenomenology of DEFSCZ and are largely mediated by neurotoxic effects of activated immune pathways, including aberrations in CCL-11, IL-1β and TNF-α signalling.

In 2001, the first author of this paper reported that schizophrenia is associated with an increased frequency of the haptoglobin (Hp)-2 gene. The precursor of Hp-2 is zonulin, a molecule that affects intercellular tight junction integrity. Recently, we reported increased plasma IgA/IgM responses to Gram-negative bacteria in deficit schizophrenia indicating leaky gut and gut dysbiosis. The current study was performed to examine the integrity of the paracellular (tight and adherens junctions) and transcellular (cytoskeletal proteins) pathways in deficit versus non-deficit schizophrenia. We measured IgM responses to zonulin, occludin, E-cadherin, talin, actin and vinculin in association with IgA responses to Gram-negative bacteria, CCL-11, IgA responses to tryptophan catabolites (TRYCATs), immune activation and IgM to malondialdehyde (MDA) and NO-cysteinyl in 78 schizophrenia patients and 40 controls. We found that the ratio of IgM to zonulin + occudin / talin + actin + viculin (PARA/TRANS) was significantly greater in deficit than in non-deficit schizophrenia and higher in schizophrenia than controls and was significantly associated with increased IgA responses to Gram-negative bacteria. IgM responses to zonulin were positively associated with schizophrenia (versus controls), while IgM to occludin was significantly associated with deficit schizophrenia (versus non-deficit schizophrenia and controls). A large part of the variance (90.8%) in negative and PHEM (psychosis, hostility, excitation and mannerism) symptoms was explained by PARA/TRANS ratio, IgA to Gram-negative bacteria, IgM to E-cadherin and malondialdehyde (MDA) and memory dysfunctions, while 53.3% of the variance in the latter was explained by PARA/TRANS ratio, IgA to Gram-negative bacteria, CCL-11, TRYCATs and immune activation. The results show an upregulated paracellular pathway with breakdown of the tight and ahherens junctions and increased bacterial translocation in deficit schizophrenia. These dysfunctions in the intestinal paracellular route together with lowered natural IgM, immune activation and production of CCL-11 and TRYCATs contribute to the phenomenology of deficit schizophrenia.

Although, staging models gained momentum to stage define affective disorders, no attempts were made to construct mathematical staging models using clinical and biomarker data in patients with major depression and bipolar disorder.The aims of this study were to use clinical and biomarker data to construct statistically-derived staging models, which are associated with early lifetime traumata (ELTs), affective phenomenology and biomarkers.In the current study, 172 subjects participated, 105 with affective disorders (both bipolar and unipolar) and 67 controls. Staging scores were computed by extracting latent vectors (LVs) from clinical data including ELTs, recurring flare ups and suicidal behaviors, outcome data such as disabilities and health-related quality of life (HR-QoL), and paraoxonase (PON)1 actvities and nitro-oxidative stress biomarkers.Recurrence of episodes and suicidal behaviors could reliably be combined into a LV with adequate composite reliability (the “recurrence LV”), which was associated with female sex, the combined effects of multiple ELTs, disabilities, HR-QoL and impairments in cognitive tests. All those factors could be combined into a reliable “ELT-staging LV” which was significantly associated with nitro-oxidative stress biomarkers. A reliable LV could be extracted from serum PON1 activities, recurrent flare ups, disabilities and HR-QoL.Our ELT-staging index scores the severity of a relevant affective dimension, shared by both major depression and bipolar disorder, namely the trajectory from ELTs, a relapsing course and suicidal behaviors to progressive disabilities. Patients were classified into three stages, namely an early stage; a relapse-regression stage; and a suicidal-regression stage. Lowered lipid-associated antioxidant defenses may be a drug target to prevent the transition from the early to the later regression stages.

Acknowledging the diverse perceptions about science-religion relationships among learners who come from various religious environments may increase learners’ willingness to learn about evolution. This study is based on a zoology course designed for in-service teachers, which aimed to provide basic scientific knowledge about evolution using the Religious Cultural Competence in Evolution Education framework. The study explores whether learners who were resistant to evolution modify their attitudes and willingness to learn about it, and whether they develop respect toward learners who hold contradicting views. Using qualitative methods, the findings indicate that using the Religious Cultural Competence in Evolution Education framework increased some formerly "resistant" learners’ willingness to learn about evolution and include it in their own teaching, albeit in varying degrees and with various reservations. The learners appreciated the freedom to express their challenges concerning evolution learning or teaching and became more willing to respect opposing perspectives, even though not all the religious learners accepted evolution as an explanation for the development of organisms. This study has international implications for bridging the gap between science and religion, thus reducing resistance to learning and teaching about evolution.

Human language is a prime example of a complex system characterized by multiple scales of description. Understanding its origins and distinctiveness has sparked investigations with very different approaches, ranging from the Universal Grammar to statistical analyses of word usage, all of which highlight, from different angles, the potential existence of universal patterns shared by all languages. Yet, a cohesive perspective remains elusive. In this paper we address this challenge. First, we provide a basic structure of universality, and define recursion as a special case thereof. We cast generative grammars of formal languages, the Universal Grammar and the Greenberg Universals in our basic structure of universality, and compare their mathematical properties. We then define universality for writing systems and show that only those using the rebus principle are universal. Finally, we examine Zipf's law for the statistics of word usage, explain its role as a complexity attractor, and explore its relation to universal writing systems as well as its similarities with universal Turing machines. Overall, we find that there are two main kinds of universality, termed {\it mechanistic} and {\it emergent}, and unveil some connections between them.

Intermediate-luminosity-optical-transients (ILOTs) are stellar outbursts with luminosity between those of classical novae and supernovae. They are divided into a number of sub-groups depending on the erupting progenitor and the properties of the eruption. Many of the ILOTs sit on the slanted Optical Transient Stripe (OTS) in the Energy-Time Diagram (ETD) that shows their total energy vs. duration of their eruption. We describe the different kinds of ILOTs that populate the OTS and other parts of the ETD. We also stand on similarities between Planetary Nebulae (PN) to ILOTs, and suggest that some PNe were formed in an ILOT event. The high energy part of the OTS is reserved to the supernova impostors -- giant eruption of very massive stars. We show results of 3D hydrodynamical simulations of supernova impostors that expose the mechanism behind these giant eruptions, and present new models for recent ILOTs. We stand on the connection between different kinds of ILOTs, and suggest that they are powered by a similar source of energy -- gravitational energy released by mass transfer.

Based on a new model of a possible origin of life, we establish an efficient and stable system undergoing structural reproduction, self-optimization and molecular evolution. This system is being formed under realistic conditions by the interaction of two cyclic processes, one of which offering vesicles as the structural environment, the other supplying peptides from a variety of amino acids as versatile building blocks. We demonstrate that structures growing in a combination of both cycles have the potential to support their own existence, to undergo chemical and structural evolution and to develop unpredicted functional properties. The key mechanism is the mutual stabilization of the peptides by the vesicles and of the vesicles by the peptides together with a constant production and selection of both. The development of the proposed system over time not only would represent one of the principles of life, but could also be a model for the formation of self-evolving structures ultimately leading to the first living cell. The experiment yields clear evidence on a vesicle-induced accumulation of membrane-interacting peptide which could be identified by liquid chromatography combined with high-resolution mass spectroscopy. We found that the selected peptide has an immediate effect on the vesicles, leading to i) reduced vesicle size, ii) increased vesicle membrane permeability, and iii) improved thermal vesicle stability.

Neuron degeneration is the most common old age complications worldwide. Alzheimer's disease (AD) is one of the most common neurodegenerative condition with limited drug options and significant adverse effects. Hence, there is a growing interest in exploring natural products for their potential pharmacological activities against AD. This study investigates the efficacy of Verbesina encelioides flower extract (VFE) in alleviating neurobehavioral damage induced by Scopolamine in rat mimicking AD model. GC-MS analysis showed that V. encelioides flower extract is rich in carotenoids like spirilloxanthin. Various behavioural models were used to assess the rats' learning and memory capabilities. Additionally, biochemical tests were conducted on the AD rat models to evaluate oxidative stress in the brain, including superoxide dismutase (SOD), nitric oxide (NO), reduced glutathione (GSH), and anti-acetylcholinesterase (AChE) enzyme assays. Findings from this study suggest that the VFE significantly improved the rats' cognitive aptitude and alleviated them from oxidative stress by reducing free radical generation. Based on the results obtained from GC-MS analysis, in silico interaction analysis of gingkolide A and spirilloxanthin with acetylcholinesterase was carried out. In summary, this study suggests that V. enceloides flower extract improves learning abilities and mitigates cognitive deficits caused by scopolamine. Thus V. enceloides could be potentially seen as natural therapeutic intervention against neurodegenerative disorders likes Alzheimer’s disease and dementia.

In this study, we designed a functional neuro-cardiac model to help us examine the role of neuronal regulation and confirm the importance of neural innervation techniques for cardiac tissue regeneration. A three-dimensional (3D) bioprinted neuro-cardiac scaffold composed of a mixture of gelatin-alginate and alginate-genipin-fibrin hydrogels was developed with a 2:1 ratio of AC16 cardiomyocytes (CMs) and retinoic acid differentiated SH-SY5Y neuronal cells (NCs) respectively. A unique semi-3D bioprinting approach was adopted where the CMs were mixed in the cardiac bioink and printed using an anisotropic accordion design to mimic the physiological tissue architecture in vivo. The voids in this 3D structure were methodically filled in using a NCs-gel mixture and cross-linked. Confocal fluorescent imaging using Microtubule-associated protein 2 (MAP-2) antibodies for labeling NCs, and the MyoD1 antibody for CMs revealed functional coupling between the two cell types in the final cross-linked structure. This data confirmed the development of a physiologically functional neuro-cardiac model that can be used to study neuro-cardiac modulation under physiological and pathological conditions.

