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

The main neurovascular unit of the Blood Brain Barrier (BBB) consists of a cellular component, which includes endothelial cells, astrocytes, pericytes, microglia, neurons and oligodendrocytes, as well as a non-cellular component resulting from the extracellular matrix. The endothelial cells are the major vital component of the BBB able to preserve the brain homeostasis; these cells are situated along the demarcation line between the bloodstream and the brain. Therefore, an alteration or the progressive disruption of the endothelial layer may clearly impair the brain homeostasis. The proper functioning of the brain endothelial cells is generally ensured by two elements: 1) the presence of junction proteins; 2) the preservation of a specific polarity involving an apical-luminal and a basolateral-abluminal membrane. In view of the above, this review intends to identify the molecular mechanisms underlying BBB function and their changes occurring in early stages of neurodegenerative processes in order to develop novel therapeutic strategies aimed to counteract neurodegenerative disorders.

‘Dysbiosis’ of the adult gut microbiota, in response to challenges such as infection, altered diet, stress, and antibiotics treatment has been recently linked to pathological alteration of brain func-tion and behavior. Moreover, gut microbiota composition constantly controls microglia matura-tion as revealed by morphological observations and gene expression analysis. However, it is un-clear whether gut microbiota influences microglia functional properties and crosstalk with neu-rons, known to shape and modulate synaptic development and function. Here, we investigated how antibiotic mediated alteration of the gut microbiota influences microglial and neuronal functions in adult mice hippocampus. Hippocampal microglia from adult mice treated with oral antibiotics exhibited increased microglia density, altered basal patrolling activity, and impaired process rearrangement in response to damage. Patch clamp recordings at CA3-CA1 synapses revealed that antibiotics treatment alters neuronal functions, reducing spontaneous postsynaptic glutamatergic currents and decreasing synaptic connectivity, without reducing dendritic spines density. The effect of dysbiosis on neuronal functions are mediated by microglia-neuron cross-talk through the CX3CL1-CX3CR1 axis, as antibiotics treatment of CX3CR1 deficient mice, mod-ulates microglia density and processes rearrangement leaving unaltered synaptic function. To-gether, our findings show that the antibiotics alteration of gut microbiota impairs synaptic effi-cacy, probably through CX3CL1-CX3CR1 signaling supporting microglia as a major player in in the gut-brain axis, and in particular in the gut microbiota-to-neuron communication pathway.

A frequent co-morbidity of cerebrovascular pathology and Alzheimer's disease pathology has been observed over past decades. Accordingly, much evidence has been reported which indicates that microvascular endothelial dysfunction, due to cerebrovascular risk factors (e.g., atherosclerosis, obesity, diabetes, smoking, hypertension, aging), precedes cognitive decline in Alzheimer's disease and contributes to its pathogenesis. By incorporating appropriate drug(s) into biomimetic (lipid cubic phase) nanocarriers, one obtains a multitasking combination therapeutic which targets certain cell-surface scavenger receptors, mainly class B type I (i.e., SR-BI), and crosses the blood-brain barrier (BBB). Such targeting allows for various Alzheimer's-related cell types to be simultaneously searched out, in vivo, for localized drug treatment. This in vivo targeting advantage may be particularly important for repurposing an FDA-approved drug, especially one which has shown the added ability to restore some cognitive functions in certain animal models of Alzheimer's disease (e.g., the anticancer drug bexarotene); this (candidate repurposing) drug up to now, by itself (i.e, without nanocarrier), displayed poor CNS penetration in human subjects.

The tissue micro environment or milieu consists of a highly dynamic population of cellular and non-cellular components which constitute a complex regulatory network aimed at maintaining the organ homeostasis. In the modern medicine the discovery of miRNAs is undoubtedly a promising field of research and they are essential in orchestrating immune system logic and their release in the gut micro milieu can directly affect bacterial gene expression. Here, we briefly review the role of microRNAs, focuses on their role on immune system components in physiological and pathophysiological gut micro milieu.

During the exploration of the surrounding environment, the brain links together external inputs, giving rise to perception of a persisting object. During imaginative processes, the same object can be recalled in mind even if it is out of sight. Here, topological theory of shape provides a mathematical foundation for the notion of persistence perception. In particular, we focus on ecological theories of perception, that account for our knowledge of world objects by borrowing a concept of invariance in topology. We show how a series of transformations can be gradually applied to a pattern, in particular to the shape of an object, without affecting its invariant properties, such as boundedness of parts of a visual scene. High-level representations of objects in our environment are mapped to simplified views (our interpretations) of the objects, in order to construct a symbolic representation of the environment. The representations can be projected continuously to an environmental object that we have seen and continue to see, thanks to the mapping from shapes in our memory to shapes in Euclidean space.

Dietary factors play an important role in shaping the gut microbiome which, in turn, regulates the molecular events in colonic mucosa. The composition and resulting metabolism of the gut microbiome have been implicated in the development of colorectal cancer (CRC). Diets low in dietary fibers and phytomolecules as well as other lifestyle-related factors may predispose to CRC. Emerging evidence demonstrates that the predominance of microbes, such as Fusobacterium nucleatum, can predispose the colonic mucosa to malignant transformation. Dietary and lifestyle modifications have been demonstrated to restrict the growth of potentially harmful opportunistic organisms. In this study, we aim to present evidence regarding the relationship of dietary factors to the gut microbiome and development of CRC.

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

Glioblastoma is one of the most difficult tumor types to treat with conventional therapy options like tumor debulking, chemo and radiotherapy. Immunotherapeutic agents like oncolytic viruses, immune checkpoint inhibitors and chimeric antigen receptor T cells have revolutionized cancer therapy, but their success in glioblastoma remains limited and further optimization of immunotherapies is needed. Several oncolytic viruses have demonstrated ability to infect tumors and trigger anti-tumor immune responses in malignant glioma patients. Leading the pack, oncolytic herpesvirus, first in its class, awaits an approval for treating malignant glioma from MHLW, the federal authority of Japan. Nevertheless, some major hurdles like the blood brain barrier, immunosuppressive tumor microenvironment, and tumor heterogeneity can engender suboptimal efficacy in malignant glioma. In this review, we discuss the current status of malignant glioma therapies with a focus on oncolytic viruses in clinical trials. Furthermore, we discuss the obstacles faced by oncolytic viruses in malignant glioma patients and strategies that are being used to overcome these limitations to 1) optimize delivery of oncolytic viruses beyond the blood brain barrier; 2) trigger inflammatory immune responses in and around tumors; and 3) use of multimodal therapies in combination to tackle tumor heterogeneity, with an end goal of optimizing the therapeutic outcome of oncolytic virotherapy.

The gut microbiota has recently been associated with susceptibility/resistance to malaria in animal models and humans, yet the impact of the gut microbiota on the risk of a malaria attack remains to be assessed. This study aims at assessing the influence of the gut microbiota on malaria attacks and Plasmodium parasitæmia in children living in a malaria-endemic area in Mali. Three hundred healthy children were included in a 16-months cohort study in Bandiagara. Their gut bacteria and fungi community structures were characterised via 16S and ITS metabarcoding from stool samples collected at inclusion. Clinician team monitored the occurrence of malaria attacks. Asymptomatic carriage of Plasmodium was assessed by qPCR. Over the 16-month period, 107 (36%) children experienced at least one occurrence of malaria attacks, and 82 (27%) at least one asymptomatic Plasmodium parasitæmia episode. A higher gut bacteria richness was independently associated with susceptibility to asymptomatic parasitæmia episodes and malaria attacks; while the Shannon H diversity and Chao-1 richness index of gut fungi community structure was relatively homogeneous in children who were and were not infected with P. falciparum. Using a linear discriminant effect size analysis of operational taxonomic units assigned to the species level, 17 bacteria, including Clostridiaceae, Eubacteriaceae, Senegalimassilia sp., Atopobiaceae and Lachnosipraceae, and seven fungi, including Dioszegia fristigensis, Ogataea polymorpha and Cutaneotrichosporon cyanovorans, were associated with susceptibility; whereas eight bacteria, including, Bifidobacterium spp., Weissela confusa and Peptostreptococcacea, and 3 fungi, Malassezia sp., Niesslia exosporoides, and Didymocrea leucaenae, were associated with resistance to malaria. Moreover, 15 bacteria, including Coproccus eutactus, Terrisporobacter petrolearius, Klebsiella pneumoniae and Ruminococcaceae, and 13 fungi, including Wallemia mellicola, were associated with susceptibility, whereas 19 bacteria, including Bifidobacterium spp., Bacteroides fragilis, Peptostreptococcacea, and Lactobacillus ruminis, and three fungi, including Cryptococcus neoformans, were associated with resistance to asymptomatic Plasmodium parasitæmia episodes. Further studies are needed to confirm these findings that point the way towards strategies aiming to reduce the risk of malaria by modulating gut microbiota components in at-risk populations.

Scientific theories on the functioning and dysfunction of the human brain require a good understanding of both its development — before and after birth, and through maturation to adulthood — and its evolution from the ancestral primate brain. Adopting a complex-systems approach, here we propose that the apparent uniqueness of humans’ cognitive capacities might best be understood as emerging from multiple nested “virtuous cycles.” In particular, we propose that the intimate link that exists between oxygen metabolic loops, cortical expansion, and ultimately cognitive and social demands is a key driver of genetic developmental programs for the human brain. Overall, our proposed evolutionary model makes explicit mechanistic links between metabolism, molecular and cellular brain heterogeneity, and behaviour that may in time provide a clearer understanding of brain developmental trajectories and their disorders.

