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.

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.

Aging is associated with an increasing dysfunction of key brain homeostasis mechanisms and represents the main risk factor across most neurodegenerative disorders. However, the degree of dysregulation and the affectation of specific pathways set apart normal aging from neurodegenerative disorders. In particular, the neuronal metabolism of catecholaminergic neurotransmitters appears to be a specifically sensitive pathway that is affected in different neurodegenerations. In humans, catecholaminergic neurons are characterized by an age-related accumulation of neuromelanin (NM), rendering the soma of the neurons black. This intracellular NM appears to serve as a very efficient quencher for toxic molecules. However, when a neuron degenerates, NM is released together with its load (many undegraded cellular components, transition metals, lipids, antibiotics) contributing to initiate and worsen an eventual immune response, exacerbating the oxidative stress, ultimately leading to the neurodegenerative process. This review focuses on the analysis of the role of NM in normal aging and catecholaminergic metabolism due to its capability as a pro-oxidant and other harmful molecules, versus its involvement in oxidative stress and aberrant immune response, which it is highly dependent on NM saturation state and its extracellular release.

Gliomas are aggressive, primary central nervous system tumours arising from glial cells. Glioblastomas are the most malignant. They are known for their poor prognosis or median overall survival. Current standard of care is overwhelmed by the heterogeneous, immunosuppressive tumour microenvironment promoting immune evasion and tumour proliferation. The advent of immunotherapy with its various modalities – immune checkpoint inhibitors, cancer vaccines, oncolytic viruses, chimeric antigen receptor T cells and NK cells have shown promise. Clinical trials incorporating combination therapies of the above have overcome the microenvironment resistance and yielded survival and prognostic benefit. Rolling these new therapies out in the real-world scenario in a low cost, high throughput manner is the unmet need of the hour. These will bring practice changing implications to the glioma treatment landscape. In this review article, we focus on describing the hallmarks of the glioma microenvironment and its interplay with the different emerging modalities of immunotherapy.

The Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) first emerged in 2019 in China and has resulted in millions of human morbidities and mortalities across the globe. It has been shown that this novel virus originated in animals, mutated, and made the cross-species jump to humans. At the time of this communication, the Coronavirus disease (COVID-19) may be on way to an endemic form, however the threat of the virus is more for susceptible (older people and immunocompromised) people. The human body has more bacterial cells than its own, thus making us more bacterial than humans. As a consequence, the bacteriomes in the human body heavily influence human health and disease. The bacteriomes in the body and the immune system seem to be in constant association during bacterial and viral infections. In this review, we identify various bacterial spp. in major bacteriomes (oral, nasal, lung, and gut) of the body in healthy humans and compare them with dysbiotic bacteriomes of COVID-19 patients. We try to identify key bacterial spp. that have a positive effect on the functionality of the immune system and human health. These select bacterial spp. could be used as potential probiotics to counter or prevent COVID-19 infections. In addition, we try to identify key metabolites produced by probiotic bacterial spp. that could have potential anti-viral effects against SARS-CoV-2. These metabolites could be subject to future therapeutic trials to determine their anti-viral efficacy.

Chronic inflammation, the activation of immune cells and their cross-talk with cardiomyocytes in the pathogenesis and progression of heart diseases has long been overlooked. However, with the latest research developments, it is increasingly accepted that a vicious cycle exists where cardiomyocytes release cardiocrine signaling molecules that spirals down to immune cell activation and chronic state of low‐level inflammation. For example, cardiocrine molecules released from injured or stressed cardiomyocytes can stimulate macrophages, dendritic cells, neutrophils and even T-cells, which then subsequently increase cardiac inflammation by co-stimulation and positive feedback-loops. One of the key proteins involved in stress-mediated cardiomyocyte signal transduction is a small GTPase RhoA. Importantly, the regulation of RhoA activation is critical for effective immune cell response and is being considered as one of the potential therapeutic targets in many immune-cell-mediated inflammatory diseases. In this review we provide an update on the role of RhoA at the juncture of immune cell activation, inflammation and cardiac disease.

Anxiety disorders manifest in women more than in men by almost twofold. This narrative review aims to summarize the sex-related biological factors, which underpin anxiety, focusing on the interactions of sex and tryptophan/serotonin with anxiety.A literature search was conducted using Google Scholar, PubMed/MEDLINE, Scopus, and EMBASE databases from inception until December 31, 2017. This review shows that sex may interact with many serotonin functions thereby modulating anxiety, including 5-HT1A and 5-HT2C receptors, 5-HT transporter and central 5-HT concentrations and metabolism. Sex-steroids modulate the expression of serotonin transporter genes, creating a difference in serotonin availability. Sex and estrous cycle phases lead to varying anxiety responses to tryptophan depletion. Testosterone, progesterone and estrogen are important factors in mediating sex differences in serotonin responses to anxiety-generating behavioral tests. At prenatal levels, there are sex-related differences in the reciprocal relationships between serotonin and the HPA-axis, which modulate anxiety-like behaviors. Activated immune-inflammatory pathways induce indoleamine-2,3-dioxynease (IDO) and the tryptophan catabolite (TRYCAT) pathway thereby increasing tryptophan degradation and increasing the production of TRYCATs including kynurenine and quinolinic acid, which may create an overall anxiogenic effect. The effects of immune activation on IDO are significantly more pronounced in women than men and therefore females may show increased levels of anxiogenic TRYCAT following immune challenge. Aberrations in the IDO-activated TRYCAT pathway are found in pregnant females and parturients and are associated with increased anxiety levels in the postnatal period. The results of this review underscore the necessity of studying the associations between serotonin and anxiety in both sexes taking into account the effects of immune activation on IDO and production of anxiogenic TRYCATs. Future anxiety research should focus on the interactions between serotonin/tryptophan and sex, sex hormones, the menstrual cycle, pregnancy, the HPA axis and the immune system through production of anxiogenic TRYCATs.

In plants and animals, endogenous biological molecules, termed damage-associated molecular patterns (DAMPs) or alarmins, are released by damaged, stressed or dying cells following abiotic stress such as radiation and drought stress. In turn, a cascade of downstream signaling events is initiated leading to the up-regulation of defense-related genes. In the present study, in an effort to investigate the conservation status of the molecular mechanisms implicated in the danger signaling, thorough in silico phylogenetic and structural analyses of the effector biomolecules were performed in taxonomically diverse plant species. On the basis of our results, the defense mechanisms appear to be largely conserved within the plant kingdom. Of note is our finding that the sequence and/or function of several components of these mechanisms were found to be conserved in animals, as well.

After decades of research, oncolytic virotherapy has recently advanced to clinical application, and currently a multitude of novel agents and combination treatments are being evaluated for cancer therapy. Oncolytic agents preferentially replicate in tumor cells, inducing tumor cell lysis and complex anti-tumor effects, such as innate and adaptive immune responses and the destruction of tumor vasculature. With the availability of different vector platforms and the potential of both genetic engineering and combination regimens to enhance particular aspects of safety and efficacy, the identification of optimal treatments for patient subpopulations or even individual patients becomes a top priority. Mathematical modeling can provide support in this arena by making use of experimental and clinical data to generate hypotheses about the mechanisms underlying complex biology and, ultimately, predict optimal treatment protocols. Increasingly complex models can be applied to account for therapeutically relevant parameters such as components of the immune system. In this review, we describe current developments in oncolytic virotherapy and mathematical modeling to discuss the benefit of integrating different modeling approaches into biological and clinical experimentation. Conclusively, we propose a mutual combination of these fields of research for more efficient development and effective treatments.

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.

Pancreatic ductal adenocarcinoma (PDA), the most frequent type of pancreatic cancer, is one of the main unfinished businesses in the biomedical and clinical fields, with still discouraging 5 year survival rates and poor therapy efficiency. PDA abundant desmoplasia has for long played the lead in the mechanisms involved in poor drug performance, being the main source of cytokines and chemokines orchestrating rapid and silent tumor progression and guilty of isolating tumor cells into a extense fibrotic reaction resulting in inefficient drug delivery. However, since immunotherapy was proclaimed the breakthrough of the year back to 2013, the focus in the stroma of pancreatic cancer has interestingly moved from activated fibroblasts to the immune compartment, trying to understand the immunosuppressive factors that play part in the strong immune evasion that characterizes PDA. PDA microenvironment is highly immune-suppressive, being basically composed of T regulatory cells (Tregs), tumor-associated macrophages (TAMs) and myeloid-derived suppressive cells (MDSCs), which boycott CD8⁺ T-cell duties in tumor recognition and clearance. Interestingly, preclinical data have highlighted the importance of this immune evasion as the source of resistance to single checkpoint immunotherapies and cancer vaccines and point at pathways inhibiting the immune attack as the key to solve the therapy puzzle. Here, we will discuss the molecular mechanisms involved in PDA immune escape as well as the state of the art of the PDA immunotherapy.

CD147/Basigin, a transmembrane glycoprotein belonging to the immunoglobulin super family, is a multifunctional molecule with various binding partners. CD147 binds to monocarboxylate transporters (MCTs) and supports their expression on plasma membranes. MCTs play an important role in glycolysis, the enzymatic conversion of glucose to pyruvate and adenosine triphosphate (ATP). Pyruvate is further converted to lactic acid which is exported from the cytoplasm by MTC-1 and MCT-4 to maintain intracellular pH and a stable metabolic state. Under physiological conditions, cellular energy production is induced by mitochondrial oxidative phosphorylation. Glycolysis usually occurs under anaerobic conditions, whereas cancer cells depend on glycolysis under aerobic conditions. T cells also require glycolysis for differentiation, proliferation, and activation. Human malignant melanoma cells expressed higher levels of MCT-1 and MCT-4, co-localized with CD147 on the plasma membrane and showed an increased glycolysis rate compared to normal human melanocytes. Silencing of CD147 by siRNA abrogated the membrane expression of MCT-1 and MCT-4 and disrupted glycolysis, inhibiting cancer cell activity. The differentiation of CD4+ T cells into Th17 cells is a pivotal process in the development of various immune disorders, including psoriasis. Studies using CD147-deficient mice demonstrated the involvement of CD147 in psoriasis. MCT-1 was absent on CD4+ T cells in CD147-deficient mice. Naïve CD4+ T-cells from CD147-deficient mice show low potential for differentiation into Th17 cells. Imiquimod-induced skin inflammation was significantly milder in CD147-deficient mice than in wild-type mice. These findings indicate that CD147/Basigin is involved in the development of malignant tumors and T cell mediated immunological disorders via regulation of glycolysis.

Brain metastasis (BrM), involving the spread of cells from a primary tumor through the blood circulation system to the brain microvasculature, eventually progresses despite multiple treatments and remains a substantial contributor to major mortality in patients with advanced- stage cancer. Molecular signatures and immune cellular components of the tumor microenvironment (TME) are emerging as essential regulators involved in establishing an organ-specific metastasis (colonization) and therapeutic response. A comprehensive understanding of detailed characterization and the immune landscape in context of process of BrM formation will greatly expand the horizon of treatments available to target these deadly diseases. In this review, we provide a comprehensive picture of the complex interactions between tumor cells and immune cellular components participated in the BrM process. Based on this knowledge, we will discuss opportunities and challenges for therapeutic strategies against BrM.