The tryptophan catabolite (TRYCAT) pathway is implicated in the pathophysiology of schizophrenia (SCZ) since the rate-limiting enzyme indoleamine-dioxygenase (IDO) may be induced by inflammatory and oxidative stress mediators. This systematic review searched PubMed, Web of Science, and Google Scholar for papers published from inception until August 2021 and meta-analyzed the association between SCZ and TRYCATs in the central nervous system (CNS) and peripheral blood. We included 61 studies comprising 2813 patients and 2948 healthy controls. In the CNS we found a significant (p<0.001) increase in the kynurenine/tryptophan (KYN/TRP) (standardized mean difference, SMD=0.769, 95% confidence interval, CI: 0.456; 1.082) and kynurenic acid (KA)/KYN+TRP (SMD=0.697, CI:0.478-0.917) ratios, KA (SMD=0.646, CI: 0.422; 0.909) and KYN (SMD=1.238; CI: 0.590; 1.886), while the 3OH-kynurenine (3HK) + KYN-3-monooxygenase (KMO)/KYN ratio was significantly reduced (SMD=-1.089, CI: -1.682; -0.496). There were significant differences between KYN/TRP, (KYN+KA)/TRP, (3HK+KMO)/KYN, KA, and KYN levels among the CNS and peripheral blood, and among serum and plasma KYN. The only useful peripheral marker of CNS TRYCATs findings was the increased KYN/TRP ratio in serum (SMD=0.211, CI: 0.056; 0.366, p=0.007), but not in plasma. There was no significant increase in a neurotoxic composite score based on KYN, 3HK, and picolinic, xanthurenic, and quinolinic acid. SCZ is accompanied by increased IDO activity in the CNS and serum, and reduced KMO activity and a shift towards KA production in the CNS. This CNS TRYCATs profile indicates neuroprotective, negative immunoregulatory and anti-inflammatory effects. Peripheral blood levels of TRYCATs are dissociated from CNS findings except for a modest increase in serum IDO activity.

Background. Rheumatoid arthritis (RA) is a chronic inflammatory and autoimmune disorder which affects the joints in the wrists, fingers, and knees. RA is often associated with depressive and anxiety symptoms as well as chronic fatigue syndrome (CFS)-like symptoms.Aim. To examine the association between depressive symptoms (measured with the Beck Depression Inventory, BDI), anxiety (Hamilton Anxiety Rating Scale, HAMA), and CFS-like (Fibro-fatigue Scale) symptoms and immune-inflammatory, autoimmune, and endogenous opioid system (EOS) markers, and lactosylceramide in RA. Methods. The serum biomarkers were assayed in fifty-nine RA and fifty-nine patients without increased psychopathology (PP) and fifty healthy controls.Results. There were highly significant correlations between the BDI, FF, and HAMA scores and severity of RA, as assessed with the DAS28-4, clinical and disease activity indices, the number of tenders and swollen joints, and patient and evaluator global assessment scores. A common latent vector (reflective model) could be extracted from the PP and RA-severity scales, which showed excellent psychometric properties. Partial least squares analysis showed that 69.7% of the variance in this common core underpinning PP and RA symptoms could be explained by the regression on immune-inflammatory pathways, rheumatoid factor, anti-citrullinated protein antibodies, CD17, and mu-opioid receptor levels. Conclusions. Depression, anxiety, and CFS-like symptoms due to RA are reflective manifestations of the phenome of RA and are mediated via the effects of the same immune-inflammatory, autoimmune, and EOS pathways and lactosylceramide that underpin the pathophysiology of RA. These PP symptoms are clinical manifestations of the pathophysiology of RA.

Background: Methamphetamine (MA) is one of the most common drugs of abuse in Thailand. MA use may cause neurotoxicity, immune-inflammatory and oxidative stress responses and, consequently, MA-induced psychosis (MIP).Aims: This study aims to examine the effects of MA use and dependence and MA withdrawal symptoms on the telomere to single copy gene (T/S) ratio and whether shortening of the latter is associated with MIP.Methods: This study included 185 MA-abuse, 118 MA-dependent, and 67 MIP patients, diagnosed using DSM-IV-TR criteria. The Semi-structured Assessment for Drug Dependence and Alcoholism (SSADDA) questionnaire was employed to collect clinical and MA-related data. MIP was confirmed using the Methamphetamine Experience Questionnaire (MEQ). The leukocyte telomere length was measured in all participants using real-time polymerase chain reaction measuring the Telomere/Single gene ratio (T/S ratio). Results: There were no significant associations between the T/S ratio and severity of MA-use, MIP, MA withdrawal symptoms including depression and psychomotor retardation. MIP was significantly predicted by alcohol dependence, antisocial personality disorder, and MA-use severity. There were significant and positive associations between the T/S ratio and previous traumatic events and life-threatening accidents. The T/S ratio was not affected by comorbid alcohol and nicotine dependence. Alcohol and nicotine dependence, antisocial personality, and severity of MA use increased risk of MA withdrawal symptoms. Conclusion: MIP and MA-use severity do not affect leukocyte telomere length, but telomere length may be affected by previous traumatic events and life-threatening accidents.

Recently we showed that schizophrenia and, especially, deficit schizophrenia is accompanied by neurocognitive impairments as measured with different cognitive batteries. The aim of this study was to examine whether a single trait underpins aberrations in 9 key Cambridge Neuropsychological Test Automated Battery (CANTAB) probes, verbal fluency (VFT), world list memory (WLM), true recall, and the Mini Mental State Examination (MMSE). We recruited 80 patients with schizophrenia and 40 healthy controls. All patients were assessed using CANTAB tests, namely paired-association learning (PAL), rapid visual information (RVP), spatial working memory (SWM), one touch stocking (OTS), intra/extradimensional set shifting (IED), and emotional recognition test (ERT). We found that a single latent trait, which is essentially unidimensional, underlies the CANTAB tests, VFT, WLM, True Recall and MMSE. The latent trait shows excellent psychometric properties and fits a reflective model and, therefore, reflects a generalized cognitive decline (GCoDe), which is the cause of aberrations in semantic and episodic memory, recall, executive functions, strategy use, rule acquisition, visual sustained attention, attention set-shifting and emotional recognition. 40.5% of the variance in GCode was explained by CCL11, IgA to tryptophan catabolites, and increased oxidative toxicity. GCoDe explains 44.8% of the variance in a single latent trait extracted from psychosis, hostility, excitation, mannerism, negative symptoms, formal thought disorders, and psychomotor retardation and 40.9% in quality of life scores. GCoDe is significantly greater in deficit than in nondeficit schizophrenia. In conclusion, GCoDe mediates the effects of neuro-immune and neuro-oxidative toxicity on the phenome of (deficit) schizophrenia.

Background. There is strong comorbidity between atherosclerosis (ATS) and depression which is attributed to increased atherogenicity, insulin resistance (IR), and immune and oxidative stress.Aim of the study. To examine the role of the above pathways and mu opioid receptor (MOR), β-endorphin, zinc, copper, vitamin D3, calcium, and magnesium in depression due to ATS / unstable angina (UA).Methods. Biomarkers were assayed in 58 controls and 120 ATS patients divided into those with moderate and severe depression according to the Beck Depression Inventory (BDI)-II score > 19 and > 29, respectively. Results. Neural network and logistic regression models showed that severe depression due to ATS/UA was best predicted by IL-6, UA, MOR, zinc, β-endorphin, calcium and magnesium and that moderate depression was associated with IL-6, zinc, MOR, β-endorphin, UA, atherogenicity, IR, and calcium. These neural networks yielded a significant discrimination of severe and moderate depression with an area under the ROC curve of 0.831 and 0.931, respectively. Using Partial Least Squares analysis, 66.2% of the variance in a latent vector extracted from the ATS/UA clinical features, BDI-II scores, atherogenicity, and IR could be explained by the regression on IL-6, IL-10, zinc, copper, calcium, MOR, and age. The BDI-II scores increased from controls to ATS to UA class III to UA class IV.Conclusions. Depression due to ATS/UA is a reflective manifestation of increased atherogenicity and IR, which are modulated by immune activation, aberrations in the endogenous opioid system, antioxidants, trace elements, and macrominerals.

Background: Hypertension, atherogenicity and insulin resistance are major risk factors of cardiovascular disorder (CVD), which shows a strong comorbidity with major depression (MDD) and bipolar disorder (BD). Activated oxidative and nitrosative stress (O&NS), inflammatory pathways, and increased atherogenicity are shared pathways underpinning CVD and mood disorders. Methods: The current study examined the effects of lipid hydroperoxides (LOOH), superoxide dismutase (SOD), nitric oxide metabolites (NOx), advanced oxidation protein products (AOPP), and malondialdehyde (MDA) on systolic (SBP) and diastolic (DBP) blood pressure in 96 mood disordered patients and 60 healthy controls. Results: A large part of the variance in SBP (31.6%) was explained by the regression on a z unit-weighted composite score (based on LOOH, AOPP, SOD, NOx) reflecting nitro-oxidative stress toxicity (NOSTOX), coupled with highly sensitive C-reactive protein, body weight and use of antihypertensives. Increased DBP was best predicted (23.8%) by body mass index and NOSTOX. The most important O&NS biomarkers predicting an increased SBP were in descending order of significance: LOOH, AOPP and SOD. Higher levels of the atherogenic index of plasma, HOMA2 insulin resistance index and basal thyroid-stimulating hormone also contributed to increased SBP independently from NOSTOX. Although there were no significant changes in SBP/DBP in mood disorders, the associations between NOSTOX and blood pressure were significant in patients with mood disorders but not in healthy controls. Conclusions: Activated O&NS pathways including increased lipid peroxidation and protein oxidation, which indicates hypochlorous stress, are the most important predictors of an increased BP, especially in patients with mood disorders.