Objective: It was aimed to investigate the cerebral vascular territories in stroke patients with NVAF as an etiologic factor. Material and Methods: A total of 104 patients who were referred to our hospital between January 2015 and September 2016, who were over 55 years of age, identified or documented as having a standard ECG or Holter ECG record on their medical history, and diagnosed with stroke were included. Our study was designed as a retrospective analysis of prospective data. Detailed history, physical examination and electrocardiography (ECG) evaluations of the patients were performed. Descriptive statistics were used in the detection of findings, and t-test, Pearson-square test and Fisher's exact test were used for differences analysis. Results: 53.8% (N = 56) of the patients were male and 46.2% (N = 48) were female. The mean age was 73.5. MCA was the most common site of vascular involvement in NVAF-dependent strokes. In MCA vascular territory, ischemic infarcts were detected most frequently in the upper and lower divisions. SCA and PCA followed MCA. Approximately 64% of the NVAF-related strokes were anterior circulation infarction (ASE) and 22% were posterior circulation infarct (PSE). There was a significant difference in age and past stroke history factors in favor of ASE (p<0.05). There was no significant difference between ASE and PSE in HT, cardiac history and DM factors (p>0.05). Conclusion: It was emphasized that the area of the vessel that underwent ischemia in the acutely displayed infarcts and the etiological factor for this vessel area could be predicted

Abstract: Tumor-targeting and blood-brain barrier (BBB)-penetrating are highly desirable for the treatment of glioma. In this study, we developed Pep-1&borneol-bifunctionalized carmustin-loaded micelles (Pep-1/Bor/CMS-M) capable of targeting to IL-13 receptor-overexpressed glioma and penetrating the brain microvascular endothelial cells-associated physiologic barriers. Pep-1/Bor/CMS-M were nearly spherical particles with a dimeter of 32.6 ± 1.1 nm and zeta potential of -21.3 ± 3.1 mV. Carmustine (CMS) released from Pep-1/Bor/CMS-M in pH 7.4 was significantly faster than in acidic environments. In human glioma BT325 cellular studies, Pep-1/Bor/CMS-M remarkably increased the cytotoxicity, notably improved the internalization and effectively induced the cell apoptosis. Likewise, in human brain microvascular endothelial cells (HBMEC) cells, Pep-1/Bor/CMS-M obviously promoted the cellular uptake, rapidly decreased the transepithelial electrical resistance (TEER) and thereby of enhancing the ability of penetration. In orthotopic Luc-BT325 glioma tumor-bearing nude mouse models, the stronger fluorescence signal and longer retention were observed in brain tissues compared with other controls, after single administration of DiD-labelled Pep-1/Bor/M (DiD/Pep-1/Bor/M). Importantly, Pep-1/Bor/CMS-M displayed the strongest inhibition of tumor growth, the longest survival period and low systemic toxicity in treating orthotopic glioma tumor-bearing nude mice. Simultaneous functionalization of Pep-1 and borneol offers a novel strategy for designing CMS-based nanomedicine and precisely treating glioma.

Cancer is the second biggest cause of death in children. With the development of chemotherapy, there is a substantial increase in overall survival rate over recent 30 years. However, the overall mortality rate in children with cancer still remains 25%, and many survivors experience a decline in overall quality of life and long-term adverse effects caused by treatments. Although cancer cells share common characteristics, pediatric cancers are different from adult cancers in their prevalence, mutation load, and drug response. Therefore, there is an urgent unmet need to develop therapeutic approaches specifically designed for children with cancer. Nanotechnology can potentially overcome the deficiencies of conventional methods of administering chemotherapy and ultimately improve clinical outcomes. The nanoparticle-based drug delivery systems can decrease the toxicity of therapy, provide a sustained or controlled drug release, improve pharmacokinetic properties of loading contents, and achieve a targeted drug delivery with achievable modifications. Further, therapeutic approaches based on combining nanoformulated drugs with novel immunotherapeutic agents are emerging. In this review, we discuss the recently developed nanotechnology-based strategies for treating blood and solid pediatric cancers.

Machine Learning (ML) approaches have been fruitfully applied to several classification problems of neurophysiological activity. Considering the relevance of emotion in human cognition and behaviour, ML found an important application field in emotion identification based on neurophysiological activity. Nonetheless, the literature results present a high variability depending on the neuronal activity measurement, the signal features and the classifier type. The present work aims to provide new methodological insight on ML applied to emotion identification based on electrophysiological brain activity. For this reason, we recorded EEG activity while emotional stimuli, high and low arousal (auditory and visual) were provided to a group of healthy participants. Our target signal to classify was the pre-stimulus onset brain activity. Classification performance of three different classifiers (LDA, SVM and kNN) was compared using both spectral and temporal features. Furthermore, we also contrasted the classifiers performance with static and dynamic (time evolving) features. The results show a clear increased in classification accuracy with temporal dynamic features. In particular, the SVM classifiers with temporal features showed the best accuracy (63.8 %) in classifying high vs. low arousal auditory stimuli.

The peripheral lymphatic system plays a crucial role in the recovery mechanisms after many pathological changes, such as infection, trauma, vascular, or metabolic diseases. The lymphatic clearance of different tissues from waste products, viruses, bacteria and toxic proteins significantly contributes to the correspondent recovery processes. However, understanding of the meningeal lymphatics functions is a challenging problem. The exploration of mechanisms of lymphatic communication with brain fluids as well as the role of the lymphatic system in the brain drainage, clearance and recovery are still in its infancy. Here we review novel concepts on the anatomy and physiology of the lymphatics in the brain, which warrant a substantial revision of our knowledge about the role of lymphatics in the rehabilitation of the brain functions after neural pathologies. We discuss a new vision on how to recruit the meningeal lymphatics by the opening of blood-brain barrier as a trigger mechanism of activation of the meningeal lymphatic drainage. This leads to innovative strategies in neurorehabilitation therapy.

Deep learning has shown remarkable results in every field, especially in the biomedical field, due to its ability to exploit large-scale datasets. A convolutional neural network (CNN) is a widely used deep learning approach to solve medical imaging problems. Over the past few years, many studies have focused on CNN-based techniques for brain tumor diagnosis. There are, however, still some critical challenges that CNNs face towards clinic application. This study presents a comprehensive review of current literature that involves CNN architectures for brain tumor classification. We compare the key achievements in the performance evaluation metrics of the applied classification algorithms. In addition, this review assesses the clinical effectiveness of the included studies to elaborate on the limitations and directions of this area for future work. No review focusing on the clinical effectiveness of previous works in this field has been published. We believe that this study has the potential to elevate the application of CNN-based deep learning methods in clinical practice and also can be a quick reference for biomedical researchers who are interested in this field.

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.

Perception and motor interaction with physical surroundings can be analyzed by the changes in probability laws governing two possible outcomes of neuronal activity, namely the presence or absence of spikes (binary states). Perception and motor interaction with physical environment are accounted partly by the reduction in entropy within the probability distributions of binary states of neurons in distributed neural circuits, given the knowledge about the characteristics of stimuli in physical surroundings. This reduction in the total entropy of multiple pairs of circuits in networks, by an amount equal to the increase of mutual information among them, occurs as sensory information is processed successively from lower to higher cortical areas or between different areas at the same hierarchical level but belonging to different networks. The increase in mutual information is partly accounted by temporal coupling as well as synaptic connections as proposed by Bahmer and Gupta [1]. We propose that robust increases in mutual information, measuring the association between the characteristics of sensory inputs and neural circuits connectivity patterns, are partly responsible for perception and successful motor interactions with physical surroundings. It is also argued that perception from a sensory input is the result of networking of many circuits to a common circuit that primarily processes the given sensory input.

Our knowledge on the plastic functions of the serotonin (5-HT) receptor subtype 7 (5-HT7R) in the brain physiology and pathology considerably advanced in the last few years. A wealth of data show that the 5-HT7R is a key player in the establishment and remodeling of neuronal cytoarchitecture during development and in the mature brain, and its dysfunction is linked to neuropsychiatric and neurodevelopmental diseases. The involvement of this receptor in synaptic plasticity is further demonstrated by data showing that its activation allows to rescue long term potentiation (LTP) and long term depression (LTD) deficits in various animal models of neurodevelopmental diseases. In addition, it is becoming clear that the 5-HT7R is involved in inflammatory intestinal diseases, possibly playing a role in the gut-brain axis, and modulates the function of immune cells. In this review, we will mainly focus on recent findings on this receptor’s role in the structural and synaptic plasticity of the mammalian brain, although we will also illustrate novel aspects highlighted in gut and immune system.

Modeling brain dynamics to better understand and control complex behaviors underlying various cognitive brain functions are of interests to engineers, mathematicians, and physicists from the last several decades. With a motivation of developing computationally efficient models of brain dynamics to use in designing control-theoretic neurostimulation strategies, we have developed a novel data-driven approach in a long short-term memory (LSTM) neural network architecture to predict the temporal dynamics of complex systems over an extended long time-horizon in future. In contrast to recent LSTM-based dynamical modeling approaches that make use of multi-layer perceptrons or linear combination layers as output layers, our architecture uses a single fully connected output layer and reversed-order sequence-to-sequence mapping to improve short time-horizon prediction accuracy and to make multi-timestep predictions of dynamical behaviors. We demonstrate the efficacy of our approach in reconstructing the regular spiking to bursting dynamics exhibited by an experimentally-validated 9-dimensional Hodgkin-Huxley model of hippocampal CA1 pyramidal neurons. Through simulations, we show that our LSTM neural network can predict the multi-time scale temporal dynamics underlying various spiking patterns with reasonable accuracy. Moreover, our results show that the predictions improve with increasing predictive time-horizon in the multi-timestep deep LSTM neural network.

The basal ganglia (BG) are a central component of the brain, crucial to the initiation, execution and learning of adaptive actions. The BG are the major site of the action of dopamine. An important aspect of the BG architecture is the existence of two paths, direct and indirect, having different projection targets and dopamine receptor expression. To understand the BG, dopamine, and related disorders, it is imperative to understand the two paths. The standard account used in neuroscience research for decades posits that the role of the direct path is to support movements, while that of the indirect path is to suppress unselected or completed movements. This account is contradicted by converging evidence. Here, we explain why the arguments supporting the standard account are flawed, and present a new account, in which the role of the indirect path is completely opposite: to support automated execution. During acute events, the direct path allows coarse responses. These are refined by competition, and the resulting focused response is executed and learned by the indirect path, assisted by cholinergic interneurons and the subthalamic nucleus (STN). The new account allows a novel understanding of the symptoms of Parkinson's disease, in particular tremor and rigidity, and of its treatment by STN deep brain stimulation.

P-glycoprotein (Pgp) determines resistance to a broad spectrum of drugs in glioblastoma multiforme (GB) because it is highly expressed in GB stem cells and in brain-blood barrier (BBB), the peculiar endothelium surrounding brain. Inhibiting Pgp activity in BBB and GB is still an open challenge. Here, we tested the efficacy of a small library of tetrahydroisoquinoline derivatives with an EC₅₀ for Pgp < 50 nM, in primary human BBB cells and in patients-derived GB, from which we isolated differentiated/adherent cells (AC, i.e. Pgp-negative/doxorubicin-sensitive cells) and stem cells (neurospheres, NS, i.e. Pgp-positive/doxorubicin-resistant cells). At 1 nM, 3 compounds increased the delivery of doxorubicin, a typical substrate of Pgp, across BBB monolayer, without altering expression and activity of other transporters. The compounds increased the drug accumulation within NS, restoring necrosis, apoptosis and reduction in cell viability induced by doxorubicin. In co-culture systems, the compounds added to the luminal face of BBB increased the delivery of doxorubicin to NS growing under BBB and rescued the drug’s cytotoxicity. Our work identified new ligands of Pgp active at low nanomolar concentrations, that effectively reduce Pgp activity in BBB and GB, and can improve chemotherapy efficacy in this tumor.