Schizophrenia is characterized by an interrelated activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory reflex system (CIRS), which downregulates the IRS. Deficit schizophrenia is characterized by a deficit in natural regulatory autoimmune responses to tryptophan catabolites. The presence and correlates of IgM isotype antibodies to oxidative specific epitopes (OSEs), nitroso (NO) and nitro (NO₂) adducts in schizophrenia remain unknown.This study measured IgM antibodies to malondialdehyde (MDA), azelaic acid, phosphatidylinositol, oleic acid, NO-tryptophan, NO-albumin, NO-cysteinyl and NO₂-tyrosine in a sample of 80 schizophrenia patients, divided into those with and those without deficit schizophrenia, and 38 healthy controls.Deficit schizophrenia was characterized by significantly lower IgM antibody levels to all OSEs as compared with non-deficit schizophrenia and controls. Lowered IgM antibodies to MDA coupled with increased IgM levels to NO-cysteinyl and NO₂-tyrosine strongly predict deficit schizophrenia versus non-deficit schizophrenia with an area under the ROC curve of 0.913. A large part of the variance (21.2 – 42.2 %) in the negative symptoms of schizophrenia and excitation is explained by IgM antibody titers to MDA (inversely) and NO-cysteinyl and/or NO₂-tyrosine (both positively). Lower IgM antibodies to MDA are significantly associated with impairments in episodic memory including direct and delayed recall.These findings further indicate that deficit schizophrenia is a distinct phenotype of schizophrenia, which is characterized by lower natural IgM antibody levels to OSEs and relative increments in nitrosylation and nitration of proteins. It is concluded that deficits in lowered IgM responses to MDA and azelaic acid (part of the CIRS) attenuate the negative immune-regulatory feedback on the primary immune response and that this process may drive negative symptoms and impairments in episodic memory and thus deficit schizophrenia.

Malaria remains a major public health problem worldwide, with eradication efforts thwarted by drug and insecticide resistance and the lack of a broadly effective malaria vaccine. In continuously exposed communities, polyclonal infections are thought to reduce the risk of severe disease and promote the establishment of asymptomatic infections. We sought to investigate the relationship between the complexity of P. falciparum infection and underlying host adaptive immune responses in an area with high prevalence of asymptomatic parasitaemia in Cameroon. A cross-sectional study of 353 individuals aged 2 to 86 years (median age = 16 years) was conducted in five villages in the Centre Region of Cameroon. Plasmodium falciparum infection was detected by multiplex nested PCR in 316 samples, of which 278 were successfully genotyped. Of these, 60.1% (167/278) were polyclonal infections, the majority (80.2%) of which were from asymptomatic carriers. Host-parasite factors associated with polyclonal infection in the study population included peripheral blood parasite density, participant age and village of residence. The number of parasite clones per infected sample increased significantly with parasite density (r = 0.3912, p<0.0001) but decreased with participant age (r = -0.4860, p<0.0001). Parasitaemia and number of clones per sample correlated negatively with total plasma levels of IgG antibodies to three highly reactive P. falciparum antigens (MSP-1p19, MSP-3 and EBA175) and two soluble antigen extracts (merozoite and mixed stage antigens). Surprisingly, we observed no association between the frequency of polyclonal infection and susceptibility to clinical disease as assessed by the recent occurrence of malarial symptoms or duration since the previous fever episode. Overall, the data indicate that in areas with high perennial transmission of P. falciparum, parasite polyclonality is dependent on underlying host adaptive immune responses, with the majority of polyclonal infections occurring in persons with low levels of protective anti-plasmodial antibodies.

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.

In order to study the effects of dietary folic acid (FA) supplementation on growth performance and immune status in weanling piglets, a single factorial randomized block design trial with 6 dietary FA levels at 0.35, 0.66, 2.19, 5.18, 7.51 or 10.81 mg/kg was conducted. A total of 108 crossbred (Landrace × Yorkshire) castrated weanling piglets (at 21 d of age) were allocated by body weight into 36 feeding cages (3 piglets/cage), which were allotted randomly into 6 dietary groups (6 cages/group). Piglets were fed ad libitum for 24 days. Blood samples were collected on the 24th day. The growth performance and the immune parameters were measured. Results showed that FA supplementation increased the serum FA level of weaned piglets (p < 0.01), and tended to increase the body weight (BW) at 45 d of age (p < 0.1) and the average daily gain (ADG) from 29 d to 45 d of age (p < 0.1). FA addition improved the feed efficiency (G/F) from 21 d to 45 d of age (p < 0.01), and with significant effects at 21 d to 45 d of age with FA 2.19 or 7.51 mg/kg (p < 0.05). Dietary FA at 0.66 or 2.19 mg/kg increased the serum CD3+CD8+ subset (p < 0.05), decreased the CD3+CD4+ / CD3+CD8+ ratio (p < 0.05); Moreover, FA addition increased the serum IFN-γ level (p < 0.05). In conclusion, the adequate dietary FA is necessary to improve the immunity and growth performance of weaned piglets at 21 d of age. The suitable dietary FA level for immune function from 21 d to 45 d of age was 0.66 mg/kg, while were 6.82 mg/kg from 21 d to 28 d of age and 5.42 mg/kg from 29 d to 45 d of age respectively for feed efficiency.

High-temperature cooking process like frying, baking, smoking, or drying can induce chemical transformations in conventional food ingredients, causing deteriorative modifications. These reactions, including hydrolytic, oxidative, and thermal changes, are a common occurrence and can result in alterations to the food's chemical composition. In this study, a combination of sucrose and histidine (Su-Hi) was transformed through a process of charring or pyrolysis. The GC-MS profiling study showed that when sucrose and histidine (Su-Hi) are exposed to high temperatures (≈240°C), they produce carbonyl and aromatic compounds including beta-D-Glucopyranose, 1,6-anhydro (10.11 %), 2-Butanone, 4,4-dimethoxy- (12.89 %), 2(1H)-Quinolinone-hydrazine (5.73%), Benzenamine (6.35%), 2,5-Pyrrolidinedione, 1-[(3,4-dimethylbenzoyl)oxy]- (5.82%), Benzene-(1-ethyl-1-propenyl) (5.62%), and 4-Pyridinamine-2,6-dimethyl (5.52%). The compounds mentioned have the ability to permeate the cell membrane and contribute to the development of cell death by necrosis in human immune cells. The evidence available suggests that a specific set of pyrolytic compounds may pose a risk to immune cells. This investigation reveals the complex relationship between high-temperature cooking-induced transformations, compound permeation inside the cells, and downstream cellular responses, emphasizing the significance of considering the broader health implications of food chemical contaminants.

There are four subtypes of adenosine receptors (ARs), named A1, A2A, A2B and A3, all of which are G protein-coupled receptors. The A2BAR, coupled to both Gαi and Gαq G proteins, is one of the several G-protein-coupled receptors that are expressed in a significantly higher level in some cancer tissues in comparison to adjacent normal tissues. There is growing evidence that the A2BAR plays an important role in tumor cell proliferation, angiogenesis, metastasis, and immune suppression. Thus, A2BAR antagonists are potentially novel attractive anticancer agents. Several antagonists targeting at the A2BAR are currently in clinical trials for various types of cancers. In this review, we first describe the signaling, agonists, and antagonists of the A2BAR. We further discuss the role of the A2BAR in the progression of various types cancers, and the rationale of using A2BAR antagonists in cancer therapy

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.

Syphilis continues to be a significant global health concern, and understanding the latest advancements in immunology and pharmacological treatment is crucial for effective disease management. This review article provides an in-depth exploration of these advancements, aiming to contribute to the growing body of knowledge on syphilis research. The epidemiology of syphilis sets the stage for this review, highlighting the persistent burden of the disease worldwide. Current trends and challenges in disease control are discussed, shedding light on the need for comprehensive prevention strategies and improved surveillance systems. The immunological aspects of syphilis are the focus of this review. The intricate interplay between the host immune response and the evasive strategies employed by Treponema pallidum, the causative agent of syphilis, are explored. These include the mechanisms of immune evasion, the role of adaptive and innate immunity, and the development of immune-mediated tissue damage. The article also highlights advancements in diagnostic methods, with emphasis on the importance of accurate and timely detection. From traditional serological tests to the emergence of novel molecular and point-of-care assays, these developments have significantly improved the efficiency and accuracy of syphilis diagnosis. In terms of pharmacological treatment, the review covers the current recommendations and emerging strategies for managing syphilis infections. The challenges posed by antimicrobial resistance are addressed, emphasizing the importance of appropriate treatment regimens and close monitoring of therapeutic efficacy. Looking to the future, this review highlights the potential of vaccine development as a preventive measure against syphilis. Promising vaccine candidates and ongoing research efforts are discussed, offering hope for an effective means of disease prevention. In conclusion, this comprehensive review explores the advancements in syphilis research, from the understanding of immunological complexities to the development of innovative treatment strategies. By collectively advancing our knowledge, we can strive towards better disease management and minimize the impact of syphilis on global public health.

Tributyltin (TBT) is an environmental contaminant present on all continents, including Antarctica, with a potent biocidal action. Its use began to be intensified during the 1970s, being effectively banned in 2003, but remaining in the environment to this day due to several factors that increase its half-life and misuse despite the bans. In addition to the endocrine disrupting effect of TBT, that may lead to imposex induction in some invertebrate species, there are several studies that demonstrated that TBT also has an immunotoxic effect. The immunotoxic effects that have been observed experimentally in vertebrates using in vitro and in vivo models involve different mechanisms, but mainly alterations in the expression and/or secretion of cytokines. In this review, we summarize and update the literature on the impacts of TBT on the immune system, as well as discuss what still needs to be done to fill the knowledge gaps regarding the impact of this endocrine disrupting-chemical on immune system homeostasis.

Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have been completed over the last two decades. We conducted a systematic review of safety and toxicity data associated with phage therapy in both animals and humans reported in English-language publications from 2008 – 2021. Overall, 69 publications met our eligibility criteria including 20 animal studies, 35 clinical case reports or case series, and 14 clinical trials. After summarizing safety and toxicity data from these publications, we discuss potential approaches to optimizing safety and toxicity monitoring with the therapeutic use of phage moving forward. In our systematic review of the literature, we found few, but no serious, adverse events associated with phage therapy. Comprehensive and standardized reporting of potential toxicities associated with phage therapy has generally been lacking in the published literature. Structured safety and tolerability endpoints are necessary when phages are administered as anti-infective therapeutics.

SARS-CoV-2 is a novel coronavirus that is the causative agent of Coronavirus infectious disease 2019 (COVD-19). As of the 17^th April 2020, it has infected 2 114 269 people resulting in 145 144 deaths. The timing, magnitude and longevity of humoral immunity is not yet understood for SARS-CoV-2. Nevertheless, understanding this is urgently required to inform the likely future dynamics of the pandemic, to guide strategies to allow relaxation of social distancing measures and to understand how to deploy limiting vaccine doses when they become available to achieve maximum impact. SARS-CoV-2 is the seventh human coronavirus to be described. Four human coronaviruses circulate seasonally and cause common colds. Two other coronaviruses, SARS and MERS, have crossed from animal sources into humans but have not become endemic. Here we review what is known about the human humoral immune response to epidemic SARS CoV and MERS CoV and to the seasonal, endemic coronaviruses. Then we summarize recent, mostly non-peer reviewed studies into SARS-CoV-2 serology and reinfection in humans and non-human primates and summarize current pressing research needs.

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.

Coronaviruses are a large family of diverse enveloped RNA viruses found in numerous animal species. They are well-known for their ability to cross species barriers and have been transmitted from bats or intermediate hosts to humans on several occasions. Four of the seven human coronaviruses (hCoVs) are responsible for approximately 20% of common colds (hCoV-229E, -NL63, -OC43, -HKU1). Two others (SARS-CoV-1 and MERS-CoV) cause severe and frequently lethal respiratory syndromes but have only spread to very limited extents in human populations. In contrast, SARS-CoV-2, while exhibiting intermediate pathogenicity, has a profound impact on public health due to its enormous spread. In this review, we discuss which initial features of the SARS-CoV-2 Spike protein and subsequent adaptations to the new human host may have helped this pathogen to cause the COVID-19 pandemic. Our focus is on host forces driving changes in the Spike protein and their consequences for virus infectivity, pathogenicity, immune evasion and resistance to preventive or therapeutic agents. In addition, we discuss the significance and perspectives of broad-spectrum therapeutics and vaccines.