Background: Primary deficit schizophrenia (DS) is characterized by enduring negative symptoms and represents a qualitatively different disease entity with respect to non-deficit schizophrenia (NDS). No studies investigated the association between the enzyme paraoxonase 1 (PON1) and DS and its phenomenology. Methods: In this case-control study, Thai women and men, aged 18-65 years, were divided in DS (n=40) and NDS (n=40) and were compared to controls (n=40). PON1 activities against 4-(chloromethyl)phenyl acetate (CMPA) and phenylacetate were determined. Moreover, subjects were genotyped for their PON1 Q192R polymorphism and IgA levels responses directed to Gram-negative bacteria were measured. Results: DS is significantly associated with the QQ genotype and the Q allele as compared with NDS and controls. PON1 activities are significantly and inversely associated with negative symptoms, formal thought disorders, psychomotor retardation, excitation and DS. The presence of the Q allele is associated with increased IgA responses to Pseudomonas aeruginosa, Morganella morganii, and Pseudomonas putida as compared with RR carriers. Conclusions: The PON1 Q allele and lower PON1 activities especially against CMPA are associated with DS, indicating lowered quorum quenching abilities as well as lowered defenses against lipoperoxidation and immune activation. It is suggested that lowered PON1 activity in DS constitutes an impairment in the innate immune system which together with lowered natural IgM may cause lower immune regulation thereby predisposing towards greater neurotoxic effects of immune-inflammatory, oxidative and nitrosative pathways and Gram-negative microbiota.

Objective: Major depression (MDD) and a lifetime history of MDD are characterized by increased nitrosylation, while bipolar disorder type 1 (BP1), but not BP2, is accompanied by highly increased levels of oxidative stress and nitric oxide (NO) production. Nevertheless, it is unknown whether nitrosylation is involved in BP and whether there are differences in nitrosylation between BP1 and BP2.Methods: Serum IgM antibodies directed against nitroso (NO)-adducts were examined in MDD, BP1, BP2 and healthy controls, namely IgM responses to NO-cysteine, NO-tryptophan (NOW), NO-arginine and NO-albumin (SBA) in association with IgA/IgM responses to Gram-negative bacteria, IgG responses to oxidized low-density lipoprotein (oxLDL) and serum peroxides.Results: Serum IgM levels against NO adducts were significantly higher in BP1 and MDD as compared with healthy controls, whereas BP2 patients occupied an intermediate position. IgM responses to NO-albumin were significantly higher in BP1 and MDD than in BP2 patients. There were highly significant associations between the IgM responses to NO-adducts and IgG responses to oxLDL and IgA/IgM responses to Gram-negative bacteria.Conclusions: BP1 and MDD are characterized by an upregulation of the nitrosylome (the proteome of nitrosylated proteins), and increased IgM responses to nitrosylated conjugates. Increased nitrosylation may be driven by increased bacterial translocation and is associated with lipid peroxidation processes. Innate like (B1 and marginal zone) B cells and increased nitrosylation may play a key role in the major affective disorders through activation of immune-inflammatory and oxidative pathways, cardiovascular comorbidity and impairments in antioxidant defenses, neuro-glial interactions, synaptic plasticity, neuroprotection, neurogenesis, etc.

In 2011, it was reviewed that there is a strong co-occurrence between major depression and chronic fatigue syndrome (CFS), with fatigue and physio-somatic symptoms being key symptoms of depression, and depressive symptoms appearing during the course of CFS. Moreover, the comorbidity between both conditions may in part be explained by activated immune-inflammatory pathways, including increased translocation of Gram-negative bacteria and increased levels of pro-inflammatory cytokines, such as interleukin (IL)-1. Nevertheless, the possible involvement of activated microglia in this comorbidity has remained unclear. This paper aims to review microglial disturbances in major depression, CFS and their comorbidity. A comprehensive literature search was conducted using the PubMed / MEDLINE database to identify studies that are relevant to this current review. Depressed patients present neuroinflammatory alterations, probably related to microglial activation, while animal models show that a microglial response to immune challenges including lipopolysaccharides is accompanied by depressive-like behaviors. Recent evidence from preclinical studies indicate that activated microglia have a key role in the onset of fatigue. In chronic inflammatory conditions, such as infections and senescence, microglia orchestrate an inflammatory microenvironment thereby causing fatigue. In conclusion, based on our review we may posit that shared immune-inflammatory pathways and activated microglia underpin comorbid depression and CFS and that activated microglia are the main orchestrators of this comorbidity. As such, microglial activation and neuro-inflammation may be promising targets to treat the overlapping manifestations of both depression and CFS.

Others have proposed that living systems are characterized by the possession of a kind of information unique to them. This information, variously called semantic, symbolic, or coding information conveys meaning from senders to recipients, most commonly among genome and other cellular components, different cells, organisms, etc., enabling all biological functions. Unlike other kinds of information, it is only indirectly quantifiable and does not increase by copying. Here, the term system information is used to encompass the entire package of coding information enabling all organisms of a species to complete their life cycles through possession of its copy (Crkvenjakov and Heng 2021). System information grows in a nonreductive evolution only during speciation proper by the acquisition of novel functions by daughter species. Contemporary science agrees that species are units of evolution but has failed to recognize and parse the importance of phases of speciation and stasis for evolution. Confinement of system information change to speciation only explains for the first time why there are species and why their number increases nearly exponentially throughout evolution. More importantly, here we define that evolution as a process operating on a planetary scale, while chance based, is non-random mathematically since it obeys the Laws of Information which dictate the behavior of System information in organisms. Growth and persistence of system information on the non-degenerative portion of Tree of Life follow the law of conservation, which states that its growth is as parsimonious (minimal) as possible and the persistence of parental system information the maximal possible in each unit speciation step. This formulation is a restatement of Loewnstain's (1999) principle of information economy and our lock-in law (Crkvenjakov and Drmanac 2007). The principle holds that since, on chance assumption, the system information change cost is directly proportional to time, more costly pathways of achieving the same new functional goal will be, almost without exception, competed out by the less costly ones. As a corollary of the conservation law, the speciation law states that speciation follows the most economical way of growth of system information while conserving the existing one, which is horizontal information transfer by molecular sex (uptake of exogenous nucleic acid into the progeny genome) by exchange among two parents from maximally possible divergent lineages. The speciation law dictates that molecular sex mode be used since it is the most parsimonious one. The molecular sex cost in information bits is zero to the recipient, which is not the case with the generally accepted mode of vertical accumulation of information bits in a population gene pool within a lineage.

Multicellularity evolved repeatedly in the history of life, but how it unfolded varies greatly between different lineages. Dictyostelid social amoebas offer a good system to study the evolution of multicellular complexity, with a well-resolved phylogeny and molecular genetic tools being available. We compare the life cycles of the Dictyostelids with closely related amoebozoans to show that complex life cycles were already present in the unicellular common ancestor of Dictyostelids. We propose frost resistance as an early driver of multicellular evolution in Dictyostelids and show that the cell signalling pathways for differentiating spore and stalk cells evolved from that for encystation. The stalk cell differentiation program was further modified, possibly through gene duplication, to evolve a new cell type, cup cells, in Group 4 Dictyostelids. Studies in various multicellular organisms including Dictyostelids, volvocine algae, and metazoans suggest as a common principle in the evolution of multicellular complexity that unicellular regulatory programs for adapting to environmental change serve as “proto-cell types” for subsequent evolution of multicellular organisms. Later, new cell types could further evolve by duplicating and diversifying the “proto-cell type” gene regulatory networks.

The success of many viruses depends upon cooperative interactions between viral genomes. For example, viruses that coinfect the same cell can share essential gene products, such as replicase, the enzyme that replicates the viral genome. However, when cooperation occurs, there is the potential for ‘cheats’ to exploit that cooperation. We suggest that: (1) the biology of viruses makes viral cooperation particularly susceptible to cheating; (2) cheats are common across a wide range of viruses, including viral entities that are already well studied, such as defective interfering genomes, and satellite viruses. Consequently, evolutionary theory developed to explain cheating offers a conceptual framework for understanding and manipulating viral dynamics. At the same time, viruses offer unique opportunities to study how cheats evolve, because cheating is relatively common in viruses, compared with taxa where cooperation is more usually studied, such as animals.

We report the analysis of activation by corticosteroids and progesterone of full-length mineralocorticoid receptor (MR) from elephant shark, a cartilaginous fish belonging to the oldest group of jawed vertebrates. Based on their measured activities, aldosterone, cortisol, 11-deoxycorticosterone, corticosterone, 11-deoxcortisol, progesterone and 19-norprogesterone are potential physiological mineralocorticoids. However, aldosterone, the physiological mineralocorticoid in humans and other terrestrial vertebrates, is not found in cartilaginous or ray-finned fishes. Because progesterone is a precursor for corticosteroids that activate elephant shark MR, we propose that progesterone was an ancestral ligand for elephant shark MR. Although progesterone activates ray-finned fish MRs, progesterone does not activate human, amphibian or alligator MRs, suggesting that during the transition to terrestrial vertebrates, progesterone lost the ability to activate the MR. Comparison of RNA-sequence analysis of elephant shark MR with that of human MR suggests that MR expression in the human brain, heart, ovary, testis and other non-epithelial tissues evolved in cartilaginous fishes. Together, these data suggest that progesterone-activated MR may have unappreciated functions in elephant shark ovary and testis.

This research presents a solution to the problem of planning the optimum area for economic crops by developed mathematical models and developed an algorithm to solve the problem of planning the optimum area by considered economic value for the maximize profit of farmers. The data were collected from farmers in 8 provinces in the northeastern region of Thailand. The 3 economic crops studied were rice, cassava and sugarcane. The solving problem methods were 1) Created mathematical models and solved the problems with Lingo V.11. 2) Improved Differential Evolution algorithms (I-DE) to solve the problems, which had 3 local search methods included (Swap, Cyclic Move and K-variable moves). The results of this study showed that in the small and medium problems instances, Lingo V.11 and DE provided equal profit outcome but DE was faster but in the large size of test instances DE generated better solution than that of Lingo v.11 when Lingo simulation time is set to 250 hours and DE simulation time has set to maximum 21.82 minutes. 2) Comparing DE and I-DE , I-DE outperforms DE in finding the better solution for all size of test instances (small, medium and large).