Recent studies have indicated that several anti-hypertensive drugs may delay the development and progression of Alzheimer’s disease (AD). However, the relationships among AD, hypertension, and oxidative stress remain to be elucidated. In the present study, we aimed to determine whether treatment with resveratrol reduces reactive oxygen species (ROS) generation in the brain, thereby reducing cognitive impairment in rats with angiotensin II (Ang-II)-induced early AD. Male WKY rats with Ang-II-induced AD were treated with losartan or resveratrol for 2 weeks. Our results revealed that treatment with resveratrol (10 mg/kg/day) decreased blood pressure, increased levels of brain-derived neurotrophic factor (BDNF) in the hippocampus, and decreased ROS production in the nucleus tractus solitarius (NTS) in the Ang-II groups. In addition, inhibition of Tau^T231 phosphorylation in the hippocampus using resveratrol significantly abolished Ang-II-induced expression of Ab precursors, active caspase 3, and glycogen synthase kinase 3b (GSK-3b)^Y216 while increasing Akt^S473 phosphorylation. Notably, resveratrol reversed impairments in hippocampal-dependent contextual memory induced by deleting NADPH oxidase and NOX2. Overall, our results suggest that resveratrol exerts neuroprotective effects against memory impairment and hippocampal damage in a rat model of early stage AD by reducing oxidative stress. These novel findings indicate that resveratrol may represent a pharmacological option for patients with hypertension at a risk of AD during old age.

Optical coherence tomography (OCT) is one of the most promising, innovative and rapidly emerging intraoperative imaging modalities for neurosurgical guidance in brain tissue imaging, "optical biopsy", brain cerebral vascular detection, nerve fibers and white matter tracts detection. In this article, we provide a short survey of cross-polarization OCT and different types of OCT probes that can be used in routine neurosurgical practice. Through different types of probes there are multiple applications where OCT can play a highly complementary role in offering the real-time microscopic assessment and imaging of normal and pathological brain tissues. The biopsy-needle based probe for CP OCT was shown to be an effective instrument for brain tissue mapping and express estimation of tissue status as well as for detecting large blood vessels to prevent causing bleeding during biopsy sampling. The folded CP OCT probe for intraoperative use for brain tissue examination was shown as a potentially efficient sensor head for CP OCT. The probe demonstrated high lateral resolution in diffractive limited probing beam quality. The length of dismountable probe tip allows using the probe under operating microscope. Due to the designed family of specialized probes CP OCT fills in the niche of devices for express brain tissue examination in situ.

Medical brain image analysis is a necessary step in the Computers Assisted /Aided Diagnosis (CAD) systems. Advancements in both hardware and software in the past few years have led to improved segmentation and classification of various diseases. In the present work, we review the published literature on systems and algorithms that allow for classification, identification, and detection of White Matter Hyperintensities (WMHs) of brain MRI images specifically in cases of ischemic stroke and demyelinating diseases. For the selection criteria, we used the bibliometric networks. Out of a total of 140 documents we selected 38 articles that deal with the main objectives of this study. Based on the analysis and discussion of the revised documents, there is constant growth in the research and proposal of new models of deep learning to achieve the highest accuracy and reliability of the segmentation of ischemic and demyelinating lesions. Models with indicators (Dice Score, DSC: 0.99) were found, however with little practical application due to the uses of small datasets and lack of reproducibility. Therefore, the main conclusion is to establish multidisciplinary research groups to overcome the gap between CAD developments and their complete utilization in the clinical environment.

Hepatocellular carcinoma (HCC), one of the leading causes of death worldwide, has a causal nexus with liver injury, inflammation, and regeneration that accumulate over decades. Observations from recent studies have accounted for the involvement of the gut-liver axis in the pathophysiological mechanism responsible for HCC. The human intestine nurtures a diversified colony of microorganisms residing in the host ecosystem. The intestinal barrier is critical for conserving the normal physiology of the gut microbiome. Therefore, a rupture of this barrier or dysbiosis cause the intestinal microbiome to serve as the main source of portal-vein endotoxins such as lipopolysaccharide, in the progression of hepatic diseases. Indeed, increased bacterial translocation is a key sign of HCC. Considering the limited number of clinical studies on HCC with respect to the microbiome, we focus on the clinical as well as animal studies involving the gut microbiota with the current understandings of the mechanism by which the intestinal dysbiosis promotes hepatocarcinogenesis. Future research might offer mechanistic insights into the specific phyla targeting the leaky gut, as well as microbial dysbiosis, and their metabolites, as key pathways that drive HCC-promoting microbiome-mediated liver inflammation and fibrosis, thereby restoring the gut barrier function.

The physics of the human brain has two components – basic physics common to all mammals and the physics of thinking inherent only in man. The development of the mental component of the structural and functional organization of the brain in phylogeny was associated with the chiral factor of the external environment, and in ontogenesis - with the social factor. The sensitivity of the brain to these factors was based on the single-connected nature of its aqueous basis, the mechanism of electromagnetic induction, and the features of the thermodynamics of the brain in a state of night sleep. In order to unify the description of the mechanism of electromagnetic processes in the brain, the concept of a quasiphoton has been introduced, combining all forms of excitation of electronic and molecular-cellular structures of the brain. Equivalent schemes of vibrational contours of neural network elements and macrostructures of the brain are proposed. Estimates of the kinetic parameters (activation energy, velocity) of the physical processes underlying the energy-information exchange of the brain with the external environment are made. Mechanisms of operative (physical) and permanent (chemical) memory of the brain, including a model of nonlocal quantum correlations, are discussed.

Stereotactic radiosurgery (SRS) has become increasingly important in the management of brain metastases due to improving systemic disease control and rising incidence. Initial trials demonstrated SRS with whole brain radiotherapy (WBRT) improved local control rates versus WBRT alone. Concerns with WBRT associated neurocognitive toxicity have contributed to greater use of SRS alone, including for patients with multiple metastases and following surgical resection. Molecular information, targeted agents and immunotherapy have also altered the landscape for the management of brain metastases. This review summarises current and emerging data on the role of SRS in the management of brain metastases.

Ischemic neuron loss contributes to brain dysfunction in patients with cardiac arrest (CA). Histidine–tryptophan–ketoglutarate (HTK) solution is a preservative used during organ transplantation. Can HTK also protect neurons from severe hypoxia (SH) following CA? We isolated rat primary cortical neurons and induced SH with or without HTK. Changes in caspase-3, hypoxia-inducible factor 1-alpha (HIF-1α), and NADPH oxidase-4 (NOX4) expression were evaluated at different time points till 72 h. Using a rat asphyxia model, we induced CA-mediated brain damage and then completed resuscitation. HTK or sterile saline was administered into the left carotid artery. Neurological deficit scoring and mortality were evaluated for 3 days. Then the rats were sacrificed for evaluating NOX4 and H2O2 level in blood and brain. In the in vitro study, HTK attenuated SH- and H2O2-mediated cytotoxicity in a volume- and time-dependent manner, associated with persisted HIF-1α expression, reductions in procaspase-3 activation and NOX4 expression. The inhibition of HIF-1α abrogated HTK’s effect on NOX4. In the in vivo study, neurological scores were significantly improved by HTK. H2O2 level, NOX4 activity and NOX4 gene expression were all decreased in the brain specimen of HTK-treated rats. Our results suggest that HTK acts as an effective neuroprotective solution.

Neuroscientists are able to detect physical changes in information entropy in available neurodata. However, the information paradigm is inadequate to fully describe nervous dynamics and mental activities such as perception. This paper provides an effort to build explanations to neural dynamics alternative to thermodynamic and information accounts. We recall the Banach–Tarski paradox (BTP), which informally states that, when pieces of a ball are moved and rotated without changing their shape, a synergy between two balls of the same volume is achieved instead of the original one. We show how and why BTP might display this physical and biological synergy meaningfully, making it possible to tackle nervous activities. The anatomical and functional structure of the central nervous system’s nodes and edges allows to perform a sequence of moves inside the connectome that doubles the amount of available cortical oscillations. In particular, a BTP-based mechanism permits scale-invariant nervous oscillations to amplify and propagate towards far apart brain areas. Paraphrasing the BPT’s definition, we could state that: when a few components of a self-similar nervous oscillation are moved and rotated throughout the cortical connectome, two self-similar oscillations are achieved instead of the original one. Furthermore, based on topological structures, we illustrate how, counterintuitively, the amplification of scale-free oscillations does not require information transfer.

Age-related macular degeneration (AMD) is a complex multifactorial disease and the primary cause of legal and irreversible blindness among individuals aged >=65 years in developed countries. Globally, it affects 30-50 million individuals, with an estimated increase of approximately 200 million by 2020 and approximately 300 million by 2040. Currently, the neovascular form may be able to be treated with the use of anti-VEGF drugs, while no effective treatments are available for the dry form. Many observational studies, such as AREDS-1 and AREDS 2, have shown a potential role of micronutrient supplementation in lowering the risk of progression of the early stages of AMD. Recently, low-grade inflammation, sustained by dysbiosis and a leaky gut, has been shown to contribute to the development of AMD. Given the ascertained influence of the gut microbiota in systemic low-grade inflammation and its potential modulation by macro- and micro-nutrients, a potential role of diet in AMD has been proposed. This review discusses the role of the gut microbiota in the development of AMD. Using PubMed, Web of Science and Scopus, we searched for recent scientific evidence discussing the impact of dietary habits (high fat and high glucose or fructose diets), micronutrients (vitamins C, E, and D, zinc, beta-carotene, lutein and zeaxanthin) and omega-3 fatty acids on the modulation of the gut microbiota and their relationship with AMD risk and progression.

Abstract: Early life gut microbiota have been increasingly recognized as major contributors to short and/or long-term human health and diseases. Numerous studies have demonstrated that human gut microbial colonization begins at birth but continues to develop a succession of taxonomic abundances for two to three years until the gut microbiota reaches adult-like diversity and proportions. Several factors, including gestational age (GA), delivery mode, birth weight, feeding types, antibiotic exposure, maternal microbiome and diet influence the diversity, abundance and function of the early life gut microbiota. Gut microbial life is essential for assisting with the digestion of food substances to release nutrients, exerting control over pathogens, stimulating or modulating the immune system and influencing many systems such as the liver, brain, and endocrine system. Microbial metabolites play multiple roles in these interactions. Furthermore, studies provide evidence supporting that imbalances of the gut microbiota in early life, referred to as dysbiosis, are associated with specific childhood or adult disease outcomes, such as asthma, atopic dermatitis, diabetes, allergic diseases, obesity, cardiovascular diseases (CVD) and neurological disorders. These findings support that the human gut microbiota may play a fundamental role in the risk of acquiring diseases that may be programmed during the early life stage. In fact, it is critical to explore the role of the human gut microbiota in early life. In this review, we summarize the general understanding of the colonization and development of the gut microbiota in early life, highlighting the recent findings regarding the relationship between the gut microbiota composition and their metabolites, and immune functions, which could significantly influence long-term health and disease. We then review known pathophysiological interactions of the early gut microbiome with a number of well characterized diseases and pose potential etiological mechanisms.