Use of antibiotics and other chemicals to combat disease outbreaks have been a bottleneck for the sustainable growth of shrimp industry. Among various replacement proposed, organic acid (OA) and their salts (OS) are commonly used by farmers and feed millers. However, in free forms, their requirement is very high (2-3 kg/MT) as they tend to disassociate before reaching the hindgut. The dosage can be reduced by microencapsulation of the ingredients. In this study, a 63-day trial was conducted to assess the effects of OA and OS (COMP) microencapsulated (ENCAP) with fat (HF), fat + alginate (HA), wax esters – (WE), and HA and WE (HAWE) on performance, digestive enzyme, immune, and resistance to Vibrio parahaemolyticus. A positive control (PC, 200 g/kg fishmeal - FM) and a negative control (NC, 130 g/kg FM) diet were formulated. Eight other diets were formulated supplementing NC diet with microencapsulated OA (OAHF, OAHA, OAWE, OAHAWE) and OS (OSHF, OSHA, OSWE, OSHAWE). Among the ENCAPs, significant difference was observed in serum malondialdehyde (P = 0.026) where HF showed the lowest level (6.4 ±0.3 mmol/L). Significant interactions between COMP and ENCAP were observed in lipid deposition (P = 0.047), serum alkaline phosphatase and acid phosphatase (P < 0.0001), and hepatopancreatic and serum phenol oxidase (P < 0.0001). Despite no differences, 96-h mortality during pathogenic Vibrio parahaemolyticus challenge in all treatment diets (45% - 56%) was lower compared to the NC diets (63%). In conclusion, use of HF microencapsulated OA diets could provide improved performance and disease resistance that could contribute to the reduction of antibiotic use by the shrimp industry.

A wide variety of bioactive peptides have been identified in the central nervous system and several peripheral tissues in the ascidian Ciona intestinalis type A (Ciona robusta). However, hemocyte endocrine peptides have yet to be explored. Here, we report a novel 14-amino acid peptide, CiEMa, that is predominant in the granular hemocytes and unilocular refractile granulocytes of Ciona. RNA-seq and qRT-PCR revealed the high CiEma expression in the adult pharynx and stomach. Immunohistochemistry further revealed the highly concentrated CiEMa in the hemolymph of the pharynx and epithelial cells of the stomach, suggesting biological roles in the immune response. Notably, bacterial lipopolysaccharide stimulation of isolated hemocytes for 1-4 hours resulted in increased CiEMa secretion. Furthermore, CiEMa-stimulated pharynx exhibited mRNA upregulation of the growth factor (Fgf3/7/10/22), vanadium binding proteins (CiVanabin1 and CiVanabin3), and forkhead and homeobox transcription factors (Foxl2, Hox3, and Dbx), but not antimicrobial peptides (CrPap-a and CrMam-a) or immune-related genes (Tgfbtun3, Tnfa, and Il17-2). Collectively, these results suggest that CiEMa plays roles in signal transduction involving tissue development or repair in the immune response, rather than in the direct regulation of immune-response genes. The present study identified a novel Ciona hemocyte peptide, CiEMa, providing insights into the molecular and functional diversity of the immune response in chordates.

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.

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.

This article describes a novel topical composition constituted by gamma-amino butyric acid (GABA) and microbial chondroitin sulfate. This composition, formulated by the author and manufactured in a certified facility in the United States of America, exhibits potential for non-invasive intervention in anxiety management, sleep quality enhancement, and promotion of brain-related functions like meditation and nonlocal consciousness. The core component comprises GABA, a key inhibitory neurotransmitter within the central nervous system, complexed with a suitable carrier molecule, microbial chondroitin sulfate. This complexation aims to enhance transdermal absorption and optimize delivery of GABA to target tissues. The proposed mechanism of action involves modulation of GABAergic signal transduction pathways. Application of the topical composition allows GABA penetration into the skin and potentially deeper tissues, where it interacts with GABA receptors. This interaction leads to mental calmness and relaxation as assessed by electroencephalography. The influence of GABAergic signaling on brain circuits demonstrated in this article, when associated with meditation and nonlocal consciousness, suggests potential for the composition to support these practices. The advantage of such an approach consists in avoiding the potential systemic side effects associated with oral or injectable administration of GABA, anxiolytics or hypnotics. Furthermore, the combination of GABA and microbial chondroitin sulfate may offer synergistic benefits, potentially enhancing the overall biological effects. In conclusion, this article presents a novel topical approach for managing anxiety, enhancing sleep quality, and potentially facilitating meditation and nonlocal consciousness through modulation of GABAergic signaling pathways. While further research is necessary, the potential for a non-invasive and potentially side-effect-free intervention in these areas is promising.

Low-grade glioma (LGG) is a highly aggressive disease in the skull. On the other hand, anoikis, a specific form of cell death induced by the loss of cell contact with the extracellular matrix, plays a key role in cancer metastasis. In this study，anoikis-related genes (ANRGs) were used to identify LGG subtypes and to construct a prognostic model for LGG patients. In addition, we explored the immune microenvironment and enrichment pathways between different subtypes. We constructed an anoikis-related gene signature using the TCGA cohort and investigated the differences in clinical features, mutational landscape, immune cell infiltration, etc. between different risk groups. Kaplan-Meier analysis showed that the characteristics of ANRGs in the high-risk group were associated with poor prognosis in LGG patients. The risk score was identified as an independent prognostic factor. The high-risk group had higher immune cell infiltration, tumor mutation load, immune checkpoint gene expression, and ICB treatment response. Functional analysis showed that these high- and low-risk groups had different immune statuses and drug sensitivity. Risk scores were used together with LGG clinicopathological features to construct a nomogram, and DCA analysis showed that the model could enable patients to benefit from clinical treatment strategies.

Studies report variable effects of sex hormones on serious diseases. Severe disease and mortality rates in COVID-19 show marked gender differences that may be related to sex hormones. Sex hormones regulate the expression of the viral receptors ACE2 and TMPRSS2, which affect the extent of viral infection and consequently cause variable outcomes. In addition, sex hormones have complex regulatory mechanisms that affect the immune response to viruses. These hormones also affect metabolism through obesity, and severe disease can result from complications such as thrombosis. This review presents the latest research on the regulatory functions of hormones in viral receptors, immune responses, complications as well as their role in COVID-19 progression. It also discusses the therapeutical possibilities of these hormones by reviewing the recent findings of clinical and assay studies.

(1) Background: We comprehensively evaluated the expression of therapeutically targetable immune checkpoint molecules on celiac disease. We have focused on the alteration of the CD200/CD200R pathway and Elafin expression in celiac disease and discussed their roles in regulating the immune response. There are limited data related to the expression or function of these molecules in celiac disease. This finding could significantly contribute to the understanding of the clinical manifestation of celiac disease; (2) Methods: CD200, CD200R and Elafin distribution was determined by ELISA and immunohistochemistry analyses in serum and biopsies of CD patients. Analyses of Th1 and Th17 cytokines were determined. PCR amplification of a fragment of the PI3 gene was carried out using genomic DNA isolated from whole blood samples of the study subjects. Different aliquots of the PCR reaction product were subjected to RFLP analysis for SNP genotyping and detection; (3) Results: We characterized the expression and function of the CD200–CD200R axis and PI3 in celiac disease. A significantly higher level of soluble CD200, CD200R and lower expression of PI3 in serum of CD patients was observed compared to healthy controls. Consistent with our results, CD200 expression is regulated by IFN-gamma. Interaction of CD200/CD200R leads to production of type Th1 and Th17 cytokines. Regarding the PI3 genotype, the CT genotype proportion SNP rs1733103 and the GG genotype SNP rs41282752, were predominant in CD patients. SNP rs1733103 showed a significant association between the SNP variables and CD; (4) Conclusions: In celiac disease the immune checkpoint is compromised or dysregulated, which can contribute to inflammation and the autoimmunity process. The study of these checkpoint points will led to the development of targeted therapies aimed at restoring immunological balance in CD. Specific coding regions of the PI3 gene splice variants predispose the Elafin protein, both at the transcriptional and post-translational levels, to modify its expression and function, resulting in reduced differential functional protein levels in patients with active celiac disease.

Coronavirus disease 2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To contain the virus, numerous preventive measures have been taken including isolation of patients, careful infection control, social distancing, and taking vaccine. So far, new confirmed and death cases are still increasing. SARS-CoV-2 invades cells by using the angiotensin converting enzyme 2 (ACE2). ACE2 is an essential enzyme of the renin-angiotensin system (RAS) which converts angiotensin II (Ang II) to angiotensin (1-7). ACE2 is expressed in different organs, including lung, heart, and kidney. A high number of COVID-19 patients developed kidney injury has been reported. Renal impairment and acute injury are associated with mortality of COVID-19, which is 14-16 times higher than other general patients. Acute Kidney Injury has been occured in 2.9 up to 43% of intensive care unit patients. The increasing evidence show that the components of RAS can activate the complement cascade, and cytokines production. Kidney injury caused by SARS-CoV-2 is related mainly to systemic and local inflammation. Moreover, the uncontrolled immune responses mediated by SARS-CoV-2 including hypercytokinaemia, secondary hemophagocytic lymphohistiocytosis, antibody dependent enhancement, complement system, and phagocytic cells activation can contribute in the virus pathogenesis leading to associated renal dysfunction. However, the role and crosstalk between of RAS components and immune response in mediating kidney injury remain undefined. In this review, we focus on the recent studies to provide the pathogenesis of SARS-CoV-2 interacting with RAS and immune responses to mediate kidney injury.

Classic Hodgkin lymphoma (cHL) is characterized by a few tumor cells surrounded by a protective, immunosuppressive tumor microenvironment composed of normal cells that are an active part of the disease. Hodgkin and Reed-Sternberg (HRS) cells evade the immune system through a variety of different mechanisms. They are invisible to antitumor effector T cells and natural killer cells and promote T cell exhaustion. Using cytokines and extracellular vesicles, they recruit normal cells, induce their proliferation, and “educate” (i.e., reprogram) them to become immunosuppressive and protumorigenic. Therefore, alternative treatment strategies, targeting not only tumor cells but also the tumor microenvironment, are being developed. Here we summarize current knowledge on the ability of HRS cells to build their microenvironment and to educate normal cells to become protective or immunosuppressive. We also describe therapeutic strategies to counteract formation of the tumor microenvironment and related processes leading to T cell exhaustion and repolarization of immunosuppressive tumor-associated macrophages.

The comprehensive anabolic effects of insulin throughout the body, in addition to the control of glycemia, also include ensuring lipid homeostasis and anti-inflammatory modulation, especially in adipose tissue (AT). The prevalence of obesity, defined as a body mass index (BMI) ≥ 30 kg/m2, has been increasing worldwide on a pandemic scale with accompanying syndemic health problems, including glucose intolerance, insulin resistance (IR) and diabetes. Impaired tissue sensitivity to insulin or IR paradoxically leads to diseases with an inflammatory component despite hyperinsulinemia. Therefore, an excess of visceral AT in obesity initiates chronic low-grade inflammatory conditions that interfere with insulin signaling via insulin receptor (INSR). Moreover, in response to IR, hyperglycemia itself stimulates a primarily defensive inflammatory response associated with the subsequent release of numerous inflammatory cytokines and a real threat of organ function deterioration. In this review, all components of this vicious cycle are characterized with particular emphasis on the interplay between insulin signaling and both the innate and adaptive immune responses related to obesity. Increased visceral AT accumulation in obesity should be considered the main environmental factor responsible for the disruption in the epigenetic regulatory mechanisms in the immune system, resulting in autoimmunity and inflammation.

The traditional herbal medicine, Hochu-ekki-to, has been shown to have preventive effects on viral infection and stress. This study aimed to evaluate the clinical effects of Hochu-ekki-to on two stress-related rat models of polycystic ovarian syndrome. Female Sprague-Dawley rats were divided into control and treatment groups, the latter of which were subjected to stress induced by exposure to adrenocorticotropic hormone (ACTH) or cold temperatures. After these stress inductions, rats were orally treated with dissolved Hochu-ekki-to once per day for 7 days. Rats subjected to the two different stressors exhibited upregulation of steroid hormone receptors (in ovaries) and reproductive hormones (in blood), and consequent stimulation of abnormal follicle development accompanied by elevation of Hsp 90 expression (in ovaries). Treatment with Hochu-ekki-to for 7 days after stress induction increased immune functions, reduced the stress-induced activation of Hsp 90, and normalized the levels of the tested steroid hormone receptors and reproductive hormones. Our findings suggest that stress stimulations may promote the activation of Hsp 90 via the dysregulation of steroid hormone receptors and reproductive hormones, but that post-stress treatment with Hochu-ekki-to improves reproductive and immune functions in the ovaries of stressed rats.