Neurological involvement following COronaVIrus Disease 19 (COVID-19) is thought to have a neuroinflammatory etiology. Co-ultraPEALut (an antiinflammatory molecule) and luteolin (an antioxidant) yielded promising results as neuroinflammation antagonists. This study aimed at describing cognitive impairment in post-COVID patient treated with co-ultraPEALut. Montreal Cognitive Assessment (MoCA), Prospective-Retrospective Memory Questionnaire (PRMQ), Fatigue Severity Scale (FSS) and a subjective evaluation were administered at baseline and after 10 months. Co-ultraPEALut-treated patients were retrospectively compared with controls. 26 co-ultraPEALut-treated patients showed significant improvement in PRMQ (T0: 51.94±10.55, T1: 39.67±13.02, p

Neurodegenerative diseases like Alzheimer's diseases are irreversible, progressive, and refractory in nature and managed very poorly. AD is manifested with the aggregation of unfolded proteins, synaptic pathology and dementia and poses challenges to the health care system globally. Only very few treatments with minimal effect are available to the patients and their caregivers. Despite numerous clinical trials which were launched for AD, unfortunately, most of them failed in satisfying the pharmacological criteria. At cellular levels, many signaling pathways have been proposed for the sterile / refractory behavior of degenerating neurons. Among those, Mitogen activated protein kinases (MAPKs) are the critical cellular networks which are involved in the development of Alzheimer’s disease. Several studies have demonstrated a favorable impact of MAPK inhibition on inflammatory programming, synaptic plasticity, and memory problems in mouse models of AD. In view of this, various clinical trials were launched with several MAPK inhibitors (with good safety profile and less side-effects) have yielded positive results in AD patients suggesting that MAPK targeting may be effective for reducing the pathogenesis of AD, but due to selectivity, dosing and patient stratification, this aspect still need development. In view of selectivity and off-target effects, only a few MAPK inhibitors have been employed in clinical trials against AD indicating a scope of development in this area. Therefore, this study focuses on MAPK based interventions as an upcoming and innovative approach for alleviating AD with special emphasis on clinical studies.

Type 2 diabetes mellitus (T2DM) is frequently accompanied by affective disorders with a prevalence of comorbid depression of around 25%. Nevertheless, the biomarkers of affective symptoms including depression and anxiety due to T2DM are not well established.Aims: This study was conducted to delineate the serum biomarkers predicting affective symptoms due to T2DM above and beyond the effects of insulin resistance and atherogenicity. Methods: The present study delineated the effects of serum levels of copper, zinc, β-arrestin-1, FBXW7, lactosylceramide (LacCer), serotonin, albumin, calcium, magnesium, IR and atherogenicity on severity of depression and anxiety in 58 men with T2DM and 30 healthy male controls. Severity of affective symptoms was assessed using the Hamilton Depression and Anxiety rating scales.Results: We found that 61.7% of the variance in affective symptoms was explained by the multivariate regression on copper, β-arrestin-1, calcium, and insulin resistance coupled with atherogenicity, while 44.4% of the variance in the latter was explained by copper, β-arrestin-1, LacCer (all positively) and calcium and FBXW7 (both negatively). Copper and LacCer (positive) and calcium and BXW7 (inverse) had significant specific indirect effects on affective symptoms which were mediated by insulin resistance and atherogenicity. Copper, β-arrestin-1, and calcium were associated with affective symptoms above and beyond the effects of insulin resistance and atherogenicity.Discussion: T2DM and affective symptoms share common pathways namely increased atherogenicity, insulin resistance, copper, and β-arrestin-1, and lowered calcium, whereas copper, β-arrestin-1, calcium, LacCer, and FBXW7 may modulate depression and anxiety symptoms by affecting T2DM.

Background: A meaningful part of schizophrenia patients suffer from physiosomatic symptoms (formerly named psychosomatic) which are reminiscent of chronic fatigue syndrome and fibromyalgia (FF) and are associated with signs of immune activation and increased levels of tryptophan catabolites (TRYCATs). Aims: To examine whether FF symptoms in schizophrenia are associated with breakdown of the paracellular pathway, zonulin, lowered natural IgM responses to oxidative specific epitopes (OSEs); and whether FF symptoms belong to the behavioral-cognitive-physical-psychosocial-(BCPS)-worsening index consisting of indices of a general cognitive decline (G-CoDe), symptomatome of schizophrenia, and quality of life (QoL)-phenomenome. Methods: FF symptoms were assessed using the Fibromyalgia and Chronic Fatigue Rating scale in 80 schizophrenia patients and 40 healthy controls and serum cytokines/chemokines, IgA levels to TRYCATs, IgM to OSEs, zonulin and transcellular/paracellular (TRANS/PARA) molecules were assayed using ELISA methods. Results: A large part (42.3%) of the variance in the total FF score was explained by the regression on the PARA/TRANS ratio, pro-inflammatory cytokines, IgM to zonulin, IgA to TRYCATs (all positively) and IgM to OSEs (inversely). There were highly significant correlations between the total FF score and G-CoDe, symtopmatome, QoL phenomenome and BCPS-worsening score. FF symptoms belong to a common core shared by G-CoDe, symtopmatome, and QoL phenomenome. Discussion: The physio-somatic symptoms of schizophrenia are driven by various pathways including increased zonulin, breakdown of the paracellular tight-junctions pathway, immune activation with induction of the TRYCAT pathway, and consequent neurotoxicity. It is concluded that FF symptoms are part of the phenome of schizophrenia and BCPS-worsening as well.

Current diagnoses of mood disorders are not cross validated. The aim of the current paper is to explain how machine learning techniques can be used to a) construct a model which ensembles risk/resilience (R/R), adverse outcome pathways (AOPs), staging, and the phenome of mood disorders, and b) disclose new classes based on these feature sets. This study was conducted using data of 67 healthy controls and 105 mood disordered patients. The R/R ratio, assessed as a combination of the paraoxonase 1 (PON1) gene, PON1 enzymatic activity, and early life time trauma (ELT), predicted the high-density lipoprotein cholesterol – paraoxonase 1 complex (HDL-PON1), reactive oxygen and nitrogen species (RONS), nitro-oxidative stress toxicity (NOSTOX), staging (number of depression and hypomanic episodes and suicidal attempts), and phenome (the Hamilton Depression and Anxiety scores and the Clinical Global Impression; current suicidal ideation; quality of life and disability measurements) scores. Partial Least Squares pathway analysis showed that 44.2% of the variance in the phenome was explained by ELT, RONS/NOSTOX, and staging scores. Cluster analysis conducted on all those feature sets discovered two distinct patient clusters, namely 69.5% of the patients were allocated to a class with high R/R, RONS/NOSTOX, staging, and phenome scores, and 30.5% to a class with increased staging and phenome scores. This classification cut across the bipolar (BP1/BP2) and major depression disorder classification and was more distinctive than the latter classifications. We constructed a nomothetic network model which reunited all features of mood disorders into a mechanistically transdiagnostic model.

Major depression is accompanied by increased IgM-mediated autoimmune responses to oxidative specific epitopes (OSEs). Nevertheless, these responses have not been examined in bipolar disorder type 1 (BP1) and BP2. IgM responses to malondialdehyde (MDA), phosphatidinylinositol, oleic acid, and azelaic acid were determined in 35 healthy controls, and 101 mood disorder patients, namely 47 major depressed (MDD), 29 BP1, and 25 BP2 patients. We also measured serum total peroxides, IgG to oxidized LDL (oxLDL), IgM to nitroso-adducts, and IgM/IgA directed to lipopolysaccharides (LPS). IgM responses to OSEs were significantly higher in MDD and BP1 as compared with controls and higher in MDD than in BP2. Partial Least Squares (PLS) analysis showed that 57.7% of the variance in the clinical phenome of mood disorders was explained by number of episodes, IgM directed to OSEs and nitroso-adducts, IgG to oxLDL, and peroxides. There were significant specific indirect effects of IgA/IgM to LPS on the clinical phenome, which were mediated by peroxides, IgM OSEs, and IgG oxLDL. Using PLS we have constructed a data-driven nomothetic network which ensembled causome (increased plasma LPS load), adverse outcome pathways (namely neuro-affective toxicity), and clinical phenome features of mood disorders in a data-driven model. Based on those feature sets, cluster analysis discovered a new diagnostic class characterized by increased plasma LPS load, peroxides, autoimmune responses to OSEs and nitroso-adducts, and increased phenome scores. Using the new nomothetic network approach, we constructed a mechanistically transdiagnostic diagnostic class indicating neuro-affective toxicity in 74.3% of the mood disorder patients.

Synthesizing evolution in the post-Darwinan era has been a very challenging endeavor, both because of the great number of perspectives regarding the same natural phenomena and because of the growing technology involving mapping the origin of novelties and selection of biological variation that surpass Darwin’s original proposal of evolution by means of natural selection. Since 1859 a lot has changed, and many have presented new perspectives on evolution; either dismissing, correcting or incorporating Darwin’s ideas. This review aims to approach these different theories focusing on virus host interactions and descriptions of host-switching events in 3 different viral lineages, as well as their implications on the understanding of host-switching phenomena itself.

In 1984, Susumu Ohno hypothesized that the nylon-degrading enzyme NylB arose de novo via a frameshift mutation within a hypothetical precursor protein (PR.C). However, Ohno never tested his hypothesis or provided supporting biological evidence. For decades, Ohno’s famous frame-shift hypothesis has been uncritically accepted as the correct explanation for the origin of NylB and has been used to illustrate how simple it is for a totally new enzyme to arise spontaneously. In this paper we test Ohno’s hypothesis in light of data not available in 1984. We searched multiple protein databases and found that the NylB protein is widely occurring, has thousands of homologs, and is found in diverse organisms and diverse habitats. Conserved domain searches showed that the NylB sequence is homologous to beta lactamases - a family of highly conserved enzymes. However, our searches showed that there is no evidence for the existence of Ohno’s hypothetical PR.C protein, nor any credible homolog. Our results effectively falsify Ohno's frameshift hypothesis. We extended this analysis to other nylonases and found all the nylonases we examined had large numbers of homologs throughout the biosphere. This falsifies the long-held assumption that all nylonases evolved after the invention of nylon in 1935.