This article presents a study on brain tumor detection using the VGG-16 model, a convolutional neural network known for its performance in computer vision tasks. The aim of the study is to classify magnetic resonance imaging (MRI) images and accurately identify the presence of brain tumors. The dataset used consists of brain tumor MRI images, categorized into two classes: "NO" (no tumor) and "YES" (tumor). The methodology involves setting up the environment, importing and preprocessing the data, building the VGG-16 model, and evaluating its performance using metrics such as accuracy, precision, and recall. The results demonstrate an accuracy of approximately 88% on the validation set and 80% on the test set, indicating the potential of the VGG-16 model in supporting healthcare professionals in diagnosing brain tumors. The study contributes to the field of medical image analysis and offers insights into the application of deep learning for brain tumor detection.

Inflammatory bowel diseases, familial adenomatous polyposis (FAP) and colorectal cancer (CRC) are associated with alterations of the intestinal microbiota. However, few data are available on the perpetuation of FAP and ulcerative colitis (UC) in relation to microbial dysbiosis. This study evaluated the UC and genetically confirmed FAP patients’ gut microbial balance in concordance to clinical outcome. Fecal materials (average mass of 0.54 g) were collected from three FAP and five UC patients to compare with healthy individuals as control group. Genomic materials of micro-biota were isolated for next generation sequencing of 16S rRNA that was performed by using QIAseq 16S/ITS panel in Illumina Miseq Platform. Data processing and bioinformatics analysis were performed via CLC Genomic Workbench bioinformatics tool. The comparison between FAP, UC and control group revealed an alteration in the intestinal microbial composition. More in details, relative abundance of class levels showed statistical significance differences among FAP, UC and control groups. Our preliminary data focused on the explanation of how dysbiosis can lead to inflammation and drive processes together with host genetic profile that leads to colorectal carcinogenesis.

The latest research cumulates staggering information about the correlation between the microbiota-gut-brain axis and neurodevelopmental disorders. This review aims to shed light on the potential influence of the microbiome on the development of the most prevalent neurodevelopmental disease, attention-deficit-hyperactive disorder (ADHD). As the etiology and pathophysiology of ADHD are still unclear, finding viable biomarkers and effective treatment still represent a challenge. Therefore, we focused on factors that have been associated with a higher risk of developing ADHD while simultaneously influencing the microbial composition. We reviewed the effect of a differing microbial composition on neurotransmitter concentrations important in the pathophysiology of ADHD. Additionally, we deduced factors that correlate with a high prevalence of ADHD while simultaneously affecting the gut microbiome such as emergency c-sections, and premature birth as the former leads to a decrease of the gut microbial diversity and the latter causes neuroprotective Lactobacillus levels to be reduced. Also, we assessed nutritional influences such as breastfeeding, ingestion of short-chain fatty acids (SCFAs) and polyunsaturated fatty acids (PUFAs) on the host’s microbiome and development of ADHD. Finally, we discussed the potential significance of Bifidobacterium as a biomarker for ADHD, the importance of preventing premature birth as prophylaxis and nutrition as a prospective therapeutic measurement against ADHD.

Existing evidence suggest that lactoferrin might be beneficial for Alzheimer’s disease. We aimed to determine the effects of lactoferrin intervention on cognitive function from APP/PS1 mice, and possible mechanisms involved in. Both young and middle-aged male APP/PS1 mice were divided into control and lactoferrin group with 16 weeks’ intervention. Lactoferrin intervention had no effects on cognitive function from both young and middle-aged mice, and no key markers involved in Aβ, tau pathology, neuro-inflammation and synaptic plasticity were altered post lactoferrin intervention. In regards to gut microbiota profiles, in the young mice, lactoferrin elevated α diversity index including ACE and Chao 1, and reduced the relative abundance of the genera Bacteroides and Alistipes and elevated Oscillibacter, in addition, Oscillibacter, Anaerotruncus, EF096579_g, EU454405_g, Mollicutes_RF39, EU474361_g, EU774448_g, and EF096976_g were specifically abundant post Lf intervention via LEfSe analysis. In the middle-aged mice, the relative abundance of the phylum Proteobacteria, as well as the genera Oscillospira, Coprococcus and Ruminococcus was significantly reduced post Lf intervention, additionally, S24_7, Bacteroidia, Bacteroidetes and Methylobacterium were specific via LEfSe analysis post lactoferrin intervention. In conclusion, dietary lactoferrin might be beneficial for gut microbiota homeostasis although might have no effects on cognition.

Perturbation in the microbial population/colony index has harmful consequences on human health. Both biological and social factors influence the composition of the gut microbiota and promote gastric diseases. Changes in the gut microbiota manifest in disease progression owing to epigenetic modification in host which influences differentiation and function of immune cells adversely. Uncontrolled use of antibiotics; chemotherapeutic drugs and change in the diet pattern usually contribute to the changes in the colony index of sensitive strains known to release microbial content in the tissue micromillieu. Ligands released from dying microbes induce TLR mimicry on interaction with TLR abnormally which skew hypoxia and sterile inflammation contributing to severity of disease like IBD autoimmunity and cancer. Various modalities/interventions practiced across the globe and future strategies for microbiota based therapeutic approaches with special emphasis on tumor and inflammatory diseases are reviewed here. Therefore the major aim and scope of this manuscript is to both discuss various modalities/interventions across the globe and to design future microbiota based therapeutic approaches for mitigating the burden with special emphasis on tumor and Inflammatory diseases.

In this paper, we propose an imagined speech-based brain wave pattern recognition using deep learning. Multiple features were extracted concurrently from eight-channel Electroencephalography (EEG) signals. To obtain classifiable EEG data with fewer number of sensors, we placed the EEG sensors on carefully selected spots on the scalp. To decrease the dimensions and complexity of the EEG dataset and to avoid overfitting during the deep learning algorithm, we utilized the wavelet scattering transformation. A low-cost 8-channel EEG headset was used with MATLAB 2023a to acquire the EEG data. The Long-Short Term Memory Recurrent Neural Network (LSTM-RNN) was used to decode the identified EEG signals into four audio commands: Up, Down, Left, and Right. Wavelet scattering transformation was applied to extract the most stable features by passing the EEG dataset through a series of filtration processes. Filtration has been implemented for each individual command in the EEG datasets. The proposed imagined speech-based brain wave pattern recognition approach achieved a 92.50% overall classification accuracy. This accuracy is promising for designing a trustworthy imagined speech-based Brain-Computer Interface (BCI) future real-time systems. For better evaluation of the classification performance, other metrics were considered, and we obtained 92.74%, 92.50% and 92.62% for precision, recall, and F1-score, respectively.

Since matter, energy and information are the three major components of the world, is there an interaction between information and matter? In the present work, the coevolution of human language and brain is taken as a case of interaction between information and brain. Some evidence that may show interactions between human language and brain revealed by previous researches is summarized in this paper, such as the language areas in the cerebral cortex of the modern human brain, the evolution of human language and brain in human history, and the genetic basis for the evolution of language. Based on the evidence, a dynamic model is developed to investigate the possible mechanism of coevolution of human language and brain. In the model, human language development and brain development reinforce each other: the developmental level of language can be promoted by advances in brain function due to language-related gene mutations, in turn, whether such mutations are selected positively can be influenced by the current developmental level of language. The coevolution of human language and brain can be taken as a case of interaction between information and matter.

Opioids are highly addictive substances with a relapse rate of over 90%. While preclinical models of chronic opioid exposure exist for studying opioid dependence, none recapitulate the relapses observed in human opioid addiction. The mechanisms associated with opioid dependence, the accompanying withdrawal symptoms and the relapses that are often observed months or years after opioid dependence are poorly understood. Therefore, we developed a novel model of chronic opioid exposure whereby the level of administration is self-directed with periods of behavior acquisition, maintenance and then extinction alternating with reinstatement. This profile arguably mirrors that seen in humans, with initial opioid use followed by alternating periods of abstinence and relapse. Recent evidence suggests that dietary interventions that reduce inflammation, including omega-3 fatty acids such as docosahexaenoic acid (DHA), may reduce substance misuse liability. Using the self-directed intake model, we characterize the observed profile of opioid use and demonstrate that a diet enriched in polyunsaturated fat acids (PUFAs) ameliorates oxycodone-seeking behaviors in the absence of drug availability and reduces anxiety. Guided by the major role gut microbiota have on brain function, neuropathology, and anxiety, we profile the microbiome composition and the effects of chronic opioid exposure and DHA supplementation. We demonstrate that withdrawal of opioids led to a significant depletion in specific microbiota genera whereas DHA supplementation increased microbial richness, phylogenetic diversity, and evenness. Lastly, we examined the activation state of microglia in the striatum and found that DHA supplementation reduced the basal activation state of microglia. These preclinical data suggest that a diet enriched in PUFAs could be used as a treatment to alleviate anxiety induced opioid-seeking behavior and relapse in human opioid addiction.

The electrical stimulation of the visual cortices has the potential to restore vision to blind individuals. Until now, the results of visual cortical prosthetics has been limited as no prosthesis has restored a full working vision but the field has shown a renewed interest these last years thanks to wireless and technological advances. However, several scientific and technical challenges are still open in order to achieve the therapeutic benefit expected by these new devices. One of the main challenges is the electrical stimulation of the brain itself. In this review, we analyze the results in electrode-based visual cortical prosthetics from the electrical point of view. We first briefly describe what is known about the electrode-tissue interface and safety of electrical stimulation. Then we focus on the psychophysics of prosthetic vision and the state-of-the-art on the interplay between the electrical stimulation of the visual cortex and phosphene perception. Lastly, we discuss the challenges and perspectives of visual cortex electrical stimulation and electrode array design to develop the new generation implantable cortical visual prostheses.