Silk is a globally renowned abundant biopolymer obtained from various sources of the Lepidoptera family, among which the most commonly used and researched are spider silk and silk worm silk. All varieties of silk have beneficial characteristics such as high tensile strength, biocompatibility, producing a reduced immune response in a biological system, biodegradability, and the ability to withstand environmental stresses as well. These features make silk suitable for a number of applications as a biomaterial. The vast potential of silk and its proteins in cosmetics, oncology, tissue engineering, TOC screenings, for preserving food, cosmetic product as a silk gel and bioremediation makes it a well-sought biopolymer among researchers. Experiments over the years have revealed that biomaterials constituting silk are very potent but are yet to be scaled up for commercial uses, but the various advantageous properties of silk biomaterial far overshadows the impeding problems of production.

Viral respiratory infections are recognized risk factors for the loss of control of allergic asthma and the induction of exacerbations, both in adults and children. Severe asthma is more susceptible to virus-induced asthma exacerbations, especially in the presence of high IgE levels. In the course of immune responses to viruses, an initial activation of innate immunity typically occurs and the production of type I and III interferons is essential in the control of viral spread. However, the Th2 inflammatory environment still appears to be protective against viral infections in general and in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections as well. As for now, literature data, although very limited and preliminary, show that severe asthma patients treated with biologics don’t have an increased risk of SARS-CoV-2 infection or progression to severe forms compared to the non-asthmatic population. Omalizumab, an anti-IgE monoclonal antibody, exerts a profound cellular effect, which is able to stabilize the effector cells becoming much more efficient from the point of view of innate immunity in contrasting respiratory viral infections. In addition to the antiviral effect, clinical efficacy and safety of this biological allows a great improvement in the management of asthma.

Cancer-associated cachexia (CAC) is a debilitating condition marked by muscle and fat loss, unresponsive to nutritional support, and contributes significantly to morbidity and mortality in patients with cancer. Immune dysfunction, driven by cytokine imbalance, contributes to CAC progression. This review explores the potential relationship between CAC and anti-cancer immune response in pre-clinical and clinical studies. Pre-clinical studies showcase the involvement of cytokines like IL-1β, IL-6, IL-8, IFN-γ, TNF-α, and TGF-β, in CAC. IL-6 and TNF-α, interacting with muscle and adipose tissues, induce wasting through JAK/STAT and NF-κB pathways. Myeloid-derived suppressor cells (MDSCs) exacerbate CAC by promoting inflammation. Clinical studies confirm elevated pro-inflammatory cytokines (IL-6, IL-8, TNFα) and immune markers like neutrophil-to-lymphocyte ratio (NLR) in patients with CAC. Thus, immunomodulatory mechanisms involved in CAC may impact the anti-neoplastic immune response. Inhibiting CAC mechanisms could enhance anti-cancer therapies, notably immunotherapy. R-ketorolac, a new immunomodulator, reversed weight loss and increased survival in mice. Combining these agents with immunotherapy may benefit patients with cancer experiencing CAC. Further research is vital to understand the complex interplay between tumor-induced immune dysregulation and CAC during immunotherapy.

The role of innate immunity in neutralization of viral infections (including COVID-19) and forming long-lasting and specific immune memory is considered. It is assumed that antiviral protection is generated by the mechanism of RNA interference (RNAi) and is based on the presence of specific viral patterns in the DNA library of the host cells.

Osteoimmunology was coined about twenty years ago to identify a strict cross talk between bone niche and immune system both in physiological and pathological activities, including cancer. Several molecules are involved in the complex interaction between bone niche, immune and cancer cells. The Receptor Activator ok NF-kB (RANK)/RANK Ligand (RANKL/Osteoprotegerin (OPG) pathway plays a crucial role in bone cells/cancer interactions with subsequently immune system control failure, bone destruction, inhibition of effect and metastasis outcome. The bidirectional cross talk between bone and immune system could became a potential target for anticancer drugs. Several studies evidenced a direct anticancer role with improved survival of bone-targeted therapies such as bisphosphonates and RANKL antagonist Denosumab. Conversely, initial data evidenced a possible anti-bone resorption effect of systemic anticancer drugs through and immunomodulation activity, i.e. new generation antiandrogens (Abiraterone) in prostate cancer. All data could open a future rationale of combined bone, immunologic and targeted therapies in cancer treatment.

Serological human birth cohort studies have identified maternal infection during pregnancy as a risk factor for development of disorders such as Autism Spectrum Disorder and schizophrenia in offspring. Similarly, in experiments using animal models, maternal immune activation (MIA) has been shown to alter neuroanatomical and behavioral development in offspring. This study employs magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) in conjunction with behavioral assays to refine our understanding of the impact of MIA on neurobiological development in exposed animals. On gestational day nine, pregnant dams were injected with either polyinosinic:polycytidylic acid (POL) to induce MIA or saline (SAL) as a control. Whole-brain MRI, localized proton MRS, and behavioral tests (open field, three chambered social approach, and prepulse inhibition) were acquired at two timepoints, during adolescence (postnatal day [PND] 35) and adulthood (PND 60). Whole-brain voxel-wise volumetric analyses revealed that MIA offspring exhibited altered volume in the hippocampus and caudate putamen (CPu) between adolescence and early adulthood. MRS data were assessed at each timepoint separately; MIA offspring during early adulthood but not adolescence exhibited trending reductions in γ-aminobutyrate (GABA) (p = 0.06) and myo-inositol (Ins) (p = 0.08) compared to saline controls. However, these metabolite differences did not reach levels of significance, even before multiple comparison corrections. Open field testing revealed that during adolescence, MIA offspring displayed a more anxious phenotype than controls wherein they spent less time in the anxiogenic center zone of the open field arena (p < 0.007), but this difference normalized by adulthood. There were no significant differences in sociability preference, novelty preference, or prepulse inhibition comparing the groups. Results suggest that early gestational exposure to MIA results in subtle neuroanatomical changes in the trajectories of development, trending behavioral changes in adolescent offspring, and slight neurochemical changes in young adult offspring. Maternal infection alone may not be enough; additional genetic or environmental risk factors may be required to elicit the more typical symptoms of neuropsychiatric disorders.

Background: First episode psychosis (FEP), schizophrenia and affective disorders are accompanied by activation of the immune inflammatory response system (IRS). The compensatory immune-regulatory reflex system (CIRS) is a regulatory immune response that is induced by the IRS but exerts negative feedback through, for example, increased levels of anti-inflammatory cytokines such as IL-4, IL-13 and IL-10. Different phenotypes of schizophrenia may exhibit distinct IRS and CIRS immune profiles.Aims: This study aims to examine the IRS and CIRS components, including macrophagic M1, T-helper (Th)-1, Th-2, Th-17 and T-regulatory (Treg) phenotypes, in antipsychotic-naïve FEP patients before and after risperidone treatment.Methods: We included 31 antipsychotic-naïve FEP patients who had measurements of IRS and CIRS biomarkers before and after treatment with risperidone for 10 weeks, and 22 healthy controls.Results: Antipsychotic-naive FEP patients showed interrelated increments in M1, Th-1, Th-2, Th-17 and Treg phenotypes and a relatively greater IRS response (especially granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-6 and IL-12) as compared with the CIRS response (IL-4, IL-13, IL-5 and IL-10). Inflammatory markers, especially IL-6 and IL-8, were significantly correlated with negative, psychotic, affective and excitation symptom dimensions. Treatment with risperidone significantly suppressed the IRS and CIRS. Baseline levels of CIRS biomarkers, especially higher soluble tumor necrosis factor receptor-1 and IL-10 predicted clinical improvement during treatment.Discussion: Our findings indicate that FEP is characterized by robust IRS (M1 + Th-1 + Th-17) and CIRS responses, suggesting that monocytes, macrophages, Th-1, Th-2, Th-17 and Treg cells are activated. The findings indicate that a) FEP patients are prone to the detrimental effects of M1, Th-1, Th-17 and Th-2 cells, which may contribute to long-lasting abnormalities in brain circuitry; and b) in FEP, the CIRS may contribute to recovery from the acute phase of illness. Enhancing the CIRS is a new drug target to treat FEP.

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.

The 2019 COVID-19 pandemic caused by SARS-CoV-2 has resulted in many fatalities worldwide. Despite various types of supportive care, mortality rates for patients with comorbidities remain high. To explore alternative treatment options, interferons (IFNs) have emerged as promising therapeutic drugs for SARS-CoV-2. This review aims to investigate the potential of IFNs as a drug with details on their mechanisms of action, and available data on their use with ongoing clinical trials, results, potential limitations, and challenges. Recently published research articles, which were systematically searched through online databases, have been selected and found that IFNs have colossal potential in treating SARS-CoV-2 infection by modulating the host's immune response and inhibiting viral replication and decreasing the severity of disease and hospitalization (p = 0.03, ±0.05) and (p = 0.04, ±0.05) respectively. However, due to less available data, more controlled and randomized trials are needed to confirm the efficacy and safety of IFN therapy. The optimal dosing and duration of IFN therapy also remain to be determined. Although further research is needed the wait for ongoing clinical trial results under investigation is also important for a better understanding of IFN therapy.

In the first year of its appearance, the 2019 coronavirus disease (COVID-19) has affected more than 150 million individuals and killed 3 million people worldwide. The pandemic has also triggered numerous global initiatives to tackle the newly emerging disease, including the development of SARS-CoV-2 vaccines and the attempt to discover potential pharmacological therapies. Nonetheless, despite the success of SARS-CoV-2 vaccines development, COVID-19 therapy remains challenging. Several repurposed drugs that were documented to be useful in small clinical trials have been shown to be ineffective in larger studies. Additionally, the pathophysiology of SARS-CoV-2 infection displayed the predominance of hyperinflammation and immune dysregulation in inducing multiorgan damage. Therefore, the potential benefits of both immune modulation and suppression in COVID-19 have been extensively discussed. Here, we reviewed the roles of immunomodulation as potential COVID-19 pharmacological modalities based on the existing data and proposed several new immunologic targets to be tested in the foreseeable future.

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.

In the last two decades many detailed full transcriptomic studies on complex biological samples have been published and included in large gene expression repositories. These studies primarily provide bulk expression signal for each sample, including multiple cell-types mixed within the global signal. The cellular heterogeneity in these mixtures does not allow the activity of specific genes in specific cell types to be identified. Therefore, inferring relative cellular composition is a very powerful tool to achieve a more accurate molecular profiling of complex biological samples. In recent decades, computational techniques have been developed to solve this problem by applying cell deconvolution methods, designed to decompose cell mixtures into their cellular components and calculate the relative proportions of these elements. Some of them, only calculate the cell proportions (supervised methods), while other deconvolution algorithms can also identify the gene signatures specific for each cell type (unsupervised methods). In these work, five deconvolution methods (CIBERSORT, FARDEEP, DECONICA, LINSEED and ABIS) were implemented and used to analyze blood and immune cells, and also cancer cells, in complex mixture samples (using three bulk expression datasets). Our study provides three analytical tools (corrplots, cell-signature plots and bar-mixture plots) that allow a thorough comparative analysis of the cell mixture data. The work indicates that CIBERSORT is a robust method optimized for the identification of immune cell-types, but not as efficient in the identification of cancer cells. We also observed that LINSEED is a very powerful unsupervised method that provides precise and specific gene signatures for each of the five main immune cell-types analyzed: neutrophils and monocytes (in the myeloid lineage), B-cells, NK cells and T-cells (in the lymphoid lineage).