Evolution of cooperation has traditionally been studied by assuming that individuals adopt either of two pure strategies, to cooperate or defect. Recent work have considered continuous cooperative investments, turning full cooperation and full defection into two opposing ends of a spectrum and sometimes allowing for the emergence of the traditionally-studied pure strategies through evolutionary diversification. These studies have typically assumed a well-mixed population in which individuals are encountered with equal probability, Here, we allow for the possibility of assortative interactions by assuming that, with specified probabilities, an individual interacts with one or more other individuals of the same strategy. A closely related assumption has previously been made in evolutionary game theory and has been interpreted in terms of relatedness. We systematically study the effect of relatedness and find, among other conclusions, that the scope for evolutionary branching is reduced by either higher average degree of, or higher uncertainty in, relatedness with interaction partners. We also determine how different types of non-linear dependencies of benefits and costs constrain the types of evolutionary outcomes that can occur. While our results overall corroborate the conclusions of earlier studies, that higher relatedness promotes the evolution of cooperation, our investigation gives a comprehensive picture of how relatedness affects the evolution of cooperation with continuous investments.

That form and function relates, is the maxim to anatomy and physiology. Yet form-function relations can be difficult to establish. Human subjects with excessive trabeculated myocardium in the left ventricle, for example, are diagnosed with non-compaction cardiomyopathy, but the extent of trabeculations may be without relation to ejection fraction. Rather than rejecting a relation between form and function, we may ask whether the salient function is assessed; is there a relation to electrical propagation, mean arterial blood pressure, propensity to form blood clots, or all? And how should extent of trabeculated muscle be assessed? While reviewing literature on trabeculated muscle, we applied Tinbergen’s four types of causation - how does it work, why does it work, how is it made, and why did it evolve - to better parse what is meant by form and function. The paper is structured around cases that highlight advantages and pitfalls of applying Tinbergen’s questions. It further uses the evolution of lunglessness in amphibians to argue lung reduction can impact on chamber septation, and it considers the evolution of an arterial outflow in fishes to argue that reductions in energy consumption may drive structural changes with little consequences to function. Concerning trabeculations, we argue they relate to pump function in the embryo in the couple of weeks before the onset of coronary circulation. In fetal and postnatal stages, a spectrum of trabeculated-to-compact myocardium makes no difference to cardiac function and in this period form and function may appear unrelated.

Water splitting technology is an efficient approach to generate hydrogen (H2) energy, which can well address the problems of environmental deterioration and energy shortage, as well as establishment of a clean and sustainable hydrogen economy powered by renewable energy sources due to the green reaction of H2 with O2. While the efficiency of H2 production by water splitting technology is intimately related with the reactions on electrode. Nowadays, the efficient electrocatalysts in water splitting reactions are the precious metal-based materials, i.e., Pt/C, RuO2 and IrO2. Ni (Co, Fe)-based layered double hydroxides (LDH) 2D materials are the typical non-precious metal-based materials in water splitting with advantages of low cost, excellent electrocatalytic performance and simple preparation methods, which exhibits a great potential for the substitution for precious metal-based materials. This review summarizes the recent progress of Ni (Co, Fe)-based LDH 2D materials for water splitting, which mainly focuses on discussing and analyzing the different strategies to modify LDH materials towards high electrocatalytic performance. We also discuss the recent achievements including their electronic structure, electrocatalytic performance, catalytic center, preparation process and catalytic mechanism. Furthermore, the characterization progress in revealing electronic structure and catalytic mechanism of LDH is highlighted in this review. Finally, we put forward some future perspectives related to design and explore advanced LDH catalysts in water splitting.

Nearly 50 years ago, Francis Crick propounded the frozen accident scenario for the evolution of the genetic code along with the hypothesis that the early translation system consisted primarily of RNA. Under the frozen accident perspective, the code is universal among modern life forms because any change in codon assignment would be highly deleterious. The frozen accident can be considered the default theory of code evolution because it does not imply any specific interactions between amino acids and the cognate codons or anticodons, or any particular properties of the code. The subsequent 49 years of code studies have elucidated notable features of the standard code, such as high robustness to errors, but failed to develop a compelling explanation for codon assignments. In particular, stereochemical affinity between amino acids and the cognate codons or anticodons does not seem to account for the origin and evolution of the code. Here I expand Crick’s hypothesis on RNA-only translation system by presenting evidence that this early translation already attained high fidelity that allowed protein evolution. I outline an experimentally testable scenario for the evolution of the code that combines a distinct version of the stereochemical hypothesis, in which amino acids are recognized via unique sites in the tertiary structure of proto-tRNAs, rather than by anticodons, expansion of the code via proto-tRNA duplication and the frozen accident.

Analysis of Fatigue Strain, Fatigue Modulus and Fatigue Damage for the modeling of concrete plays a vital role in the evolution material behaviour which is heterogeneous and anisotropic in nature. In this paper, the Level-S nonlinear fatigue strain curve, fatigue modulus curve, residual strain curve of concrete in compression, tension, flexure and torsional fatigue loading were proposed using strain life approach. The parameters such as physical meaning, the ranges, and the impact on the shape of the curve were discussed. Then, the evolution model of fatigue modulus was established based on the fatigue strain evolution model, fatigue modulus evaluation model, residual strain evaluation model, secondary strain evaluation model. The hypothesis of fatigue modulus is inversely related with the fatigue strain amplitude. The fatigue evolution of concrete damages the bond between material grains, changed the orientation of structure of molecules and affects the elastic properties resulting in the reduction of material stiffness and modulus by utilizing strain life analysis, regarding stiffness degradation and inelastic deformation by formation of microcracking, macro cracking, cracking which is heterogeneous and anisotropic in nature . This paper presents the Fatigue Strain Life Model and analyses of fatigue strain, fatigue modulus and damage parameters of concrete which is capable of predicting stiffness degradation, inelastic deformation, strength reduction under fatigue loading. Hence, the obtainable results were compared with experimental results for the validation of the proposed model.

Fossils constitute the principal repository of data that allow for independent tests of hypotheses of biological evolution derived from observations of the extant biota. Traditionally, transformational series of structure, consisting of sequences of fossils of the same lineage through time, have been employed to reconstruct and interpret morphological evolution. More recently, a move toward an updated paradigm was fueled by the deliberate integration of developmental thinking in the inclusion of fossils in reconstruction of morphological evolution. The vehicle for this is provided by structural fingerprints – recognizable morphological and anatomical structures generated by (and reflective of) the deployment of specific genes and regulatory pathways during development. Furthermore, because the regulation of plant development is both modular and hierarchical in nature, combining structural fingerprints recognized in the fossil record with our understanding of the developmental regulation of those structures produces a powerful tool for understanding plant evolution. This is particularly true when the systematic distribution of specific developmental regulatory mechanisms and modules is viewed within an evolutionary (paleo-evo-devo) framework. Here, we discuss several advances in understanding the processes and patterns of evolution, achieved by tracking structural fingerprints with their underlying regulatory modules across lineages, living and fossil: the role of polar auxin regulation in the cellular patterning of secondary xylem and the parallel evolution of arborescence in lycophytes and seed plants; the morphology and life history of early polysporangiophytes and tracheophytes; the role of modularity in the parallel evolution of leaves in euphyllophytes; leaf meristematic activity and the parallel evolution of venation patterns among euphyllophytes; mosaic deployment of regulatory modules and the diverse modes of secondary growth of euphyllophytes; modularity and hierarchy in developmental regulation and the evolution of equisetophyte reproductive morphology. More generally, inclusion of plant fossils in the evo-devo paradigm has informed discussions on the evolution of growth patterns and growth responses, sporophyte body plans and their homology, sequences of character evolution, and the evolution of reproductive systems.

Background Scientific literature in psychology considers personality as an organization of ways of being, knowing, and acting that ensures unity, coherence and continuity, stability and planning of the individual's relations with the world (Caprara & Gennaro, 1994). Personality is the outcome of two distinct constructs: Temperament and Character. So, personality is the result of the interaction between biological aspects (temperament) and the experiences that anybody experiences in his own life, interacting with the environment (Cloninger et al., 1993). Scientific literature now largely agrees that adversity in the early years of life has broad long-term consequences on the neuroendocrine, immune, and metabolic systems (Kim et al., 2019), as well as on neuroplasticity and neuronal morphology that alter the overall evolution of (van Bodegom, et al., 2017; Edwards et al., 2010). Here we analyze the hypothesis that maternal environmental factors (air and chemical pollutants, maternal health, eating behaviors, maternal and fetal stresses, caregivers' behaviors, etc.) can cause epigenetic alterations in the offspring in the prenatal and perinatal period that shape the trait's personality of the offspring themselves and that orient part of their character in adult life. Methods The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used to develop this systematic review. PubMed, Scopus, PsycINFO, and Biosis databases were searched for primary research articles published between 2010 and 2023 looking for English language articles containing the term "prenatal" and any of the following terms: "anxiety"; "brain development"; "depression"; "gestation"; "maternal health"; "maternal stress"; "mental health"; "newborn health"; "perinatal programming"; "pregnancy"; "prenatal stress"; "resilience to stress"; "transgenerational epigenetic inheritance"; "personality"; "personality trait"; "environmental epigenetics". Retrieved articles were screened and a subset of relevant abstracts was then selected for a more detailed evaluation. The final studies selected consisted of those resources that directly evaluated the relationship between maternal environmental factors and the personality traits of the offspring. Results and Conclusions One hundred and eleven studies were identified but only three met the primary question. There is evidence to support the hypothesis of correlations between environmental exposure during the intrauterine fetal period and personality traits of the newborn. Limits: multiple limitations were found based on the lack of research on this specific topic, although such a field of research can be important for developing effective strategies for primary prevention.

Optic neuritis (ON) is the most common cause of vision loss in young adults. It manifests as acute or subacute vision loss, often accompanied by retrobulbar discomfort or pain on eye movements. Typical ON is associated with Multiple Sclerosis and is generally mild and steroid-responsive, whereas atypical forms are characterized by unusual features, such as optic disc edema, poor treatment response and bilateral involvement, and are often associated with autoantibodies against aquaporin-4 (AQP4) and Myelin Oligodendrocyte Glycoprotein (MOG). However, in rare cases AQP4 and MOG antibodies will come back negative, plunging the clinician in a diagnostic conundrum. Seronegative ON warrants a broad differential diagnosis, including autoantibody-associated, granulomatous, and systemic disorders. These rare forms need to be identified promptly, as their management and prognosis is greatly different. The scope of this review is to describe possible, rarer etiologies of ON when AQP4 and MOG antibodies are negative and discuss their diagnosis and treatment.