Methylmercury is a neurotoxin present in fish tissues that permeates the blood-brain barrier after consumption. Previous research has shown that methylmercury is harmful to neurons, causing pH alterations, oxidative stress, excitotoxicity, and parenchymal damage. Methylmercury is a known factor of neurological disorders including Alzheimer's and Parkinson's. The method by which methylmercury passes through the blood-brain barrier is largely unknown. According to preliminary studies, one way methylmercury crosses the blood-brain barrier is by creating a complex with L-Cysteine, which facilitates its passage by the LATs system through mimicking another amino acid existing in the body. The human blood-brain barrier was studied using C. elegans as a model organism. It was hypothesized that if methylmercury passes through the blood-brain barrier of C. elegans faster with L-Cysteine present than without L-Cysteine present, the methylmercury's adverse effects (death and locomotive difficulty) will occur sooner. Each of the four experimental groups contained one C. elegans: the control, the L-Cysteine group, the methylmercury group, and the methylmercury and L-Cysteine combination group. The effects of L-Cysteine and methylmercury on C. elegans were studied using three metrics: viability, locomotive disability, and time for locomotive effects to occur. The group that received both methylmercury and L-Cysteine had reduced viability rates and a decreased time for locomotive difficulty to develop, supporting the hypothesis. These findings suggest that L-Cysteine aids methylmercury permeation through the blood-brain barrier. Because the experiment indicates how methylmercury penetrates the blood-brain barrier, these results aid in finding a therapeutic solution to reverse methylmercury neurotoxicity in the brain. Additionally, this study further opens channels into potential therapeutic and preventative measures for dementia, improving morbidity and mortality in neurodegenerative diseases.

AMR and drug void have caused huge panic today with few thousand death per year. MDR Typhoid was a serious old disease and caused serious health hazard in humen and animals demanding an update on molecular biology of the status on transferable genetic elements. R-plasmids combined in F’-plasmid and the new MDR conjugative plasmids were shown abundant in Sanmonella ranging 70-440kb with similarities. BlaTEM, blaCTX-M, blaOXA, blaNDM mdr genes were abundant in >50 plasmids analyzed and metal resistant gene clusters are predominant in most large plasmids. Among the acetyltransferase all catA1, aacA1 and aac-1b-cr genes were located. Abundant streptomycin phosphotransferases (StrAB) and rarely colistin resistant Mcr-5/9 phosphoethanolamine–lipid A transferase were detected. Altered isomeric dihydropterote synthases (Sul1/2/3) were present giving sulfamethoxazole resistance and dhfr gene frequently associated giving trimethoprim resistance. Metal resistant gene clusters like SilABC (CusABC), PcoAB, RcnA, terABC, and merABCXT etc were found in many Salmonella enterica plasmids. Toxin genes like HipA and virulence genes like spvABD were located in few plasmids increasing virulence and pathogenesis. Drug efflux genes tetA or tetB and OqxB, floR, CmlA were frequent where as QepA and EamA genes were rarely seen. Thus, Salmonella metal resistant genes combined with antibiotic resistant genes has tried to overcome the both toxic antibiotics and metalions causing Typhoid AMR. Such acquisition spreads salmoniasis in the live stocks (pig, cow, chicken) where toxic soil and water dominate increasing chance of MDR typhoid in human.

The composition of bacteria in the gastrointestinal tract of piglets is easily affected by environmental changes, particularly during the weaning period. Compound strains of Lactobacillus reuteri and Lactobacillus salivarius were supplemented to piglets during pre- and post-weaning to determine their effects in improving the growth performance and ameliorating the diarrhea rate and stress caused by antioxidation in piglets. A larger number of L. reuteri and L. salivarius colonized the distal segment of the ileum and the total numbers of Lactobacillus spp. and Bifidobacterium were higher in the ileal mucous membrane and cecal lumen with probiotics supplementation. The numbers of antioxidative and immune molecules were increased in the plasma following compound bacteria (CL) supplementation, whereas cortisol and endotoxin levels were lower and growth hormone and insulin-like growth factor 1 were higher. Spearman’s and KEGG analysis of the bacterial operational taxonomic unit and antioxidative and immune indices and metabolic genes indicated that the body growth modulation by CL supplementation could be attributed to optimization of the intestinal bacterial composition. Collectively, these results suggest that supplementation with CL could reduce stress and improve the growth performance of piglets during weaning by optimizing the intestinal bacterial composition.

This review systematically explored structural, functional, and metabolic features of the cisgender brain compared with the transgender brain before hormonal treatment and the heterosexual brain compared to the homosexual brain from the analysis of the neuroimaging literature up to 2018, and identified and discussed subsequent studies published up to March 2021. Our main aim was to help identifying neuroradiological brain features that have been related to human sexuality to contribute to the understanding of the biological elements involved in gender identity and sexual orientation. We analyze 39 studies on gender identity and 24 on sexual orientation. Our results suggest that some neuroanatomical, neurophysiological, and neurometabolic features in transgender individuals resemble those of their experienced gender despite the majority resembling those from their natal sex. In homosexual individuals the majority resemble those of their same sex heterosexual population rather than their opposite sex heterosexual population. However, it is always difficult to interpret findings with non-invasive neuroimaging. Given the gross nature of these measures, it is possible that more differences too subtle to measure with available tools yet contributing to gender identity and sexual orientation could be found. Conflicting results contributed to the difficulty of identifying specific brain features which consistently differ between cisgender and transgender or between heterosexual and homosexual groups. The small number of studies, the small-to-moderate sample size of each study, and the heterogeneity of the investigations made it impossible to meta-analyze all the data extracted. Further studies are necessary to increase the understanding of the neurological substrates of human sexuality.

HIV-1 is a complicated and perplexing virus. It infects T cells, reverse transcribes its RNA into DNA, utilizes its host DNA machinery to replicate its HIV-DNA, translates the HIV-DNA into proteins, assembles itself for a budding escape from the T cell, and rapidly mutates its conformation. Partially, due to its complexity, there remains no cure for HIV or AIDs. However, recently with the discovery of TALENs, the use of zinc fingers, and most of all the applications of CRISPR-Cas9 technology, has given researchers new hope in finding alternative gene therapies and treatments for diseases. With more focus on CRISPR-Cas9, this new and novel technology uses a guiding RNA, sgRNA, to lead a Cas9 nuclease to its target for deletion or to change that DNA site. CRISPR-Cas9 can delete point mutations and multiple DNA sites. Because CRISPR can alter DNA sequences, several scientists have conducted research into CRISPR, possibly treating more diseases such as cancer, diabetes, and even HIV. HIV-1 drew the focus of a researcher named Dr. Ebina in 2013 when he was the first to design and apply CRISPR-Cas9 to genes found in the binding sites of HIV-1, inhibiting HIV-1 gene expression. Since 2013, several other researchers have blocked HIV replication and infection through CRISPR-Cas9 targeting the receptors of T cells called the CC chemokine receptor 5 or CCR5. HIV-1 binds to the CD4 receptor of T cells, which consists of co-receptors CCR5 and CXCR4. If CCR5 expression can be removed, the HIV virus cannot bind to T-cells, blocking the initial attachment stage, and discontinuing the infection. However, there remain obstacles and issues for the CRISPR deletion of CCR5 for treating HIV-1. The issues include: 1) finding new and safe methods of CRISPR-Cas9 delivery, 2) clearing the latent HIV reservoirs, 3) improving the sgRNA design to avoid off-target mutations or deletions, and 4) effectively analyze the viral escape of HIV from CRISPR-Cas9 modifications. Therefore, the purpose of this review is to discuss possible techniques for removing the obstacles that can lessen the potential of CRISPR to delete CCR5, repressing HIV-1 into long-term remission or a functional cure.

Probiotics are increasingly used by consumers and practitioners to reduce gastrointestinal (GI) distress and improve gut function. Here, we sought to determine whether addition of supplemental bacteriophages (PreforPro) could enhance the effects of a common probiotic, Bifidobacterium animalis subsp. lactis (B. lactis) on GI health. We conducted a 4-week, randomized, parallel-arm, double-blind, placebo-controlled trial where primary outcomes included self-assessments of GI health, a daily stool log, and 16s rRNA analysis of gut microbial populations. We observed within group improvements in GI inflammation (p=0.01) and a trending improvement in colon pain (p=0.08) in individuals consuming B. lactis with PreforPro, but not in the group consuming only the probiotic. There was also a larger increase in Lactobacillus and short chain fatty acid-producing microbial taxa detected in stool of participants taking PreforPro with B. lactis compared to the probiotic alone. Overall, these results suggest the addition of PreforPro as a combination therapy may alter gut ecology to extend the GI benefits of consuming B. lactis or other probiotics.

Stress plays a central role in functioning for all life forms. As humans, we experience stress in a multitude of ways through various types of stimuli. Due to the constancy of stressors in our lives, the nervous system has learned to allosterically adapt to the stimuli, but when the body cannot adapt, chronic stress can have morphological and degenerative impacts on neuroanatomy and cognitive function that may or may not be reversible. This literature review aimed to identify the specific neuroanatomical structures impacted most by the long-term effects of chronic stress and the subsequent relationship the morphological changes had on cognitive function in rodent models. We examined articles published from PubMed, Google Scholar, and Science Direct, while focusing the search on anatomical and neurodegenerative effects associated with chronic stress stimuli. The degenerative effects of various types simulated physiological chronic stress showed the most impact on neurogenesis and neuronal development, brain plasticity, and spatial learning and memory with association to the hippocampus. The hippocampus, amygdala, prefrontal cortex, and hypothalamic-pituitary-adrenal axis (HPA) all had reversible and non-reversible morphological alterations, which also had a direct impact on the brain’s cognitive abilities. While studies regarding chronic stress are still being conducted, future research may be able to further highlight why stressful stimuli can particularly impact these structures and the tangential impacts that it may have on related or adjacent structures.

Three different fields intersect in search of an understanding of the point-of-origin of modern-age diseases: 1) D-amino acids and their role under stress conditions; 2) evolutionary origin of the mitochondrion organelle in the eukaryotic cell; and 3) gut microbiota and human healthHere it is first suggested that D-amino acids function as universal signaling agents, after having evolved as prokaryotic communication, part of an organic communication process that governs the basic activities of all the cells and coordinates cell action.Mitochondria (symbiotic prokaryotic organelles), are creative source of D-amino acids as signaling agents in the central nervous system and in the neuroendocrine systems.Amino acids racemases catalyzes the conversion between the L-enantiomers ( protein building blocks) into D-enantiomers (signaling agents).It is suggested that hectic modern life may affect human health by causing stress to the gut microbiota. These affected, gut microbiota then secrete D-amino acids that enter the blood stream, as signaling agents, causing communication errors in the central nervous system, and in the neuroendocrine systems due to excessive quantity of D-amino acids.Treating gut microbiota with inhibitors of amino acids racemases or finding D-amino acid scavengers may be used in developing novel therapeutic strategies for diseases related to the central nervous system and neuroendocrine systems caused by stressed gut microbiota.