Antibiotics have been used in various fields such as livestock farm and fish farm as well as hospital in order to treat diseases caused by bacteria. However, the antibiotics that are not completely decomposed, but remains as residue and discharge to aquatic environment, can cause an imbalance in the gut flora of host, as well as regulate abnormal host gene regulatory system. We investigated the effects of chronic exposure with the low concentrations of erythromycin and ampicillin on gut microbiome and immune and stress-related gene expression using Korea native ricefish (Oryzias latipes). As a result of microbiome analysis, the proportion of Proteobacteria was increased in the ricefish when exposed to erythromycin and ampicillin chronically, whereas the proportion of other bacterial phyla decreased. In addition, the immune and stress-related genes were significantly influenced in the ricefish under the chronic antibiotics exposure. These results show that the internal microbial flora and the host gene expression are susceptible even in the low concentration of chronic antibiotic existing environments. This study provides the importance of the appropriate use of antibiotics dose to maintain the sustainable and healthy aquaculture industry and water ecosystem.

Abstract Background The number of immune-related endocrine dysfunctions (irEDs) has concurrently increased with the widespread use of immunotherapy in clinical practice and further expansion of the approved indications for immune checkpoint inhibitor (ICI) combinations using different modalities of anti-cancer treatment. Method A retrospective analysis was conducted on consecutive patients >18 years of age with advanced solid malignancies who had received at least one dose of anti-programmed cell death protein 1 (anti-PD-1) and/or anti-CTLA4 antibodies between January 2014 and December 2019 at a Hong Kong university hospital. Patients were reviewed for up to two months after the last administration of an ICI. The types, onset times and grades of irEDs, including hypothyroidism, hyperthyroidism, adrenal insufficiency and immune-related diabetes mellitus, were recorded. Factors associated with irEDs were identified using multivariate analysis. Result A total of 953 patients (male: 603, 64.0%; median age: 62.0 years) received ICIs during the study period. Of these, 580 patients (60.9%) used ICI-alone, 132 (13.9%) used dual-ICI, 187 (19.6%) used an ICI combined with chemotherapy (chemo+ICI), and 54 (5.70%) used immunotherapy with a targeted agent (targeted+ICI). A significantly higher proportion of patients using targeted+ICI had irEDs and hypothyroidism; in contrast, a higher proportion of patients using dual-ICI had adrenal insufficiency. There was no significant difference in the incidence of irED between the younger (<65 years) and older (>65 years) patients. Using logistic regression, only treatment type was significantly associated with irEDs. Notably, older patients had a higher risk of having immune-related diabetes mellitus. Conclusions This large, real-world cohort demonstrates that combining ICI with targeted therapy has a higher risk of overall irED and hypothyroidism. Immunotherapy is safe and well-tolerated regardless of age, but close monitoring of fasting glucose is needed in older populations.

Keywords: Cell-free DNA, sepsis, oxidative stress, immunoredox modulation, cecal ligation and puncture, toll-like receptor

This study investigates the expression and prognostic value of TRIM6 in gliomas, the most prevalent primary brain and spinal cord tumors. Our results show that TRIM6 is predominantly overexpressed in glioma tissues and is associated with reduced overall survival, disease-specific survival, and progression-free interval. Furthermore, TRIM6 expression is correlated with WHO grade and primary treatment outcomes. Functional analysis indicates that interactions between cytokines and their receptors play a critical role in the prognosis of glioma patients. A protein-protein interaction network reveals 10 hub genes closely linked to cytokine-cytokine receptor interaction. In vitro experiments demonstrate that silencing TRIM6 impairs the proliferation, invasion, and migration of glioma cells, while overexpressing TRIM6 enhances these abilities. Additionally, TRIM6 expression is positively associated with the abundance of innate immune cells and negatively associated with the abundance of adaptive immune cells. In summary, TRIM6 is significantly upregulated in gliomas and linked to poor prognosis, making it a potential diagnostic and prognostic biomarker. TRIM6 plays a crucial role in promoting cell viability, clonogenic potential, migration, and invasion in glioma cells. It may regulate glioma progression by modulating cytokine-cytokine receptor interaction, leading to an inflammatory response and an imbalance in immunomodulation, thereby representing a potential therapeutic target.

Bovine respiratory disease is still a major concern in feedlots and has major economic impact. Another consequence of respiratory infections is the use of antimicrobial molecules to control bacterial pathogens. This can participate to the emergence and shedding of antimicrobial re-sistance that can threaten animal as well as human health. Appeasing pheromones with their capacity to reduce stress and thus their ability to preserve the functions of the immune system have been proposed to reduce the use of antimicrobial substances. In the current report we as-sessed the effect of appeasing pheromone administration on bovine health and performance during the fattening period. Zootechnical and health parameters as well as whole blood immune transcript expressions were measured over weeks in young bulls to determine the effect of the pheromone. We observed a reduction of clinical signs at day 30 in young bulls who received the pheromone and a higher expression of interleukin 8 transcripts in this group than in the control group. Our results are in line with previous reports in bovine and other mammals and ask for further studies to shed more light on the beneficial impact of appeasing pheromones and to de-cipher their exact mechanisms of action.

Triple negative breast cancer (TNBC) is an aggressive subtype of the disease with poor clinical outcomes and limited therapeutic options. Immune checkpoint blockade (CP) has surged to the forefront of cancer therapies with widespread clinical success in a variety of cancer types. However, the percentage of TNBC patients that benefit from CP as a monotherapy is low and clinical trials have shown the need for combined therapeutic modalities. Specifically, there has been interest in combining CP therapy with radiation therapy where clinical studies primarily with external beam have suggested their therapeutic synergy, contributing to the development of anti-tumor immunity. Here, we have developed a therapeutic platform combining radionuclide therapy (RT) and immunotherapy utilizing a radiolabelled biomolecule and CP in an E0771 murine TNBC tumor model. Survival studies show that while neither monotherapy is able to improve therapeutic outcomes, the combination of RT + CP extended overall survival. Histologic analysis showed that RT + CP increased necrotic tissue within the tumor and decreased levels of F4/80+ macrophages. Flow cytometry analysis of the peripheral blood also showed that RT + CP suppressed macrophages and myeloid-derived suppressive cells, both of which actively contribute to immune escape and tumor relapse.

Immune complexes (ICs) made of antibody-bound antigens exhibit immunomodulatory activities exploitable in a vaccination strategy to optimize vaccine efficacy. The modulatory effects of ICs are typically attributed to the Fc fragments of the antibody components, which engage Fc receptors, complement and complement receptors on various immune cells. These Fc-mediated functions facilitate the critical interplay between innate and adaptive immune systems to impact the quality and quantity of the elicited adaptive responses. In addition to the Fc contribution, the Fab fragment also plays an immunoregulation role. The antigen-binding domains of the Fab fragment can bind their specific epitopes at high affinity to sterically occlude these antigenic sites from recognition by other antibodies. Moreover, the Fab-mediated binding have been demonstrated to induce allosteric alterations at nearby or distant antigenic sites. In this review article, we survey published studies to illuminate how the immunomodulatory functions of ICs have been investigated or utilized in a vaccination strategy to fight against an array of infectious pathogens, culminating with IC vaccine designs aimed at preventing HIV-1 infection. In particular, we highlight IC vaccine candidates that exploit Fab-mediated steric and allosteric effects to direct antibody responses away or toward the V1V2 domain, the V3 loop, and other antigenic sites on the HIV-1 envelope gp120 glycoprotein. Like other HIV-1 vaccine approaches, the path for IC-based vaccines to reach the clinic faces major hurdles yet to be overcome; however, investigations into this vaccine strategy have provided insights into the multifaceted activities of antibodies beyond their conventional roles in the host defense against HIV-1 and other microbial pathogens.

Background: Migraine is the commonest complex neurological disorder affecting over a billion people worldwide. Neuroinflammation has long been considered to play an important role in the pathophysiology of migraine. The main aim of this single-centre, proof of concept, retrospective study was to determine the possible clinical utility of systemic immune-inflammatory response in migraine with and without aura in a hospitalized cohort. We measured the role of universally available serial white blood cell counts to calculate the serial systemic immune-inflammatory indices (SSIIi) and the potential association between aura and SSIIi changes in a cohort of migraine patients admitted to tertiary care center in Melbourne Australia.Main body: We retrospectively assessed patients' medical records presenting to Western Health with migraine over an 18 month period. Patients were classified as either having migraine with aura (MA) or without aura (MO) based on ICHD-3 criteria. Baseline demographics and brain imaging findings in each group were evaluated. Patients with two sets of white blood cell counts during the admission were included in the analysis. SSIIi were calculated as, neutrophil counts x platelet counts / lymphocyte counts. Correlation between SSIIi and MA and MO were assessed using SPSS27.Conclusion: SSIIi were elevated in MA and MO followed by a downward trend in both groups, with MA being statistically significant. This proof-of-concept study suggests the potential role of systemic inflammation in pathobiology of migraine. SSIIi appear to show clinical utility. Further comprehensive ,controlled , multicenter studies are required to clarify the exact role of systemic inflammatory response and the clinical utility of SSIIi in a subset of migraine in the Emergency department setting.

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.

Cisplatin-based chemotherapy has long been viewed as the first-line chemotherapy for advanced and metastatic urothelial carcinoma (UC). However, many patients with UC have been classified as “cisplatin-ineligible patient”, which requires alternative chemotherapy due to their poor responses. In fact, vast majority of those who initially responded to cisplatin-based chemotherapy eventually progressed. Understanding of UC tumor immunology provided an immunopathogenic bases for immune checkpoint inhibitors, targeting PD-1 and CTLA-4, to treat cisplatin ineligible metastatic UC and patients with platinum-refractory metastatic UC. In 2020, data from the trail further showed that PD-L1 inhibitors benefit prolonged survival and progression-free survival as maintenance therapy. Besides immune-targeting therapies, manipulation of tumor microenvironment via metabolic pathways alternation, such as inhibiting tumor glycolysis, lactate accumulation and exogenous glutamine uptake, has been investigated in the past few years. In this comprehensive review, we started by introducing traditional chemotherapy of UC, and summarized current evidences supporting the use of immune checkpoint inhibitors and highlighted ongoing clinical trials. Lastly, we reviewed the tumor metabolic characteristic and the anti-tumor treatments targeting metabolic pathways.

This research is aimed to investigate the effects of Lactoplantibacillus plantarum (L. plantarum) on growth performance, oxidation resistance, immunity, as well as cecal microbiota in broilers. This work classed three hundred and sixty 1-day-old broilers as three groups randomly, including control (CON, basal diet), antibiotic (ANT, 75 mg kg-1 chlortetracycline added into basal diet), or probiotic group (LP, 5×108 CFU kg-1 Lactoplantibacillus plantarum HJLP-1 contained within basal diet). Animal were then fed for 42 days, and each group consisted of 15 broilers for 8 replicates. Compared with CON, L. plantarum supplementation significantly improved the average weight daily gain (AWDG) (P < 0.05) while reducing feed-to-gain ratio over the entire supplemental period (P < 0.05). Birds fed L. plantarum had marked lower serum ammonia and xanthine oxidase levels (P < 0.05) than those in ANT and CON. Significant improvements (P < 0.05) of superoxide dismutase, catalase, serum IgM and IgY contents in broilers fed L. plantarum were also observed when compared those in CON and ANT groups. Both L. plantarum and antibiotics decreased the pro-inflammatory factor IL-1β level significantly (P < 0.05), while only L. plantarum promoted the anti-inflammatory factor IL-10 level dramatically in the serum (P < 0.05) compared with CON. The L. plantarum dramatically (P < 0.05) increased acetic acid and butyric acid concentrations in the cecal contents，when compared to those in CON and ANT. Among the differences revealed by 16S rRNA analysis, L. plantarum markedly improved the community richness of cecal microbiota. At the genus level, butyric acid-producing bacteria Ruminococcus and Lachnospiraceae were found in higher relative abundance in samples of L. plantarum treated birds. In conclusion, dietary L. plantarum supplementation promoted the growth and health of broilers, likely by inducing a shift in broiler gut microbiota toward short-chain fatty acid (SCFA)-producing bacteria. Therefore, L. plantarum has tremendous potential as an alternative for antibiotics in poultry breeding.