The hybrid method proposed in the study, ANFIS-GWO, combines the Adaptive Neuro-Fuzzy Inference System (ANFIS) with Grey Wolf Optimization (GWO) for the diagnosis of liver disorders. ANFIS is a powerful tool that combines the advantages of neural networks and fuzzy logic to create a hybrid model capable of handling complex and uncertain data. GWO is a metaheuristic optimization algorithm inspired by the social behaviour of grey wolves. In the ANFIS-GWO method, the hyperparameters of ANFIS are optimized using GWO. This optimization process aims to fine-tune the ANFIS model based on the available dataset, which consists of 7 characteristic attributes and 354 samples related to liver diseases. By adopting the hyper-parameters, the ANFIS-GWO method enhances the overall performance and accuracy of the diagnostic system. To evaluate the effectiveness of the ANFIS-GWO intelligent medical system, the study employs classification accuracy, sensitivity, and specificity analysis. Classification accuracy measures the overall correctness of the system in predicting liver disease cases. Sensitivity refers to the system’s ability to correctly identify individuals with liver disorders, while specificity measures its ability to correctly identify those without liver disorders. Experimental results demonstrate that the performance of the ANFIS-GWO method surpasses that of traditional Fuzzy Inference Systems (FIS) and ANFIS models that do not undergo an optimization phase. This suggests that the integration of GWO optimization significantly improves the diagnostic accuracy of the ANFIS model for liver disease diagnosis.

UPF3B is a constituent of the classical nonsense-mediated mRNA decay (NMD) pathway that degrades both the aberrant transcripts and a set of physiological transcripts. In higher eukaryotes, UPF3B have significant biochemical functions in diverse cellular processes including NMD and translation. UPF3B plays a crucial role in neuronal development and differentiation. Next-generation sequencing technologies identified several loss-of-function mutations in the UPF3B gene that results in neuro-developmental disorders in humans. To uncover the mechanistic role of UPF3B in neuronal functions, we have generated the UPF3B-knockout mammalian cell line model system using CRISPR-Cas9 gene editing method. RNA-Sequencing Analysis of cellular transcriptome from UPF3B-KO cells identified specific genes involved in cell growth and neuronal functions. Altered expression of genes related to the axon guidance pathway delineated the UPF3B function to regulate the neuron-specific genes. Functional enrichment analysis identified the genes involved in the disorders related to mental health and intellectual disability. Our study has the potential to identify the direct players of intellectual disability and will have broader implications.

There is evidence that chronic fatigue spectrum disorders (CFAS-D) including Myalgic Encephalomyelitis (ME), chronic fatigue syndrome (CFS) and chronic fatigue with physiosomatic symptoms including when due to comorbid medical disease are characterized by neuroimmune and neuro-oxidative biomarkers. The present study was performed to delineate the protein-protein interaction (PPI) network of CFAS-D and to discover the pathways, molecular patterns and domains enriched in their PPI network. We performed network, enrichment and annotation analysis using differentially expressed proteins and metabolics, which we established in CFAS-D patients. PPI network analysis revealed that the backbone of the highly connective CFAS-D network comprises NFKB1, CTNNB1, ALB, peroxides, NOS2, TNF, and IL6, and that the network comprises interconnected immune-oxidative-nitrosative and Wnt/catenin subnetworks. MultiOmics enrichment analysis shows that the CFAS-D network is highly significantly associated with cellular (antioxidant) detoxification, hydrogen peroxide metabolic process, peroxidase and oxidoreductase activity, IL10 anti-inflammatory signaling, and neurodegenerative, canonical Wnt, the catenin complex, cadherin domains, cell-cell junctions and TLR2/4 pathways; and the transcription factors NF-κB and RELA. The top-10 DOID annotations of the CFAS-D network include four intestinal, three immune system disorders, cancer and infectious disease. Custom GO term annotation analysis revealed that the CFAS-D network is associated with a response to a toxic substance, lipopolysaccharides, bacterium or virus. In conclusion, CFAS-D may be triggered by a variety of stimuli and their effects are mediated by aberrations in the cross-talks between redox, NF-κB, and Wnt/catenin signaling pathways leading to dysfunctions in multicellular organismal homeostatic processes.

A meta-analysis showed a significant association between activated immune-inflammatory and nitro-oxidative (IO&NS) pathways and suicide attempts (SA). There are no data whether suicidal ideation (SI) is accompanied by activated IO&NS pathways and whether there are differences between SA and SI. The current study searched PubMed, Google Scholar, and Web of Science, for articles published from inception until May 10, 2021, and systematically reviewed and meta-analyzed the association between recent SA/SI (< 3 months) and IO&NS biomarkers. We included studies which compared psychiatric patients with and without SA and SI and controls (either healthy controls or patients without SA or SI) and used meta-analysis (random-effect model with restricted maximum-likelihood) to delineate effect sizes with 95% confidence intervals (CI). Our search included 59 studies comprising 4.034 SA/SI cases and 12.377 controls. Patients with SA/SI showed activated IO&NS pathways (SMD: 0.299; CI: 0.200; 0.397) when compared to controls. The immune profiles were more strongly associated with SA than with SI, particularly when compared to healthy controls, as evidenced by activated IO&NS pathways (SMD: 0.796; CI: 0.503; 1.089), an immune-inflammatory response (SMD: 1.409; CI: 0.637; 1.462), inflammation (SMD: 1.200; CI: 0.584; 1.816), and neurotoxicity (SMD: 0.904; CI: 0.431; 1.378). The effects sizes of the IO&NS, immune-inflammatory response and inflammatory profile were significantly greater in SA than in SI. In conclusion: increased neurotoxicity due to inflammation and nitro-oxidative stress and lowered neuroprotection may explain at least in part why psychiatric patients show increased SA and SI. The IO&NS pathways are more pronounced in recent SA than in SI.

Background: Suicide attempts (SA) frequently occur in patients with mood disorders and schizophrenia, which are both accompanied by activated immune-inflammatory and nitro-oxidative (IO&NS) pathways. Methods: We searched PubMed, Google Scholar, and Web of Science, for articles published from inception until February 1, 2021. We included studies that compared blood biomarkers in psychiatric patients with (SA+) and without SA (SA-) and heathy controls and we combined different IO&NS biomarkers into immune, inflammatory, and neurotoxic profiles and used meta-analysis (random-effect model with restricted maximum-likelihood) to delineate effect sizes with 95% confidence interval (CI).Findings: Our search included 51 studies comprising 4.945 SA+ patients and 24.148 controls. We stratified the control group into healthy controls and SA- patients. SA+ patients showed significantly (p<0.001) increased immune activation (SMD: 1.044; CI: 0.599-1.489), inflammation (SMD: 1.109; CI: 0.505, 1.714), neurotoxicity (SMD: 0.879; CI: 0.465, 1.293), and lowered neuroprotection (SMD: 0.648; CI: 0.354, 0.941) as compared with healthy controls. When compared with SA- patients, those with SA+ showed significant (p<0.001) immune activation (SMD: 0.290; CI: 0.183, 0.397), inflammation (SMD: 0.311; CI: 0.191, 0.432), and neurotoxicity (SMD: 0.315; CI: 0.198, 0.432), and lowered neuroprotection (SMD: 0.341; CI: 0.167, 0.515). Patients with current, but not lifetime, SA showed significant (p<0.001) levels of inflammation and neurotoxicity as compared with controls. Conclusions: Patients with immune activation are at a higher risk of SA which may be explained by increased neurotoxicity due to inflammation and nitro-oxidative stress. This meta-analysis discovered new biomarkers of SA and therapeutic targets to treat individuals with SA.

End-stage renal disease (ESRD) is associated with fatigue and physio-somatic symptoms. The aims of this study are to delineate the associations between severity of fatigue and physio-somatic symptoms and glomerular filtration rate, inflammatory biomarkers, and Wnt/catenin-pathway proteins. The Wnt-pathway related proteins β-catenin, Dickkopf-related protein 1 (DKK1), R-spondin-1, and sclerostin were measured by ELISA technique in 60 ESRD patients and 30 controls. The Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale was used to assess severity of FF symptoms. ESRD is characterized by a significant increase in the total FF score, muscle tension, fatigue, sadness, sleep disorders, GI symptoms, and a flu-like malaise. The total FF score was significantly correlated with serum levels of urea, creatinine, phosphate, and copper (positively), and β-catenin, eGFR, hemoglobin, albumin, and zinc (inversely). The total FF score was associated with the number of total dialysis and weekly dialysis sessions, and these dialysis characteristics were more important in predicting FF scores than eGFR measurements. Partial Least Squares analysis showed that the FF score comprised two factors which are differently associated with biomarkers: a) 43.0% of the variance in fatigue, GI symptoms, muscle tension, sadness, and insomnia is explained by hemoglobin, albumin, zinc, β-catenin, and R-spondin-1; and b) 22.3% of the variance in irritability, concentration and memory impairments by increased copper and cations/chloride ratio, and male sex. ESRD patients show high levels of fatigue and physio-somatic symptoms which are associated with hemodialysis and mediated by dialysis-induced changes in inflammatory pathways, the Wnt/catenin pathway, and copper.