The search for new chemical compounds with antitumor pharmacological activity is a necessary process for creating more effective drugs for each specific malignancy type. This review presents the outcomes of screening studies of natural compounds with high anti-glioma activity. Despite significant advances in cancer therapy, there are still some tumors currently considered completely incurable including brain gliomas. This review covers the main problems of the glioma chemotherapy including drug resistance, side effects of common anti-glioma drugs, and genetic diversity of brain tumors. The main emphasis is made on the characterization of natural compounds isolated from marine organisms because taxonomic diversity of organisms in seawaters significantly exceeds that of terrestrial species. Thus, we should expect greater chemical diversity of marine compounds and greater likelihood of finding effective molecules with antiglioma activity. The review covers at least 15 classes of organic compounds with their chemical formulas provided as well as semi-inhibitory concentrations, mechanisms of action, and pharmacokinetic profiles. In conclusion, the analysis of the taxonomic diversity of marine species containing bioactives with antiglioma activity is performed noting cytotoxicity indicators and to the tumor cells in comparison with similar indicators of antitumor agents approved for clinical use as antiglioblastoma chemotherapeutics.

Stereotactic radiosurgery (SRS) is considered the initial treatment for lung cancer patients with small-sized and limited number of brain metastases. The objective of this study was to assess clinical outcomes of SRS treatment using CyberKnife (CK) for recursive partitioning analysis (RPA) class II/III patients with one to three brain metastases from lung cancer and identify which patients in the high RPA class could benefit from SRS. A total of 48 lung cancer patients who received CK-based SRS for their metastatic brain lesions from 2010 to 2017 were retrospectively analyzed. Radiographic response was evaluated during follow-up period. Overall survival (OS) and intracranial progression-free survival (IPFS) were calculated and prognostic variables associated with OS and IPFS were evaluated. Median follow-up time was 6.6 months. Local control rates at 6 months and 1-year following SRS were 98% and 92%, respectively. The median OS of all patients was 8 months. One-year and 2-year OS rates were 40.8% and 20.9%, respectively. In multivariate analysis, uncontrolled primary disease (p = 0.008) and ECOG performance status of 2 or 3 (p = 0.001) were independent prognostic factors for inferior OS. These two factors were also significantly associated with inferior IPFS. In subgroup analysis according to RPA class, primary disease status was the only prognostic factor, showing statistically significant OS differences in both RPA class II and III (controlled vs. uncontrolled: 41.1 vs. 12.3 months in RPA class II, p = 0.031; 26.9 vs. 4.1 months in RPA class III, p = 0.011). Our results indicated that SRS could be an effective treatment option for RPA class II/III patients with brain metastases from lung cancer in the modern treatment era. SRS might be particularly considered for patients with controlled primary disease.

Background: Obesity and diabetes are two metabolic disorders linked by an inflammatory process named insulin resistance (IR). Various research on the role of gut microbiota in developing obesity and its associated disorders has led to the growing interest in probiotic supplementation. Considering the life-threatening complications of diabesity this mini-review explored the effects of probiotic supplementation on IR in obesity-associated diabetes. Method: This review is based on recent articles from 2005-2020, studying the role of probiotic supplementation on glucose and insulin parameters in healthy and diabetic mouse models. Result: Probiotic supplementation altered the gut microbiota composition, increased short-chain fatty acid production, and decreased pro-inflammatory cytokines. Additionally, they decreased intestinal permeability, circulating lipopolysaccharide, and metabolic endotoxemia hence improved insulin sensitivity and reduced obesity. Although multi-strain probiotic supplementation showed greater benefits than single strain interventions, variations in the concentration of probiotics used and the duration of treatment also influenced the results. Conclusion: Probiotic supplementation could manipulate the gut microbiota by reducing intestinal permeability, inflammation and ameliorate IR and obesity-associated diabetes in animal models which requires further long-term clinical studies in humans.

Starting from the tenets of human imagination, i.e., the concepts of lines, points and infinity, we provide a biological demonstration that the skeptical claim “human beings cannot attain knowledge of the world” holds true. We show that the Euclidean account of the point as “that of which there is no part” is just a conceptual device, untenable in our physical/biological realm: terms like “lines, surfaces and volumes” label non-existent, arbitrary properties. We also elucidate the psychological and neuroscientific features hardwired in our brain that lead us humans to think to points and lines as truly occurring in our environment. Therefore, our current scientific descriptions of objects’ shapes, graphs and biological trajectories in phase spaces need to be revisited, leading to a proper portrayal of the real world’s events. In order to provide also a positive account, we view miniscule bounded physical surface regions as the basic objects in a biological context in a traversal of spacetime instead of the usual Euclidean points. Our account makes it possible to erase a painstaking problem that causes many theories to break down and/or being incapable of describing extreme events: the unwanted occurrence of infinite values in equations, such as singularity in the description of black holes. We propose a novel approach, based on point-free geometrical standpoints, that banishes infinitesimals and leads to a tenable physical/biological geometry. We conclude that points, lines, volumes and infinity do not describe the world, rather they are fictions introduced by ancient surveyors of land surfaces.

Victor Vasarely’s (1906-1997) important legacy to the study of human perception is brought to the forefront and discussed. A large part of his impressive work conveys the appearance of striking three-dimensional shapes and structures in a large-scale pictorial plane. Current perception science explains such effects by invoking brain mechanisms for the processing of monocular (2D) depth cues. Here in this study, we illustrate and explain the local effects of 2D color and contrast cues on the perceptual organization in terms of figure-ground assignments, i.e. which local surfaces are likely to be seen as “nearer” or “bigger” in the image plane. Paired configurations are embedded in a larger, structurally ambivalent pictorial context inspired by some of Vasarely’s creations. The figure-ground effects these configurations produce reveal a significant correlation between perceptual solutions for “nearer” and “bigger” when no other monocular depth cues are given in the image. In consistency with previous findings on similar, albeit simpler visual displays, a specific color may compete with luminance contrast in resolving the planar ambiguity of a complex pattern context. Vasarely intuitively understood, and successfully exploited, this kind of subtle context effect in his art, well before empirical investigations had set out to study and explain their genesis in terms of information processing by the visual brain.

There is an important role non-human primates (NHP) play in biomedical research. Phylogenetic proximity of any of the NHP species to Homo sapiens assures that much better translatability of research outcomes from model studies involving human diseases can be achieved than from those generated with other pre-clinical systems. Our group and others used during past two decades NHPs in research directed towards viral and autoimmune disorders of the gastrointestinal tract. This review summarizes progress made in the area of enteric viral infections and its applicability to human disease.

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.

This review examines the evidence supporting the role of dysbiosis in the development of obses-sive-compulsive disorders (OCD). We review the molecular mechanisms and role of the microbiota in the microbiota-gut-brain axis, focusing on the endocrine, nervous, and immune pathways. We then propose a model that positions dysbiosis as the central unifying element in the neurochemi-cal, immunological, genetic, and environmental factors leading to OCD. Based on this, we review the animal and human clinical evidence for the use of microbial reprogramming strategies such as probiotic or fecal microbiota transplants to treat OCD. Finally, we discuss the unique challenges that must be addressed in future clinical interventions.

A risk of ischemic stroke increases exponentially after menopause. Even a mild-ischemic stroke can result in increased frailty. Frailty is a state of increased vulnerability to adverse outcomes, which subsequently increases risk of cerebrovascular events and severe cognitive decline, particularly after menopause. Several interventions to reduce frailty and subsequent risk of stroke and cognitive decline have been proposed in laboratory animals and patients. One of them is whole body vibration (WBV). WBV recuperates cerebral function and cognitive ability that deteriorates with increased frailty. The goal of the current study is to test the efficacy of WBV in reducing post-ischemic stroke frailty and brain damage in reproductively senescent female rats. Reproductively senescent Sprague–Dawley female rats were exposed to transient middle cerebral artery occlusion (tMCAO) and randomly assigned to either WBV or control groups. Animals placed in the WBV group underwent 30 days of WBV (40 Hz) treatment performed twice daily for 15 min each session, 5 days each week. The motor functions of animals belonging to both groups were tested intermittently and at the end of treatment period. Brains were then harvested for inflammatory markers and histopathological analysis. The results demonstrate a significant reduction in inflammatory markers and infarct volume with significant increases in brain-derived neurotrophic factor and improvement in functional activity after tMCAO in middle-aged female rats that were treated with WBV as compared to the control group. Our results may facilitate a faster translation of the WBV intervention for improved outcome after stroke, particularly among frail women.

Liver cirrhosis is one of the most prevalent chronic liver diseases worldwide. In addition to viral hepatitis, genetic conditions such as steatohepatitis, autoimmune hepatitis, sclerosing cholangitis, and Wilson’s disease can also lead to cirrhosis. Moreover, alcohol can cause cirrhosis on its own and exacerbate chronic liver disease from other causes. The treatment of cirrhosis can be divided into addressing the cause of cirrhosis and reversing liver fibrosis. To this date, there is still no clear consensus on the treatment of cirrhosis. Recently, there has been a lot of interest in potential treatments that modulate the gut microbiota and gut-liver axis for the treatment of cirrhosis. According to recent studies, modulation of the gut microbiome by probiotics ameliorates the progression of liver disease. The precise mechanism for relieving cirrhosis via gut microbial modulation has not been identified. This paper summarizes the role and effects of the gut microbiome in cirrhosis based on experimental and clinical studies on absorbable antibiotics, probiotics, prebiotics, and synbiotics. Moreover, it provides evidence of a relationship between the gut microbiome and liver cirrhosis.

People who suffer a mild traumatic brain injury (mTBI) have heterogeneous symptoms and disease trajectories, which make it difficult to precisely diagnose and assess complications long-term. Insufficient information is available regarding how to precisely diagnose and assess mTBI. This study identified and compared deficits in cognitive, psychosocial, visual functions, and balance performance between college students with and without histories of mTBI. Global DNA methylation ratio (5-mC%) in blood was also compared as a peripheral epigenetic marker. Twenty-five volunteers participated in this pilot study, including 11 mTBI cases (27.3% females; mean age of 28.7 years, SD=5.92) and 14 healthy controls (64.3% females; mean age of 22.0, SD=4.13). All the participants were assessed for cognitive (by NIH toolbox—executive function, memory, and processing speed), psychological (by PROMIS—depression, anxiety, and sleep disturbances), visual function (by King-Devick and binocular accommodative tests), postural balance performance (by a force plate), and blood 5-mC% (global methylation) levels. Students with mTBI reported significantly poorer episodic memory, severe anxiety, and more sleep disturbance problems. They also had higher blood 5-mC% level (all p’s<.05). No significant differences were found in visual function and postural balance. These findings validate changes in cognitive, psychosocial, and global DNA methylation long after mTBI.