Sporothrix brasiliensis is the most pathogenic species, responsible for the Brazilian cat-transmitted sporotrichosis hyperendemics. In this scenario, investigation of pathogen-host interaction can provide relevant information for future treatment strategies. To this end, the invertebrate Galleria mellonella has proven to be a suitable alternative to evaluate the virulence of pathogenic fungi since the insect immune system is similar to the mammalian innate immune response. The aim of this work was to investigate phenotypic and molecular aspects of the immune response of G. mellonella throughout the S. brasiliensis infection. Hemocyte density and the evolution of the fungal load were evaluated. In parallel, RT- qPCR expression analysis of genes encoding antimicrobial peptides (Gallerimycin and Galiomycin) and stress management genes (C7 Contig 15362 and C8 Contig 1910) was conducted. Fungal load and hemocyte densities were proportionally increasing simultaneously to the deleterious morphological events and larvae mortality. Gallerimycin, C7 Contig 15362, and C8 Contig 19101 genes were positively regulated (p&lt;0.05) at distinct moments of S. brasiliensis infection, characterizing a time-dependent and alternately modulated profile. Galiomycin gene expression remained unchanged. Our results contribute to the future proposal of potential alternative pathways to treat and, consequently, control S. brasiliensis zoonosis, a major public Health in Latin America.

Hepatitis B Virus (HBV) is a challenge for global health services, affecting millions and leading hundreds to end-stage liver disease each year. This comprehensive review explores the interactions between HBV and the host, examining their impact on clinical outcomes. HBV infection encompasses a spectrum of severity, ranging from acute hepatitis B to chronic hepatitis B, which can potentially progress to cirrhosis and hepatocellular carcinoma (HCC). Occult hepatitis B infection (OBI), characterized by low HBV DNA levels in hepatitis B surface antigen-negative individuals, can reactivate and cause acute hepatitis B. The identification of diverse HBV genotypes reveals distinct geographical distributions and associations with clinical outcomes. Moreover, single nucleotide polymorphisms (SNPs) within the host genome have been linked to several clinical outcomes, including cirrhosis, HCC, OBI, hepatitis B reactivation, and spontaneous clearance. The immune response plays a key role in controlling HBV infection by eliminating infected cells and neutralizing HBV in the bloodstream. Furthermore, HBV can modulate host metabolic pathways involved in glucose and lipid metabolism and bile acid absorption, further influencing disease progression. HBV clinical outcomes correlate with three levels of viral adaptation. In conclusion, the clinical outcomes of HBV infection could result from complex immune and metabolic interactions between the host and HBV. These outcomes can vary among populations and are influenced by HBV genotypes, host genetics, environmental factors, and lifestyle. Understanding the degrees of HBV adaptation is essential for developing region-specific control and prevention measures.

In several mammalian species including humans, complex stimulation patterns such as cognitive challenge and physical exercise lead to improvements in organ function, organism health and performance, as well as possibly longer lifespans. The hypothesis is presented here that activity-dependent transcriptional programs, induced by these environmental stimuli, temporarily and lightly de-differentiate somatic cells such as neurons and muscle cells into a state that resembles functionally younger cells to allow cellular remodeling and adaptation of the organism to environmental change. This cellular adaptation program targets several process classes that are heavily implicated in aging, such as mitochondrial metabolism, cell-cell communication, intracellular signaling and epigenetic information processing and leads to functional improvements in these areas. I reverse engineer these activity-dependent gene programs, identify critical molecular nexus points such as CREB, MEF2 and cFos and speculate as to how one might leverage them to prevent and attenuate human aging-related decline of body function, enhance human performance and restore more youthful levels of function and morphology. The findings presented here can serve as a basis for the study and development of effective longevity efforts as the underlying gene programs could be used as markers for treatment success and as targets for therapy development.

Background: We investigated the tumor immune response in gastric cancer patients receiving third line nivolumab monotherapy to identify immune-related biomarkers for better patient se-lection. Methods: Nineteen patients (10 males, median age 67 years) who received nivolumab as a third or later line therapy were enrolled. We analyzed the tumor immune response in durable clinical benefit (DCB) and non-DCB patients. Pre-treatment and early-on-treatment tumor transcriptomes were examined, and gene expression profiles, immunograms, and T cell receptor (TCR) repertoire were analyzed. Results: DCB was observed in 15.8% of patients, with comparable secondary endpoints (ORR, OS, PFS) to previous trials. Individual immunograms showed no significant changes before and ear-ly-on-treatment, nor consistent alterations among DCB cases. The intratumoral immune response was suppressed by previous treatments in most third or later line nivolumab recipients. TCR repertoire analysis revealed newly emerged clonotypes in on-treatment tumors, but clonal re-placement did not impact efficacy. High T cells/Tregs ratios and a low UV radiation response gene signature were linked to DCB and treatment response. Conclusions: This study emphasizes the tumor immune response's importance in nivolumab ef-ficacy for gastric cancer. High T cells/Tregs ratios and specific gene expression signatures show promise as potential biomarkers for treatment response. Larger cohort validation is crucial to optimize immune checkpoint inhibitors in gastric cancer treatment.

Aquaculture is one of the fastest-growing animal food-producing agricultural industries in the world and proper performance of fish in morphological, physiological and immunological aspects is important for fish production and sustainable expansion of aquaculture. But several inhibitors like disease, pathogen, and adverse environment can overpower these performances. At present, antibiotics in preventing these inhibitors have been seen as becoming favorable to those inhibitors. So, Bacillus, an important group of probiotic bacteria can be an alternative to these antibiotics in aquaculture. Bacillus has been seen used in different experiments, mainly as a supplement in feed at various concentrations. Bacillus showed effective results like improved growth with minimum cost, improvement in reproduction, hematology, improved immune response and disease, and stress resistance as well as better proximate composition in different fish species. Application of Bacillus strains has proven efficient in improving water quality by reducing ammonia and nitrite toxicity, harmful algal blooms and utilization of H⁺ ion. Larger application of probiotic Bacillus instead of the hazardous synthetic chemicals would promote eco-friendly low-input sustainable aquaculture for food and nutritional security of the increasing world population. So many more experiments should be conducted in commercially important fishes for better growth and health of fishes which will certainly increase fish

Background: COVID-19 vaccines have been a game changer in the pandemic, their extensive use was favorable compared to the burden of COVID-19 complications. Despite the low incidence of complications, it was important to analyze them carefully to understand the underlying mechanisms and predisposing factors. For instance, myopericarditis especially from mRNA vaccines, and its relatively higher prevalence in young adults and adolescents has raised a public concern about the use of this vaccine in this group. We aimed through this review to compare the age likelihood of ADEM from COVID-19 vaccines, with that reported in myopericarditis cases; secondary outcome parameters included the gender and number of doses needed to induce COVID-19 vaccines related ADEM. Methodology: A literature search has been conducted on relevant databases to retrieve all case reports/series and systematic reviews describing ADEM with possible linkage to COVID-19. Exclusion criteria included any report not including the desired outcome parameters. Our results were then qualitatively compared with a similar systematic review reporting myopericarditis from COVID-19 vaccines. Results: In 38 cases with ADEM, mean age was 49±16 compared to 25±14 in myopericarditis, females were more likely to be affected, and while most of myopericarditis cases develop after the second dose, most of ADEM cases develop after the first dose (76%). Moreover, age>56 years was more predictive of negative outcome after ADEM in the form of death or permanent vegetative state. Conclusion: The discrepancy in age, gender and number of doses needed to induce complications between ADEM and myopericarditis, signify that the tissue affected is the major orchestrator of the age, gender, and dose characteristics, and not the type of vaccines. A leakier blood brain barrier with aging, might allow easier passage of autoantibodies and cytokines into the brain while lack of inhibitory immune checkpoints in the myocardium in young age might explain the higher prevalence of those cases in young adults and adolescents.

Background: The Ibizan Hound is a canine breed native to the Mediterranean region, where leishmaniasis is an endemic zoonosis. Several studies indicate a low prevalence of this disease in dogs, whereas other canine breeds present a high prevalence. However, the molecular underlaying mechanisms yet remains unknown. Methods: In this study, we analyze the haplotypes of genes encode cytokines related to immune response of Leishmania infantum infection in twenty-four Boxer and twenty-four Ibizan hound apparently healthy using CanineHD DNA Analysis BeadChip including 165,480 mapped positions. Results: The results show that several haplotypes of genes encoding Interleukin 6 (IL6) and Interferon gamma (IFNG) are related to Interferon gamma (IFN-γ), and Interleukins (IL) 2 and 18 serum levels. Our results indicate that the regulation of immune response is different in the two canine breeds analyzed and are related to the haplotype compositions of the genes encoding these cytokines. Conclusions: Future studies are needed to elucidate whether these differences and haplotypes are related to different phenotypes in immune response and expression gene regulation to L. infantum infection in dogs.

Thirty-six healthy 21-day-old weaned ternary piglets (Duroc × Landrace × Yorkshire) were randomly divided into 2 treatments with 18 replicates per treatment and 1 pig per replicate. The control group was fed with basal diet and the test group was fed with diets supplemented with 1 kg/t tea residue. The test period was 28 days. The results are as follows: The addition of tea residue in the diet has no significant effect on the growth performance of weaned piglets (P > 0.05), but it could significantly reduce the diarrhea rate of piglets from 1 to 7 days and 1 to 28 days (P < 0.05). Compared with the control group, the dietary supplementation of tea residue had no significant effect on nutrient apparent digestibility, plasma biochemical indexes and plasma immune indexes (P > 0.05), but increased the content of glutathione in plasma (P < 0.05). Tea residue had no significant effect on the morphology of jejunum and ileum of piglets (P > 0.05), but it could significantly reduce the content of chloride ion in feces (P < 0.05). Compared with the basal diet group, there was no significant difference in the relative expression of TMEM16A and CFTR mRNA in the colon of weaned piglets (P > 0.05). The whole-cell patch clamp recording showed that the TMEM16A and CFTR ion channels could be activated by ionomycin and forskolin, respectively. However, when the HT-29 cells transfected with TMEM16A and CFTR channels were treated with tea residue extract, it could significantly inhibit the chloride current of the TMEM16A and CFTR ion channels (P < 0.05).

Anthocyanins (ACNs) have attracted considerable attention for their potential to modulate the immune system. Research has revealed their antioxidant and anti-inflammatory properties, which play a crucial role in immune regulation by influencing key immune cells such as lymphocytes, macrophages, and dendritic cells. Moreover, ACNs contribute to maintaining a balance between proinflammatory and anti-inflammatory cytokines, thus promoting immune health. Beyond their direct effects on immune cells, ACNs significantly impact gut health and the microbiota, essential factors in immune regulation. Emerging evidence suggests that they positively influence the composition of the gut microbiome that enhance the immunomodulatory effects of ACNs. Furthermore, these compounds synergize with other bioactive substances, such as vitamins and minerals, further enhancing their potential as immune-supporting dietary supplements. However, detailed clinical studies must fully validate these findings and determine safe dosages for different populations. Incorporating these natural compounds into functional foods or supplements can revolutionize the management of immune-related conditions. Personalized nutrition and healthcare strategies can be developed to enhance overall well-being and immune resilience by fully understanding the mechanisms underlying their actions. Recent advancements in delivery methods have focused on improving the bioavailability and effectiveness of ACNs, providing promising avenues for future applications.