Recently, a breakdown of paracellular and vascular pathways and activated neuroimmune and oxidative pathways were established in (deficit) schizophrenia. The aim of the current study was to delineate a) the differences in these pathways between stable phase, first (FES) and multiple (MES) episode schizophrenia, and b) the pathways that determine the behavioral-cognitive-physical-psychosocial (BCPS)-worsening in FES/MES. This study included 21 FES and 58 FES patients and 40 healthy controls and measured indicants of serum IgA to C1q, and leaky gut, immune activation, and oxidative stress toxicity (OSTOX) biomarkers. We constructed a BCPS-worsening index by extracting a latent vector from symptomatic, neurocognitive, and quality of life data. FES patients showed significantly higher IgA to C1q, cadherin, catenin, plasmalemma vesicle-associated protein, and IgA/IgM to Gram-negative bacteria than FES patients and controls. In FES patients, the BCPS-worsening score was predicted (48.7%) by IgA to Klebsiella pneumoniae and lowered paraoxonase 1 activity. In MES patients, the BCPS-worsening score was explained (42.7%) by increased tumor necrosis factor-α, OSTOX, and number of episodes. In schizophrenia, 34.0% of the variance in the BCPS-worsening score was explained by IgA to K. pneumoniae, OSTOX, and number of episodes. Increased IgA to K. pneumoniae was the single best predictor of residual psychotic symptoms in FES and MES. This study delineated different mechanistic processes in FES, including breakdown of adherens junctions, bacterial translocation, and C1q circulating immune complexes; and FES, including immune and oxidative stress neurotoxic pathways. FES and MES comprise different staging subtypes, i.e., FES and MES with and without worsening.

The hybridization of machine learning methods with soft computing techniques is an essential approach to improve the performance of the prediction models. Hybrid machine learning models, particularly, have gained popularity in the advancement of the high-performance control systems. Higher accuracy and better performance for prediction models of exergy destruction and energy consumption used in the control circuit of heating, ventilation, and air conditioning (HVAC) systems can be highly economical in the industrial scale to save energy. This research proposes two hybrid models of adaptive neuro-fuzzy inference system-particle swarm optimization (ANFIS-PSO), and adaptive neuro-fuzzy inference system-genetic algorithm (ANFIS-GA) for HVAC. The results are further compared with the single ANFIS model. The ANFIS-PSO model with the RMSE of 0.0065, MAE of 0.0028, and R² equal to 0.9999, with a minimum deviation of 0.0691 (KJ/s), outperforms the ANFIS-GA and single ANFIS models.

Major depression (MDD) is accompanied by higher serum IgM/IgA responses to LPS of Gram-negative bacteria, suggesting increased bacterial translocation and gut dysbiosis. Gut dysbiosis may occur in bipolar disorder (BD) and there are differences between MDD and BD type 1 (BP1) and -2 (BP2) in nitro-oxidative stress biomarkers associated with leaky gut. This study examines serum IgM/IgA responses directed to LPS of 6 Gram-negative bacteria in 29 BP1, 37 BP2, 44 MDD and 30 healthy individuals. MDD plus BD was best discriminated from controls by increased IgM/IgA responses to Pseudomonas aeruginosa. BP1 patients showed higher IgM responses to Morganella morganii as compared with MDD and BP2 patients. Patients with melancholia showed higher IgA responses to Citrobacter koseri as compared to controls and non-melancholic depression. The total score on the Hamilton Depression Rating Scale was significantly associated with IgA responses, especially C. koseri. IgG responses to oxidized low-density lipoprotein were significantly associated with signs of increased bacterial translocation. In conclusion, not only MDD but also BP1 and BP2 are accompanied by an immune response due to the increased load of plasma LPS of gut commensal bacteria while these aberrations in the gut-brain axis are most pronounced in BP1 and patients with melancholic features. Activated oxidative stress pathways and autoimmune responses to oxidative specific epitopes in mood disorders may be driven by a breakdown in gut paracellular, transcellular and/or vascular pathways. If replicated, drugs that protect the integrity of the gut barrier may offer novel therapeutic opportunities for BP1 and MDD.

A simple in vitro biosensor for the detection of β-amyloid 42 in phosphate-buffer saline (PBS) and undiluted human serum was fabricated and tested based on our platform sensor technology. The bio-recognition mechanism of this biosensor was based on the effect of the interaction between antibody and antigen of β-amyloid 42 to the redox couple probe of K₄Fe (CN) ₆ and K₃Fe (CN) ₆. Differential pulse voltammetry (DPV) served as the transduction mechanism measuring the current output derived from the redox coupling reaction. The biosensor was a three-electrode electrochemical system, and the working and counter electrodes were 50 nm thin gold film deposited by sputtering technique. The reference electrode was a thick-film printed Ag/AgCl electrode. Laser ablation technique was used to define the size and structure of the biosensor. Cost-effective roll-to-roll manufacturing process was employed in the fabrication of the biosensor making it simple and relatively inexpensive. Self-assembled monolayers (SAM) of 3-Mercaptopropionic acid (MPA) was employed to covalently immobilize the thiol group on the gold working electrode. A carbodiimide conjugation approach using N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDC) and N–hydroxysuccinimide (NHS) was undertaken for cross-linking antibody of β-amyloid 42 to the carboxylic groups on one end of the MPA. The antibody concentration of β-amyloid 42 used was 18.75µg/mL. The concentration range of β-amyloid 42 in this study was from 0.0675µg/mL to 0.5µg/mL for both PBS and undiluted human serum. DPV measurements showed excellent response in this antigen concentration range. Interference study of this biosensor was carried out in the presence of Tau protein antigen. Excellent specificity of this β-amyloid 42 biosensor was demonstrated without interference by other species such as T-tau protein.

Horseshoe crabs represent the most ancestral chelicerate lineage characterized by marine ecology and the possession of lateral compound eyes. While considered living fossils, recent studies reported an unusual number of Pax6 transcription factor genes in the Atlantic horseshoe crab Limulus polyphemus. Pax genes encode a family of ancient metazoan transcription factors, which comprise seven subfamilies. Among these, the members of the Pax6 subfamily confer critical functions in the development of the head, the visual system, and further body plan components. Arthropods are characterized by two Pax6 subfamily homologs that were discovered in Drosophila and named eyeless (ey) and twin of eyeless (toy). However, whole genome sequence searches uncovered three homologs of ey and two homologs of toy in L. polyphemus. These numbers are explained by the occurrence of three whole genome duplications (WGD) in the lineage to the last common ancestor of L. polyphemus and its closely related three additional members of the extant horseshoe crab species cluster. Here we report comparative sequence evidence for the functional conservation of the five L. polyphemus Pax6 transcription factor homologs. Our analyses reveal that all paralogs are conserved in the approximately 135 million-year-old horseshoe crab species cluster and that they evolve under strong purifying selection. These findings identify subfunctionalization as the likeliest post-WGD outcome for the five Pax6 homologs. While awaiting confirmation by gene expression studies, this scenario would reconcile the discrepancy between the WGD-expanded gene repertoires and phenotypic stasis in the horseshoe crabs.

There are no theorems (proven theories) in the biological sciences. We propose that the 3 31 nt minihelix tRNA evolution theorem be universally accepted as one. The 3 31 nt minihelix theorem completely describes evolution of type I and type II tRNAs from ordered precursors (RNA repeats and inverted repeats). Despite diversification of tRNAome sequences, statistical tests overwhelmingly support the theorem. Furthermore, the theorem relates the dominant pathway for the origin of life on Earth, specifically, how tRNAomes and the genetic code may have coevolved. Alternate models for tRNA evolution (i.e., 2 minihelix, convergent and accretion models) are falsified. In the context of the pre-life world, tRNA was a molecule that via mutation could modify anticodon sequences and teach itself to code. We relate the clearest history to date of the chemical evolution of life on Earth. From analysis of tRNA evolution, ribozyme-mediated RNA ligation was a primary driving force in evolution of complexity during the pre-life to life transition on Earth.

In a recent article, Smoom et al. identified an important amino acid variation in the helicase RTEL1 of the Algerian mouse (Mus spretus). Since the latter has telomeres five times shorter than the laboratory mouse (belonging to the Mus musculus species), they introduced this variation in laboratory mice, in order to obtain an engineered strain with human-length telomeres. Succeeding in doing this, they established the “Telomouse” strain. Here I demonstrate that, in reality, Mus spretus does not show this variation: the key amino acid is conserved in all rodent species, which all have human-length telomeres (including wild Mus musculus species). This finding in no way compromises the value of the research of Smoom et al. and the utility of the Telomouse strain. Rather, it raises the question of how the telomere length of Mus musculus (as a species) should be considered and the important consequences it has on studies on inter-species comparison.

Land plants have undergone their great diversification and evolution in the past 400 million years. Although appearing complex and hard to grasp, the evolution of plants centers around an invariable core development process, SRC (Sexual Reproductive Cycle). Various modifications have been added sequentially to this core process, and thus creating various novel organs and distinguishing their bearers one from another. Reproductive organs of all land plants, including sporangium, megasporangium, metamegasporangium (= ovule), and various metamegasporangium complexes, are derived from terminal sporangia in the earliest land plants. Throughout the million-year-long evolution, plants sequentially recruit associating accessories to protect their vulnerable core parts (spore and gamete). The occurrence of every single of these novelties is a stair marking land plant reproduction evolution and leads to enhanced offspring development conditioning (ODC).

The ability to perceive and respond to light stimuli is fundamental not only for spatial vision, but also to many other light mediated interactions with the environment. In animals, light perception is performed by specific cells known as photoreceptors and, at molecular level, by a group of GPCRs known as Opsins. Sea urchin larvae possess a group of photoreceptor cells (PRCs), deploying a Go-Opsin (Opsin3.2), which have been shown to share transcription factors and morphology with PRCs of the ciliary type, contributing to raising new questions on how this sea urchin larva PRC is specified and whether it shares a common ancestor with ciliary PRCs or it evolved independently through convergent evolution. To answer these questions, we combined immunohistochemistry and fluorescent in situ hybridization to investigate how the Opsin3.2 PRCs develop in the sea urchin Strogylocentrotus purpuratus larva. Subsequently, we applied single cell transcriptomics to investigate the molecular signature of the Sp-Opsin3.2 cells, and show that they deploy an ancient regulatory program responsible for photoreceptors specification. Finally, we also discuss the possible functions of the Opsin3.2 cells based on their molecular fingerprint, and we suggest that they are involved in a variety of signaling pathways, including those entailing the thyrotropin-releasing hormone.