The idea of using the lytic power of viruses against the malignant cells has been entertained for many decades. However, oncolytic viruses (OV) gained broad attention as an emerging anti-cancer therapy only recently with the successful implementation of the oncolytic herpesvirus to treat advanced melanoma. OVs offer an attractive therapeutic combination of tumor-specific cell lysis together with immune stimulation, yet the latter effect is less well studied. Nevertheless, OVs can be envisaged as potential in situ tumor vaccines. The therapeutic potential of OVs can be instigated further by using the molecular biological and biotechnological tools to modify the existing viruses for their optimal tumor selectivity and enhanced immune stimulation. Furthermore, OVs can be readily combined with other therapeutic agents to increase the efficacy of the existing therapeutic schemes. In this review, we discuss biotechnological advances in the development of therapeutic applications of OVs in Russia. Particular emphasis is made on the OV-mediated treatment of glioblastoma. In addition, we highlight the challenges of oncolytic virotherapy, and describe the strategies to optimize current approaches to improve clinical outcomes.

Brain Tumor is one of the severe diseases and occurrence of this disease threats human life. Detection of brain tumor in advance can secure patient’s life from unwanted loss. Well-timed and swift disease detection and treatment strategy can lead to improved quality of life in these patients. This paper attempts to use Machine Learning based ensemble approaches for recognising patients with brain tumor. Ensemble technique based AdaBoost classifier and 10-fold stratified cross-validation method are assembled in single platform is proposed in this paper for prediction of brain tumor. This prediction is compared against three baseline classifiers such as Gradient Boost, Random Forest and Extra Trees classifier. Experimental result implies the superiority of this model with an accuracy of 98.97%, f1-score of 0.99, kappa statistics score of 0.95 and MSE of 0.0103.

Nutrition is crucial for the management of patients affected by chronic kidney disease (CKD) to slow down disease progression and to correct symptoms. The mainstay of the nutritional approach to renal patients is protein restriction coupled with adequate energy supply to prevent malnutrition. However, other aspects of renal diets, including fiber content, can be beneficial. This paper summarizes the latest literature on the role of different types of dietary fiber in CKD, with special attention to intestinal microbiota and the potential protective role of renal diets. Fibers have been identified based on aqueous solubility, but other features, such as viscosity, fermentability, and bulking effect in the colon should be considered. A proper amount of fiber should be recommended not only in the general population but also in CKD patients, to achieve an adequate composition and metabolism of intestinal microbiota and to reduce the risks connected with obesity, diabetes, and dyslipidemia.

Children with central nervous system (CNS) malignancies often suffer from high symptom burden and risk of death. Pediatric palliative care is a medical specialty, provided by an interdisciplinary team, which focuses on enhancing quality of life and minimizing suffering for children with life-threatening or life-limiting disease, and their families. Primary palliative care skills which include basic symptom management, facilitation of goals-of-care discussions, and transition to hospice can and should be developed by all providers of neuro-oncology care. This chapter will review the fundamentals of providing primary palliative care

One of the major unsolved mysteries of biological science concerns the question of where and in what form information is stored in the brain. I propose that memory is stored in the brain in a mechanically encoded binary format written into the conformations of proteins found in the cell-extracellular matrix adhesions that organise each and every synapse. The MeshCODE framework outlined here represents a unifying theory of data storage in animals, providing read-write storage of both dynamic and persistent information in a binary format. Mechanosensitive proteins that contain force-dependent switches can store information persistently, which can be written or updated using small changes in mechanical force. These mechanosensitive proteins, such as talin, scaffold each synapse, creating a meshwork of switches that together form a code, the so-called MeshCODE. Large signalling complexes assemble on these scaffolds as a function of the switch patterns and these complexes would both stabilise the patterns and coordinate synaptic regulators to dynamically tune synaptic activity. Synaptic transmission and action potential spike trains would operate the cytoskeletal machinery to write and update the synaptic MeshCODEs, thereby propagating this coding throughout the organism. Based on established biophysical principles, such a mechanical basis for memory would provide a physical location for data storage in the brain, with the binary patterns, encoded in the information-storing mechanosensitive molecules in the synaptic scaffolds, and the complexes that form on them, representing the physical location of engrams. Furthermore, the conversion and storage of sensory and temporal inputs into a binary format would constitute an addressable read-write memory system, supporting the view of the mind as an organic supercomputer.

Both lactic acid and short chain fatty acid (SCFA) play important roles in maintenance of intestinal epithelial structure and function. Trilactic glyceride (TLG) obtains both excellences of lactic acid and SCFA. This study was to investigate the effects of trilactic glyceride on growth performance, blood parameters, liver function, intestinal morphology and intestine function of piglets. Twelve weaned piglets (21±2 d) were randomly allocated to two treatment groups: 1) control group, piglets fed the basal diet; 2) TLG group, piglets fed the basal diet supplemented with 0.5 % TLG. On day 21 of the trial, D-xylose (0.1 g/kg·BW) was orally administrated to all piglets and blood samples were collected 1 h thereafter. Then, all the piglets were sacrificed to examine intestinal mucosal morphology and collect fatty tissue, liver and intestinal mucosa for further analysis. The results showed that: compared with the control group, TLG group decreased blood ALB and GGT on day 10 and 20, TLG group decreased blood TP and increased blood TG on day 20 of the trail (p < 0.05); TLG group decreased blood D-xylose and LDL, increased blood HDL (p < 0.05). These data suggested that supplementing trilactic glyceride had beneficial impacts on promoting nutrients’ metabolism, maintaining intestinal integrity, and alleviating oxidative stress and diarrhoea. Further research of molecular mechanisms showed changing expression levels of related proteins and genes, suggesting that these could be involved in the regulation of the impact. The community composition of the gut microbiota was also found to be altered in several operational taxonomic units within the genus, Prevotella (order Bacteroidales), and the order, Clostridiales.

Compelling epidemiologic data support the critical role of dietary fructose in the epidemic of obesity, metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). The metabolic effects of fructose on the development of metabolic syndrome and NAFLD are not completely understood. High fructose intake impairs copper status, and copper-fructose interactions have been well documented in rats. Altered copper-fructose metabolism leads to exacerbated experimental metabolic syndrome and NAFLD. A growing body of evidence has demonstrated that copper levels are low in NAFLD patients. Moreover, hepatic and serum copper levels are inversely correlated with the severity of NAFLD. Thus, high fructose consumption and low copper availability are considered two important risk factors in NAFLD. However, the causal effect of copper-fructose interactions as well as the effects of fructose intake on copper status remain to be evaluated in humans. The aim of this review is to summarize the role of copper-fructose interactions in the pathogenesis of the metabolic syndrome and discuss the potential underlying mechanisms. This review will shed light on the role of copper homeostasis and high fructose intake and point to copper-fructose interactions as novel mechanisms in the fructose induced NAFLD.

Background: Coronavirus disease (COVID-19) related pneumonia is leaded by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which infects host cells through receptors named Angiotensin-converting enzyme 2 (ACE2). Smoking is thought to be related to poor disease prognosis, as a large amount of evidence highlights the negative effects of smoking on lung health and its causal relationship with various respiratory diseases. Methods: We first evaluated the role of ACE2 expression level with tobacco effect. And correlation analyses were used to identify the related genes of ACE2 both in smoker trait and human normal multi-tissues. After intersections, hub genes were later used to further GSEA and co-regulated mechanisms were explored by GeneMANIA. We used UALCAN to perform survival curves of pan-cancers included 33 types of cancers. New clinical model of top co-occurrence cancer type was constructed and validated. Results: Effected by cigarette smoking, the expression level of ACE2 expressed statistically upwards in current smokers compared with never smokers, upwards in groups after acute smoke exposed compared with normal control. But no strong evidence detected in third-hand smoke, as poor amounts of samples, only 4. A little trend of expressing upwards became in groups after third-hand smoke compared with groups after clean air exposing. 4 genes included PIR, ADH7, AKR1C2 and AKR1C3 were identified as ACE2 related genes in smoker trait and human normal multi-tissues. Then, we made the survival curves of pan-cancers in 4 genes. Brain lower grade glioma was the co-occurrence type as both ACE2, PIR and AKR1C3 had the significantly prognostic situation. Later, we made the new clinical prediction model as the C-index was 0.827 and the Area Under Curves (AUCs) of 1-year survival, 2-year survival and 3-year survival were 0.921(95%CI, 0.882-0.961), 0.911(95%CI, 0.860-0.962) and 0.878(95%CI, 0.818-0.939). In inner validation, the AUCs of 1-year survival, 2-year survival and 3-year survival were 0.777(95%CI, 0.640-0.914), 0.916(95%CI, 0.842-0.990) and 0.888(95%CI, 0.768-1.000). In outer validation one, the AUCs of 1-year survival, 2-year survival and 3-year survival were 0.764(95%CI, 0.672-0.856), 0.848(95%CI, 0.783-0.913) and 0.748(95%CI, 0.656-0.841). And in outer validation two the AUCs of 1-year survival, 2-year survival and 3-year survival were 0.740(95%CI, 0.654-0.826), 0.766(95%CI, 0.688-0.843) and 0.794(95%CI, 0.721-0.866). Conclusions: In our study, we compared the ACE2 expression level between smokers and non-smokers crowds and identified associated hub genes. Then we explored the further role of hub genes in tumor fields to identify the correlation and influence between the avoidable host factors such as smoking on COVID-19 contamination and tumor. ACE2 and AKR1C3 are potential prognostic genes for brain lower grade glioma, and we created the web dynamic nomogram and encapsulation app through validations.

Parenting has been robustly associated with offspring psychosocial development, and these effects are likely reflected in brain development. However, the claim that parenting influences offspring brain development in humans, as measured by structural and functional Magnetic Resonance Imaging (MRI), is subject to numerous methodological limitations. To interpret the state of the parenting and brain development literature, we review these limitations. Four limitations are common. First, most literature has been cross-sectional. Where longitudinal, studies rarely included multiple assessments of brain structure or function, precluding measurement of actual brain development. Second, parenting has largely been measured via selfor parent-report, as opposed to observational assessment. Third, there has been a focus on extreme forms of developmental adversity which do not necessarily lie on a continuum with normative parenting. Fourth, although not a limitation per se, studies have generally focused on negative as opposed to positive parenting behaviours. While not all studies are subject to all these limitations, the study of parenting in relation to offspring brain development is in its infancy.

Current lines of research into mood disorders indicate that immune mediators participating in the pathophysiology of chronic somatic disorders have potent influences on brain functions, even when these mediators are produced in peripheral tissues. Elevated levels of circulating immune molecules have been consistently associated with depressive symptoms in a number of clinical populations and experimental models, to the extent that major depressive disorder (MDD) is now seen, at least in part, as a disorder of immunity. This paradigm has brought to the fore the use of anti-inflammatory therapies as adjunctive to standard antidepressant therapy with the hope to improve treatment efficacy, particularly in those cohorts that do not respond well to standard medication. Such new practice requires the availability of biomarkers to tailor these new therapies to those most likely to benefit but also clear mechanisms of action describing the interaction between peripheral immunity and brain function. These mechanisms are generally studied in preclinical models that try to recapitulate the human disease through peripherally induced sickness behaviour as the model for immune-induced MDD. After an appraisal of the data in rodent models and their adherence to the data in clinical cohorts, we propose a modified model of periphery-brain interaction that goes beyond the currently established view of interaction between peripheral cytokines and microglia cells as the driver of depression. Instead, we suggest that brain barriers are primary actors in the communication between body and brain and, as a consequence, in the pathophysiology of the disease. This model suggests novel biomarkers, novel targets for therapies as well as a novel mechanism for resistance to standard treatments.