Pulmonary hypertension (PH) has a high mortality, and few treatment options. Adaptive immune mediators of PH in mice challenged with antigen/particulate matter (antigen/PM) has been the focus of our prior work. We identified key roles of type 2 and type 17 responses in C57BL/6 mice. Here, we focused on type 2 response related cytokines, specifically Resistin-like-molecule (RELM)α, a critical mediator of hypoxia-induced PH. Because of strain differences in the immune responses to type 2 stimuli, we compared C57BL/6J and BALB/c mice. A model of intraperitoneal antigen sensitization with subsequent, intranasal challenges with antigen/PM (ovalbumin and urban ambient PM2.5) or saline was used in C57BL/6 and BALB/c wild type or RELMα-/- mice. Vascular remodeling was assessed by histology, right ventricular (RV) pressure, RV weights and cytokines were quantified. Upon challenge with antigen/PM2.5, both C57BL/6 and BALB/c mice developed pulmonary vascular remodeling; these changes were more prominent in the C57BL/6 strain. Compared to wild type mice, RELMα-/- had significantly reduced pulmonary vascular remodeling in BALB/c, but not in C57BL/6 mice. RV weights, RV IL-33 and RV ST2-IL-33-receptor were significantly increased in BALB/c wild type mice, but not in BALB/c-RELMα-/- or in C57BL/6-wild type or C57BL/6-RELMα-/- mice. RV systolic pressures (RVSP) were higher in BALB/c compared to C57BL/6J mice, and RELMα-/- were not different from their respective wild type controls. In BALB/c mice, RELMα was a key contributor to antigen/PM2.5 induced pulmonary vascular remodeling, RV thickening and RV cytokine responses, highlighting the significance of the genetic background. The RELMα-/- animals demonstrated significantly decreased expression of RELMβ and RELM which makes these mice comparable to a situation where human RELMα levels would be significantly modified, as humans only have one RELM molecule.

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.

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. The characterization of new biomarkers of COVID-19 is extremely important. Few studies measured the soluble receptor for advanced glycation end product (sRAGE), angiotensin-converting enzyme 2 (ACE2), calcium and magnesium in COVID-19. Aims: To measure sRAGE, ACE2, interleukin (IL)-6, IL-10, CRP, calcium, magnesium, and albumin in COVID-19 patients in association with peripheral oxygen saturation (SpO2) and chest CT scan abnormalities (CCTA) including ground glass opacities. Methods. This study measured sRAGE, ACE2, IL-6, IL-10, CRP using ELISA techniques, and calcium, magnesium, and albumin using a spectrophotometric method in 60 COVID-19 patients and 30 healthy controls.Results. COVID-19 is characterized by significantly increased IL-6, CRP, IL-10, sRAGE, ACE2, and lowered levels of SpO2, albumin, magnesium and calcium. Neural networks showed that a combination of calcium, IL-6, CRP, and sRAGE yielded an accuracy of 100% in detecting COVID-19 patients with calcium being the most important predictor followed by IL-6, and CRP. COVID-19 patients with CCTAs showed lower SpO₂ and albumin levels than those without CCTAs. SpO2 was significantly and inversely correlated with IL-6, IL-10, CRP, sRAGE, and ACE2, and positively with albumin, magnesium and calcium. Patients with positive IgG results showed a significant elevation in the serum level of IL-6, sRAGE, and ACE2 compared to the negatively IgG patient subgroup.Conclusion. The results show that immune-inflammatory and RAGE pathway biomarkers may be used as external validating criterion for the diagnosis COVID-19. Those pathways coupled with lowered SpO2, calcium and magnesium are drug targets that may help to reduce the consequences of COVID-19.

Background Enfortumab vedotin shows promise as a targeted therapy for advanced urothelial carcinoma, particularly in patients who previously received platinum-based chemotherapy and immune checkpoint inhibitors. The EV-301 phase III trial demonstrated a significantly improved overall survival and response rates compared with standard chemotherapy. However, more data, especially from larger real-world studies, are needed to assess its effectiveness in Japanese patients. Methods A total of 6,007 urothelial cancer patients treated with pembrolizumab as second-line treatment were analyzed. Among them, 619 patients received enfortumab vedotin after pembrolizumab, while 394 received docetaxel or paclitaxel after pembrolizumab. Results The enfortumab vedotin group showed a longer overall survival than the paclitaxel/docetaxel group (p=0.013, hazard ratio: 0.71). In the multivariate analysis, enfortumab vedotin induction was an independent risk factor for the overall survival (p=0.013, hazard ratio: 0.70). There were no significant differences in the cancer-specific survival. Conclusions Enfortumab vedotin prolonged the overall survival in Japanese patients with advanced or metastatic urothelial carcinoma compared with paclitaxel or docetaxel after pembrolizumab treatment.

Hepatocellular carcinoma is the most common primary liver cancer and the fourth leading cause of cancer death worldwide. A total of 70-80% of patients are diagnosed at an advanced stage with a dismal prognosis. Sorafenib has been the standard of care for almost a decade until 2018 when FDA approved an alternative first-line agent namely lenvatinib. Whereas FOLFOX4 results an alternative first-line treatment for the chinese clinical oncology guidelines. In addition to cabozantinib, regorafenib, and ramucirumab, two therapeutics against the PD-L1/PD1 axis have been recently approved for subsequent-line therapy, as nivolumab and pembrolizumab. However, similar to other solid tumors, the response rate of single-agent targeting PD-L1/PD1 axis is low. Therefore a lot of combinatory approaches are under investigation, including the combination of different immune checkpoint inhibitors, the addition of immune checkpoint inhibitors after resection or during locoregional therapy, immune checkpoint inhibitors in addition to kinase inhibitors, anti-angiogenic therapeutics, and others. This review focuses on the use of ICIs for the hepatocellular carcinoma with an attent evaluation of new ICIs based combinatory approaches.

With the progress of immunotherapy in cancer, oncolytic viruses (OVs) are getting more and more attention during the past decade. Due to their cancer-selective and immunogenic property, OVs are considered ideal candidates to be combined with immunotherapy to increase both specificity and efficacy in cancer treatment. OVs preferentially replicate in and lyse cancer cells, generating pathogen-associated molecular patterns (PAMPs) and danger (damage)-associated molecular patterns (DAMPs). These signals trigger innate immune response to modulate the solid tumor microenvironment, resulting in in situ autovaccination leading to adaptive anti-virus and anti-tumor immunity. Here, we summarize the conceptual updates of oncolytic virotherapy, immunotherapy, and the strategies to enhance the virus-mediated anti-tumor immune response, including: 1. Arm OVs with cytokines to modulated innate and adaptive immunity; 2. Combine OVs with immune checkpoint inhibitors to release T cell inhibition; 3. Combine OVs with immune co-stimulators to enhance T cell activation.

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.

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.

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.

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.

Autoimmune kidney diseases arise from a loss of tolerance to antigens, often with unclear triggers. In this review we explore the role of the gut microbiome and how disease, diet and therapy can alter the gut microbiota consortium. Perturbations in the gut microbiota may induce the translocation of microbiota-derived inflammatory molecules such as liposaccharide (LPS) and other toxins systemically by penetrating the gut epithelial barrier. Once in the blood stream these pro-inflammatory mediators activate immune cells which release pro-inflammatory molecules many of which are antigens in autoimmune diseases. The ratio of gut bacteria Bacteroidetes:Firmicutes is associated with worse outcomes in multiple autoimmune kidney diseases including Lupus nephritis, MPO-ANCA vasculitis and Goodpasture’s syndrome. Therapies which enhance short chain fatty acid (SCFA)-producing bacteria in the gut have powerful therapeutic potential. Dietary fibre is fermented by gut bacteria which in turn release SCFAs which protect the gut barrier as well as modulate immune responses towards a tolerogenic anti-inflammatory state. Herein, we describe where the current field of research is and the strategies to harness the gut microbiome as potential therapy.

Metastases cause high mortality in several cancers and immunotherapies are expected to be effective in the prevention and treatment of metastatic disease. However, only a minority of patients benefit from immunotherapies. This creates a need for novel therapies that are efficacious regardless of the cancer types and metastatic environments they are growing in. Preclinical immuno-oncology models for studying metastases have long been limited to syngeneic or carcinogenesis-inducible models that have murine cancer and immune cells. However, the translational power of these models has been questioned. Interactions between tumor and immune cells are often species-specific and regulated by different cytokines in mice and humans. For increased translational power, mice engrafted with functional parts of human immune system have been developed. These humanized mice are utilized to advance understanding the role of immune cells in the metastatic process, but increasingly also to study the efficacy and safety of novel immunotherapies. From these aspects, this review will discuss the role of immune cells in the metastatic process and the utility of humanized mouse models in immuno-oncology research for metastatic cancers, covering several models from the perspective of efficacy and safety of immunotherapies.

Maternal-derived immunity is a critical component for survival and success of offspring in pigs to protect from circulating pathogens like Type 2 Porcine Reproductive and Respiratory Syndrome Virus (PRRSV-2). The purpose of this study was to investigate the transfer of anti-PRRSV immunity to piglets from gilts that received modified-live virus (MLV) alone (TRT 0), or in combination with one of two autogenous inactivated vaccines (AIVs, TRT 1+2). Piglets from these gilts were challenged with the autogenous PRRSV-2 strain at two weeks of age and their adaptive immune response (IR) was evaluated until 4 weeks post inoculation (wpi). The systemic humoral and cellular IR was analyzed in the pre-farrow gilts, and in piglets, pre-inoculation, and at 2- and 4-wpi. Both AIVs partially protected the piglets with reduced lung pathology and increased weight gain; TRT 1 also lowered piglet viremia best explained by the AIV-induced production of neutralizing antibodies in gilts and their transfer to the piglets. In piglets, pre-inoculation, the main systemic IFN-γ producers were CD21α+ B cells. From 0 to 4 wpi, the role of these B cells declined and CD4 T cells became the primary systemic IFN-γ producers. In lungs, CD8 T cells were the primary and CD4 T cells the secondary IFN-γ producers including a novel subset of porcine CD8α-CCR7- CD4 T cells, potentially terminally differentiated CD4 TEMRA cells. In summary, this study demonstrates that maternal AIV vaccination can improve protection of pre-weaning piglets against PRRSV-2; it shows the importance of transferring neutralizing antibodies to piglets; and it introduces two novel immune cell subsets in pigs – IFN-γ producing CD21α+ B cells and CD8α-CCR7- CD4 T cells.

Immune-mediated bowel diseases (IMBD), including Ulcerative colitis and Crohn's disease, represent a significant global health burden with their complex etiology and increasing prevalence. The connection between intestinal parasites and the gut microbiome in immune-mediated bowel disease is a complex and evolving field of research. Several studies have demonstrated that intestinal parasites can modulate the composition and function of the gut microbiome. Parasitic infections can result in alterations in the gut microbial community, including changes in microbial diversity, abundance, and metabolic activity. These changes can influence the immune response and contribute to the development of IMBDs. In contrast, the gut microbiome serves a pivotal function in maintaining intestinal homeostasis and immune regulation. Dysbiosis, characterized by changes in the gut microbial composition, has been associated with the pathogenesis of IMBDs. Imbalances in the gut microbiota can result in increased gut permeability, chronic inflammation, and aberrant immune responses, all of which are hallmarks of IMBDs. The bidirectional interaction between intestinal parasites and the gut microbiome further complicates the understanding of immune-mediated bowel diseases. Certain parasites, such as hookworms and Necator americanus, have been found to downregulate immune responses and may have therapeutic potential in treating celiac disease. On the other hand, infections with parasites like Strongyloides stercoralis and Blastocystis have been shown to mimic the symptoms of IBD, highlighting the intricate relationship between parasites and the pathogenesis of these diseases. Additional investigation is required to comprehensively elucidate the mechanisms that underlie the association between intestinal parasites and the gut microbiome in immune-mediated bowel disease. This knowledge could potentially lead to the development of targeted therapeutic strategies that aim to restore gut microbiota homeostasis and alleviate the symptoms of these debilitating conditions. By understanding and harnessing the complex interplay between parasites, the gut microbiome, and the host immune system, researchers may uncover novel approaches for the management and treatment of immune-mediated bowel diseases.