The presence of homosexual behavior in the human population represents an evolutionary puzzle, as such behavior leads to obvious reproductive disadvantages. Recently, it was revealed that the length of telomeres inherited by offspring is determined, among other things, by the age of father. Older fathers pass longer telomeres to their children. The length of telomeres is generally considered as one of the factors determining the individual life span, which suggests that children of older fathers live longer. This phenomenon may provide a plausible explanation for the persistence of homosexuality among humans. Homosexuality is a partially inheritable trait. As homosexual males do not actively pursue reproductive sex, they are much likelier to become fathers later in life, if they reproduce at all. Through delayed reproduction, homosexual and bisexual subpopulations contribute to the increasing mean length of telomeres in population, which results in the gradually increasing life span. However, longer telomeres inherited from homosexual father are passed together with the genes predisposing to homosexual behavior, which helps to sustain a substantial pool of “gay genes” despite their reproductive disadvantage. The described effects are likely to be small but may results in a significant demographical shifts (increased longevity and sustained presence of homosexual sub-population) over multiple generations. The introduction of effective contraception (and the consequent serious increase of the mean age of fathering the children) may provide a similar mechanism for extending the mean telomere length in population, with consequences for longevity and general health.

Data from DR17 of the SDSS in the g, i, r, u, z bands were used to compute galaxy number counts and galaxy density per square degree in the composite bJ band over two areas of sky centred on the North Galactic Cap (NGC) and above the South Galactic Cap (SGC), with areas of 5,954 and 859 sq. deg. respectively and a combined count of 622,121 galaxies within the limits of redshift ≤0.4 and bJ≤20. The comparative densities confirmed an extensive void in the Southern sky with a deficit of 26% out to a redshift z∼0.15. Number counts in the K−, R−, I−, H−, B− and U−bands were derived from the Durham Extragalactic Astronomy and Cosmology catalogue and were well fitted to a general relativity (GR) cosmological model over their whole range, requiring only modest luminosity evolution, except for a steeper curve in the B−band at faint magnitudes required a star-burst evolutionary model to account for the excess faint number counts. Extending the SDSS redshift-number count survey to fainter and more distant galaxies with redshift ≤1.20 and bJ≤24 showed a secondary peak in the number counts that may account for this observed apparent excess of faint blue galaxy counts. Individual examination of a sample of these galaxies suggested that many were QSOs, bright X-ray or radio sources, or evolving irregular galaxies with rapid star formation rates. This sub-population at redshifts 0.45−0.65 may account for the excess counts observed in the B− optical band.

Hox genes represent an important gene family that is involved in the segmentation pattern and identity of the segments during the formation of the body plan in metazoans. For many years, several studies have sought to establish a correlation between the evolution of these genes and the evolution of large groups of metazoans. Here, we use publicly available sequences of Hox gene clusters to reconstruct the evolutionary history of anterior Hox genes. We show that information harbored by these genes, in part, reflects the evolution and diversification of most animal archetypes, but in many cases, there were conflicts between the evolutionary history of some genes and the history of large groups, these cases may have occurred due to specific and similar selective pressures in relatively distant groups, which may have led to evolutionary convergences. Our findings also reveal that the evolution of Hox genes (and clusters) as a multigene family is consistent to a birth-and-death model constrained by development, where there is a trade-off between a relatively fast gene turnover and their central developmental roles

Bioluminescence – i.e., the emission of visible light by living organisms - is defined as a biochemical reaction involving, at least, a luciferin substrate, an oxygen derivative, and a specialised luciferase enzyme. In some cases, the enzyme and the substrate are durably associated and form a photoprotein. While this terminology is educatively useful to explain bioluminescence, it gives a false idea that all luminous organisms are using identical or homologous molecular tools to achieve light emission. As usually observed in biology, reality is more complex. To date, 11 different luciferins have indeed been discovered, and several non-homologous luciferases lato sensu have been identified which, all together, confirms that bioluminescence emerged independently multiple times during the evolution of living organisms. While some phylogenetically related organisms may use non-homologous luciferases (e.g., at least four convergent luciferases are found in Pancrustacea), it has also been observed that phylogenetically distant organisms may use homologous luciferases (e.g., parallel evolution observed in some cnidarians, tunicates and echinoderms that are sharing a homologous luciferase-based system). The evolution of luciferases then appears puzzling. The present review takes stock of the diversity of known “bioluminescent proteins”, their evolution and potential evolutionary origins. A total of 134 luciferase and photoprotein sequences have been investigated (from 75 species and 11 phyla), and our analyses identified 12 distinct types – defined as a group of homologous bioluminescent proteins. The literature review indicated that genes coding for luciferases and photoproteins have potentially emerged as new genes or have been co-opted from ancestral non-luciferase/photoprotein genes. In this latter case, the homologous gene’s co-options may occur independently in phylogenetically distant organisms.

Supervised machine learning (SML) is a powerful method for predicting a small number of well-defined output groups (e.g., potential buyers of a certain product) by taking as input a large number of known well-defined measurements (e.g., past purchases, income, ethnicity, gender, credit record, age, favorite color, favorite chewing gum). SML is predicated upon the existence of a training dataset in which the correspondence between the input and output is known to be true. SML has had enormous success in the world of commerce, and this success may have prompted a few scientists to employ it in the study of molecular and genome evolution. Here, we list the properties of SML that make it an unsuitable tool in certain evolutionary studies. In particular, we argue that SML cannot be used in an evolutionary exploratory context for the simple reason that training datasets that are known to be a priori true do not exist. As a case study, we use an SML study in which it was concluded that most human genomes evolve by positive selection through soft selective sweeps (Schrider and Kern 2017). We show that in the absence of legitimate training datasets, Schrider and Kern (2017) used (1) simulations that employ many manipulatable variables and (2) a system of cherry-picking data that would put to shame most modern evangelical exegeses of the Bible. These two factors, in addition to the lack of methodological detail and negative controls, lead us to conclude that all evolutionary inferences derived from so-called SML algorithms (e.g., S-HIC) should be taken with a huge shovel of salt.

Ruminants perhaps appeared about 50 million years ago (Ma). Five ruminant families had been extinct and about 200 species in 6 ruminant families are living today. The first ruminant family probably was small omnivore without functional ruminal microbiota to digest fiber. Subsequently, other ruminant families evolved around 18-23 Ma along with woodlands and grasslands. Probably, ruminants started to consume selective and highly nutritious plant leaves and grasses similar to concentrates. By 5-11 Ma, grasslands expanded and some ruminants used more grass in their diets with comparatively low nutritive values and high fibers. Historically, humans have domesticated 9 ruminant species that are mostly utilizer of low quality forages for human benefits. Thus, the non-functional rumen microbiota to predominantly concentrate fermenting microbiota, followed by predominantly fiber digesting microbiota had evolved for mutual complementary benefits of holobiont over the million years. The core microbiome of ruminant species seems the resultant of hologenome interaction in an evolutionary unit. The inertia and resilience properties of ruminal ecosystem seem to be due to this core microbiota, which makes the ecosystem most stable in response to perturbations because this core microbiota has evolutionary advantages with logically more generalists (i.e., wide metabolic versatile and redundancy). Also, a part of the ruminal microbiome shows highly plasticity, which is likely useful for evolutionary adaptability of holobiont. This review discusses ecological characteristics of ruminal microbial community in evolutionary perspectives. The updated understanding of ecological traits of ruminal microbiome would be helpful to better modulate the ruminal fermentation favorably for human benefits.

We provide a biochronology of Jurassic planktonic foramininfera, using first order linkage to ammonite and nannofossil stratigraphy and geochronology. This enigmatic and understudied group of microfossils occurred from middle Toarcian through Tithonian time, from ~180 to ~143 Ma; its origin is unknown. There are three genera: Globuligerina, Conoglobigerina and Petaloglobigerina. The genus Globuligerina, with a smooth to pustulose test surface texture appeared in Toarcian (late Early Jurassic) and Conoglobigerina, with a rough reticulate test surface texture in Oxfordian (early Late Jurassic) time. The genus Petaloglobigerina, with a petaloid last whorl and one or more twisted and claviform chambers evolved in early Kimmeridgian time from Globuligerina balakhmatovae. We recognize stratigraphic events from eleven species across four evolutionary lineages, calibrated to Geologic Time Scale 2020. A dramatic faunal change over, which is not well documented led to the survival of only one taxon, most likely Gobuligerina oxfordiana in the Tithonian. During the Berriasian several new taxa appeared.

Heart failure with preserved ejection fraction (HFpEF) is a leading form of human cardiovascular disease and commonly associated with systemic hypertension. Unique evolved adaptations in giraffe myocardia may be a natural animal model of resistance to HFpEF. In humans, pressure-overload induced left ventricular thickening (PLVT) impairs diastolic relaxation, elevates left atrial pressures and may progress to heart failure with symptoms including exercise intolerance. In healthy giraffe, the left ventricle thickens as developmental neck lengthening widens the vertical distance between the heart and head increasing pressures needed to maintain constant brain perfusion. Yet, diastolic relaxation and exercise capacity are unimpaired, a critical adaptation for prey species such as giraffe. The proximate mechanisms underlying this unique cardiovascular physiology are not yet characterized. Developmental PLVT in giraffe emerges as a species-specific evolved adaptation which offers a roadmap for identifying innovations in therapeutic and prevention strategies for HFpEF.

The present review provides an in-depth look into the complex topic of delimiting species in sea anemones. For most part of history this has been based on a small number of variable anatomic traits, many of which are used indistinctly across multiple taxonomic ranks. Early attempts to classify this group succeeded to comprise much of the diversity known to date, yet numerous taxa were mostly characterized by the lack of features rather than synapomorphies. Of the total number of species names within Actiniaria, about 77% are currently considered valid and more than half of them have several synonyms. Besides the nominal problem caused by large intraspecific variations and ambiguously described characters, genetic studies show that morphological convergences are also widespread among molecular phylogenies. On the contrary, spatial distribution has been emerging as a more reliable parameter to explain cryptic relationships among sea anemones. Integrative approaches and genome-wide data have been especially helpful to unveil the mechanisms behind the speciation process, which is typically marked by large genetic differences among populations, even from neighbouring localities. This paper further discusses current gaps in our knowledge and offers some future directions on how to address the issue of species delimitation in the extremely polymorphic group of sea anemones.