Commercial formulates of beneficial microbes have been used to enrich the rhizosphere microbiome of tomato plants grown in pots located in a glasshouse. These plants have been subjected to attacks by soil-borne parasites, such as root-knot nematodes (RKNs), and herbivores, such as the miner insect Tuta absoluta. The development of both parasites and the symptoms of their parasitism were restricted in these plants with respect to plants left untreated. A mixture, named in the text as Myco, containing plant growth promoting rhizobacteria (PGPR), opportunistic biocontrol fungi (BCF), and arbuscular mycorrhizal fungi (AMF) was more effective in limiting pest damages than a formulate containing the sole AMF (Ozor). Therefore, Myco-treated plants inoculated with RKNs were taken as a model to further study which biocontrol agent (BCA) was specifically responsible of plant immunization and the molecular pathways exploited to achieve such an immunization. The PGPR contained in Myco were not able to reduce nematode infection, rather, they worsened symptoms on plants, compared with those observed on untreated plants. When plants were treated with suspensions of Bacillus subtilis at concentrations similar to those provided with Myco and then inoculated with RKNs, infection was actually more severe than that on untreated plants. Therefore, it was argued that both BCF and AMFwere the microorganisms that, colonizing roots, synergistically stimulate plant immune system against RKNs. Beneficial fungi lowered the activities of the defense supporting enzymes endochitinases and β-1,3-glucanase to be able to colonize the roots. However, as early as three days after nematode inoculation, these enzyme activities, and the expression of the encoding pathogenesis related genes (PR-2, PR-3) were found to be enhanced in roots with respect to not inoculated plants, thus indicating that plants had been primed against RKNs. Addition of paclobutrazol, which reduced salicylic acid (SA) levels in cells, and of diphenyliodonium chloride, which inhibits superoxides generation, completely abolished the repressive effect of Myco on nematode infection and presumably plant immune reaction. Inhibitors of copper enzymes and of the alternative cyanide-resistant respiration did not significantly alter resistance induction by Myco. When Myco-treated plants were subjected to a moderate water stress and inoculated with nematodes, they retained numbers of developed individuals in the roots similar to those present in regularly watered plants, in contrast to what occurred in roots of untreated stressed plants that hosted very few individuals because of poor nutrient availability.

Respiratory Syncytial Virus (RSV) causes severe inflammation and airway pathology in children and the elderly by infecting the epithelial cells of the upper and lower respiratory tract. RSV replication is sensed by intracellular pattern recognition receptors upstream of the IRF and NF-B transcription factors. These proteins coordinate an innate inflammatory response via Bromodomain containing protein 4 (BRD4), a protein that functions as a scaffold for unknown transcriptional regulators. To better understand the pleiotropic regulatory function of BRD4, we examine the BRD4 interactome and identify how RSV infection dynamically alters it. To accomplish these goals, we leverage native immunoprecipitation and Parallel Accumulation – Serial Fragmentation (PASEF) mass spectrometry to examine BRD4 complexes isolated from human alveolar epithelial cells in the absence or presence of RSV infection. In addition, we explore the role of BRD4’s acetyl-lysine binding bromodomains in mediating these interactions by using a highly selective competitive bromodomain inhibitor. We identify 101 proteins that are significantly enriched in the BRD4 complex and are responsive to both RSV-infection and BRD4 inhibition. These proteins are highly enriched in transcription factors and transcriptional coactivators. Among them, we identify members of the AP1 transcription factor complex, a complex important in innate signaling and cell stress responses. We independently confirm the BRD4/AP1 interaction in primary human small airway epithelial cells. We conclude that BRD4 recruits multiple transcription factors during RSV infection in a manner dependent on acetyl-lysine binding domain interactions. This data suggests that BRD4 recruits transcription factors to target its RNA processing complex to regulate gene expression in innate immunity and inflammation.

Background: Cutaneous Melanoma (SKCM) is characterized by significant heterogeneity in its molecular, genomic, and immunologic characteristics. Methods: Whole transcriptome RNAseq data from The Cancer Genome Atlas of SKCM (n=328) was utilized. The immune microenvironment was characterized using CIBERSORTX to identify immune cell type composition. Unsupervised hierarchical clustering was performed based on immune cell type content. Samples were separated into those obtained from the primary tumor site and regional skin or soft tissue (locoregional), or distant metastasis and regional lymph node (metastatic). Analysis of overall survival (OS) was performed using Kaplan-Meier estimates and Cox-regression multivariable analyses. Results: Four immune clusters were identified, largely defined by lymphocyte:monocyte (L:M) ratio, monocyte-enrichment, and M0-macrophage-enrichment (L:MLow, MonocyteHigh, M0High; L:MLow, MonocyteMid, M0Low; L:MMid, MonocyteLow, M0Low; L:MHigh, MonocyteLow, M0Low). The L:MLow, MonocyteHigh, M0High cluster demonstrated significantly worse OS than clusters 2-4 in the locoregional group (HR 2.804, 95% CI 1.262–6.234, p=0.0114). Membership in the L:MLow, MonocyteHigh, M0High cluster was an independently poor prognostic factor for survival (HR 3.03, 95% CI 1.12–8.20, p=0.029). The L:MLow, MonocyteHigh, M0High cluster correlated with higher rates of metastasis and decreased predicted response to immune checkpoint blockade compared to the other clusters as determined by the Tumor Immune Dysfunction and Exclusion tool (TIDE). Conclusion: Distinct tumor immune clusters with a M0-macrophage-enriched, L:M ratio low phenotype in the primary melanoma tumor site independently characterize an aggressive phenotype that may differentially respond to treatment.

To investigate the effects of plant polysaccharides combined with boric acid on digestive function, immune function, and harmful gas and heavy metal contents in faeces of finishing pigs, for this study, 90 healthy three-way cross-bred pigs were selected and randomly divided into five groups: Con) A control, fed basic feed; BA) fed basic feed supplemented with 40 mg/kg of boric acid; BA+APS) fed basic feed supplemented with 40 mg/kg of boric acid and 400 mg/kg of Astragalus polysaccharides; BA+GLP) fed basic feed supplemented with 40 mg/kg of boric acid with 200 mg/kg of Ganoderma lucidum polysaccharides; and BA+EPS) fed basic feed supplemented with 40 mg/kg of boric acid and 500 mg/kg of Echinacea polysaccharides. Compared with the Con, the average daily gain (ADG) and trypsin activity were higher in BA, along with there being increased glutathione peroxidase (p < 0.05); furthermore, lower malondialdehyde content and harmful substance emissions from manure were observed (p < 0.05). Compared with BA, increases in ADG, gain-to-feed ratio (G/F), trypsin, and maltase activities were observed in BA+EPS (p < 0.05), as well as a lower NH3 emissions (p < 0.05). Compared with BA, BA+APS exhibited higher ADG, average daily feed intake (ADFI), G/F, trypsin, and maltase activities (p < 0.05), while H2S emissions were lower (p < 0.05). And Taken together, our findings reveal that supplementation with boric acid and plant polysaccharides in the diet of finishing pigs synergistically improved their growth performance, trypsin and maltase activities, and immune function, while also discovered the intestinal digestive enzymes, serum inflammatory factors, oxidative stress responseand emissions of harmful gases and heavy metals from feces and urine were tightly related, further reducing the impact of fecal pollution generated by modern animal husbandry on the environment.

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.

Immunotherapy is an effective therapeutic option for several cancers. In the last years, the introduction of checkpoint inhibitors (ICIs) has shifted the therapeutic landscape in oncology and improved patient prognosis in a variety of neoplastic diseases. However, to date, the selection of the best patients eligible for these therapies, as well as the response assessment is still challenging. Patients are mainly stratified using immunohistochemical analysis of the expression of anti-gens on biopsy specimens, such as PD-L1 and PD-1, on tumor cells, on peritumoral immune cells, and/or in the tumor microenvironment (TME). Recently, the use and development of imaging biomarkers able to assess in-vivo cancer-related processes are becoming more important. Today, positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is used routinely to evaluate tumor metabolism, and also to predict and monitor response to immunotherapy. Although highly sensitive, FDG-PET, in general, is rather unspecific. Novel radiopharmaceuticals (immuno-PET radiotracers) able to identify specific immune system targets are under investigation in pre-clinical and clinical settings. In this review, we will provide an overview of the main new immuno-PET radiotracers in development. We will also review the main players (immune cells, tumor cells, and molecular targets) involved in immunotherapy. Furthermore, we report current applications and the evidence of using [18F]FDG PET in immunotherapy, including the use of artificial intelligence (AI).

Clustered regularly interspaced short palindromic repeats or CRISPR, one of the major technological tools from nature's toolbox, has revolutionized the scientific world with its potential use in humans and plants. CRISPR Cas9 was first known as an adaptive immune system of bacteria. It is a system that cleaves foreign DNA. It has been exploited to be used as a genome editing tool for correcting genetic diseases in humans, for plants to create stress-resistant plants, and for a variety of different purposes. This review provides a basic overview of its applications in different areas of biological research. It has immense potential for a variety of researches, but it's still a mystery for science. It feels like scientists just know a tip of an iceberg.

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.

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.

Seven human coronaviruses (hCoVs) are known to infect humans. The most recent one, SARS-CoV-2, was isolated and identified in January 2020 from a patient presenting with severe respiratory illness in Wuhan, China. Even though viral coinfections have the potential to influence the resultant disease pattern in the host, very few studies have looked at the disease outcomes in patients infected with both HIV and hCoVs. Groups are now reporting that even though HIV-positive patients can be infected with hCoVs, the likelihood of developing severe CoV-related diseases in these patients is often similar to what is seen in the general population. This review aimed to summarize the current knowledge of coinfections reported for HIV and hCoVs. Moreover, based on the available data, this review aimed to theorize why HIV-positive patients do not frequently develop severe CoV-related diseases.

Nowadays, the human population is facing the third and may be the worst pandemic caused by human coronaviruses (CoVs). The virus was first reported in Wuhan, China on 31 December 2019 and spread within short time to almost all countries of the world. Genome analysis of the early virus isolates has revealed high similarity with SARS-CoV and hence the new virus was officially named SARS-CoV-2. Since CoVs have the largest genome among all RNA viruses, they can adapt many point mutation and recombination events; particularly in spike gene, that enable these viruses to rapidly change and evolve in nature. CoVs are known to cross the species boundaries by using different cellular receptors. SARS-CoV-2 is believed to originate in bats and transmitted to human being through an ill-defined intermediate host. In the current review, different aspects of SARS-CoV-2 biology and pathogenicity are discussed including virus genetics and evolution, spike protein and its role in evolution and adaptation to novel hosts, and virus transmission and persistence in nature. In addition, the immune response developed during SARS-CoV-2 infection is demonstrated with special reference to the interplay between immune cells and their role in disease progression. We believe that SARS-CoV-2 outbreak will not be the last and spillover of CoVs from bats will continue. Therefore, establishing intervention approaches to reduce the likelihood of future CoVs spillover from the natural reservoirs is a priority.

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.

Immune dysfunction has long been reported by medical professionals regarding astronauts suffering from opportunistic infections both during their time in space and a short time period afterwards once back on Earth. Various species of prokaryotes on board these space missions or cultured in a microgravity analogue exhibit increased virulence, enhanced formation of biofilms, and in some cases develop specific resistance for specific antibiotics. This poses a substantial health hazard to the astronauts confined in constant proximity to any present bacterial pathogens on long space missions with a finite number of resources including antibiotics. Furthermore, some bacteria cultured in microgravity develop phenotypes not seen in Earth gravity conditions, providing novel insights into bacterial evolution and research.

Despite considerable progress in the diagnosis of various diseases, an ideal, simple tool for diagnosing patients with respiratory tract infections has not yet been invented. Many simple diagnostic tests are widely available to most doctors, provided they are aware of the prevalence of primary immunodeficiency. Other, more accurate studies are available only to immunologists. The aim of the study was to investigate the occurrence of dependence between selected physical parameters of serum such as: electrical conductivity, electrical permeability, dielectric loss factor, and selected parameters of the immune system. In addition, we have also included the ionogram (Na, K, Cl, Ca, Mg) and glucose concentration. As a result of research, the statistically significant, but very weak correlations between impedance magnitude |Z| and platelet counts (PLT), mean platelet volume (MPV) and chloride ions (Cl-) were found. The statistically significant differences according |Z| between children with and without deficiency in parameters of the immune system were noticed. Values of |Z| are higher in the case of children without deficiency in parameters of the immune system. The method of impedance measurements presented in our work is significantly easier then biosensors presented by other scientists. Taking into account our results, it can be stated that this method is promising for fast and easy detection of immunological disorders.