Intracortical microelectrodes that can be implanted have the ability to capture fast-changing neuron action potentials in the living brain. Despite this potential, many obstacles must still be overcome for reliable, long-term, high-quality recordings and accurate analysis of brain activity. These challenges include improving recording quality, enhancing recording stability, increasing recording capacity, and adding multi-functional features. One potential approach to enhance implantable microelectrodes involves the advancement of materials, refinement of implantation methodologies, and augmentation of the number of sites for recording. However, these challenges are still being actively researched, and advancements in microelectrode technology are underway. The difficulties with implantable microelectrodes are evaluated, and solutions are presented from different perspectives. The latest advancements in microelectrode technology are reviewed and condensed, and future possibilities are explored.

Each individual has a unique gut microbiota; therefore the genes in our microbiome outnumber the genes in our genome by about 150 to 1. Perturbation in host nutritional status influences gut microbiome composition and vice versa. The gut microbiome can help in producing vitamins, hormones, and other active metabolites that support the immune system; harvest energy from food; aid in digestion; protect against pathogens; improve gut transit and function; send signals to the brain and other organs, oscillating the circadian rhythm and coordinate with host metabolism through multiple cellular pathways. Gut microbiota can be influenced by host genetics, medications, diet, and lifestyle factors from preterm to aging. So before prescribing a customized treatment, it is crucial to monitor and count the gut flora as a focused biomarker. Many nutritional approaches that have been developed help in maintaining and restoring an optimal microbiome such as specific diet therapy, nutrition interventions and customized eating patterns. One of these approaches is time-restricted feeding/eating (TRF/E), a type of intermittent fasting (IF) in which a subject abstains from food intake for a specific time window. Such a dietary modification might alter and restore the gut microbiome for proper alignment of cellular and molecular pathways throughout the lifespan. In this review, we have highlighted that gut microbiota would be a targeted biomarker and TRF/E would be a targeted approach for restoring the gut microbiome associated molecular pathways like hormonal signaling, the circadian system, metabolic regulators, neural responses, and immune-inflammatory pathways. Consequently, modulation of gut microbiota through TRF/E could contribute in proper utilization and availability of the nutrients and in this way confer protection against diseases for harnessing personalized nutrition approaches to improve human health.

Natural killer (NK) cell therapy is one of the most promising treatments for Glioblastoma Multiforme (GBM). However, this emerging technology is limited by the availability of sufficient numbers of fully functional cells. Here, we investigated the efficacy of NK cells that were expanded and treated by interleukin-2 (IL-2) and heat shock protein70 (HSP70), both in vitro and in vivo. Proliferation and cytotoxicity assays were used to assess the functionality of NK cells in vitro, after which treated and naïve NK cells were administrated intra-cranially and systemically to compare the potential antitumor activities in our in vivo rat GBM models. In vitro assays provided strong evidence of NK cell efficacy against C6 tumor cells. In vivo tracking of NK cells showed efficient homing around and within the tumor site. Furthermore, significant amelioration of the tumor in rats treated with HSP70/Il-2 treated NK cells as compared to those subjected to non-treated NK cells, as confirmed by MRI, proved the efficacy of adoptive NK cell therapy. Moreover, results obtained with systemic injection confirmed migration of activated NK cells over the blood brain barrier and subsequent targeting of GBM tumor cells. Our data suggest that administration of HSP70/Il-2 treated NK cells may be a promising therapeutic approach to be considered in the treatment of GBM.

Hereditary Parkinson’s disease (PD) can be triggered by an autosomal dominant overdose of alpha-Synuclein (SNCA) as stressor or the autosomal recessive deficiency of PINK1 Serine/Threonine-phosphorylation activity as stress-response. We demonstrated the combination of PINK1-knockout with overexpression of SNCAA53T in double mutant (DM) mice to exacerbate locomotor deficits and to reduce lifespan. To survey posttranslational modifications of proteins underlying the pathology, brain hemispheres of old DM mice underwent quantitative label-free global proteomic mass spectrometry, focused on Ser/Thr-phosphorylations. As exceptionally strong effect, we detected >300-fold reductions of phosphoThr1928 in MAP1B, a microtubule-associated protein, and a similar reduction of phosphoSer3781 in ANK2, an interactor of microtubules. MAP1B depletion is known to trigger perturbations of microtubular mitochondria trafficking, neurite extension and synaptic function, so it was noteworthy that relevantly decreased phosphorylation was detected also for other microtubule and microfilament factors, namely MAP2S1801, MARK1S394, MAP1AT1794, KIF1AS1537, 4.1NS541, 4.1GS86 and ADD2S528. While the MAP1B heavy chain supports regeneration and growth cones, its light-chain assists DAPK1-mediated autophagy. Interestingly, relevant phosphorylation decreases of DAPK2S299, VPS13DS2429 and VPS13CS2480 in the DM brain affected regulators of autophagy, which are implicated in PD. Overall, significant downregulations were enriched for PFAM C2 domains, other kinases, and synaptic transmission factors upon automated bioinformatics, while upregulations were not enriched for selective motifs or pathways. Validation experiments confirmed the change of LC3 processing as reflection of excessive autophagy in DM brain, and dependence of ANK2/MAP1B expression on PINK1 levels. Our new data provide independent confirmation in a mouse model with combined PARK1/PARK4/PARK6 pathology that MAP1B/ANK2 phosphorylation events are implicated in Parkinsonian neurodegeneration. These findings expand on previous observations in D. melanogaster that the MAP1B ortholog futsch in the presynapse is a primary target of the PARK8 protein LRRK2, and on a report that MAP1B is a component of the pathological Lewy body aggregates in PD patient brains. Similarly, ANK2 gene locus variants are associated with the risk of PD, ANK2 interacts with PINK1/Parkin-target proteins such as MIRO1 or ATP1A2, and ANK2-derived peptides are potent inhibitors of autophagy.

Mental stress state recognition using electroencephalogram (EEG) signals for real-life applications needs a conventional wearable device. This requires an efficient number of EEG channels and an optimal feature set. The main objective of the study is to identify an optimal feature subset that can best discriminate mental stress states while enhancing the overall performance. Thus, multi-domain feature extraction methods were employed, namely, time domain, frequency domain, time-frequency domain, and network connectivity features, to form a large feature vector space. To avoid the computational complexity of high dimensional space, a hybrid feature selection (FS) method of minimum Redundancy Maximum Relevance with Particle Swarm Optimization and Support Vector Machine (mRMR-PSO-SVM) is proposed to remove noise, redundant, and irrelevant features and keep the optimal feature subset. The performance of the proposed method is evaluated and verified using four datasets, namely EDMSS, DEAP, SEED, and EDPMSC. To further consolidate, the effectiveness of the proposed method is compared with that of the state-of-the-art heuristic methods. The proposed model has significantly reduced the features vector space by an average of 70% in comparison to the state-of-the-art methods while significantly increasing overall detection performance.

In quantum approaches to consciousness, the authors try to propose a model and mechanism for the mind-brain interaction using modern physics and some quantum concepts which do not exist in the classical physics. The independent effect of mind on the brain has been one of the challenging issues in the history of science and philosophy. In some recent mind-brain interaction models, the direct influence of mind on matter is either not accepted (as in Stapp’s model) or not clear, and there have not been any clear mechanism for it (as in Penrose-Hameroff’s model or in Eccles’s model). In this manuscript we propose a model and mechanism for mind’s effect on the matter using an extended Bohmian quantum mechanics and Avicenna’s ideas. We show that mind and mental states can affect brain’s activity without any violation of physical laws. This is a mathematical and descriptive model which shows the possibility of providing a causal model for mind’s effect on matter. It is shown that this model guarantees the realistic philosophical constraints and respects the laws of nature. In addition, it is shown that it is in agreement with the Libet style experimental results and parapsychological data. To propose this model, we obtained a modified (non-unitary) Schrödinger equation via second quantization method which affects the particle through a modified quantum potential and a new term in the continuity equation. At the second quantized level, which is equivalent to quantum field theory level (QFT), we can use the path integral formalism of Feynman. We show that there are three methods to extend Bohmian QM via path integral formalism, which has different interpretations. By numerical simulation of trajectories in the two-slits experiment, we show their differences and choose one of these methods for our mind-brain model which can be the basis for explaining some phenomena which are not possible to explain in the standard Bohmian QM.

Manual interpretation of these huge amounts of image volumes are susceptible to inter-reader variability and human error. Thus, accurate automated CAD scheme is highly desirable in clinical pathological diagnosis. In this research, plethora of machine learning paradigms (e.g. feature extraction, dimensionality reduction and supervised classification methods) were explored, evaluated, compared and analyzed to identify the optimal pathway for brain MR images (normal vs neoplastic) binary classification task. External validation dataset was used to test the generalizability of the optimal predictive models implemented. Relevant and informative features were selected to construct cross-validated decision tree and eventually simple rule set was built based on the decision tree. The experimental results show that almost all pattern recognition paradigms achieve high accuracy with careful selection of number of attributes. LDA+ELM with 55 features are the optimal pipelines which achieve perfect classification when training and test data are of same source; and achieving (accuracy=97.5%, AUC=0.989, sensitivity=95% and specificity=100%) under balanced test dataset; (accuracy=99.5%, AUC=0.988, sensitivity=95% and specificity=100%). Cross-validated decision tree model also shows comparable performance: accuracy=98.8%, AUC=99.1%, sensitivity=99.6% and specificity=98.2%. Three highly relevant and robust attributes are visualized and selected for construction of decision tree models and finally a rule sets are read directly off the decision tree. This rule sets can potentially serve as fast and accurate classification algorithm.

Brain cancer is the tenth leading cause of death in the U.S. Glioblastoma multiforme (GBM) is the most lethal primary malignant central nervous system tumor in adults. The present study employed samples from 1985-2014 to discover the difference in prognosis among glioblastoma subtypes after the evolution of treatment modalities over the past few years. The current study aims to find the differences between Glioblastoma multiforme (GBM) and giant cell glioblastoma (GCG) in terms of prognosis among adults and elderly patients in the U.S. This study is a historical cohort type of study and is conducted on adults and elderly individuals with GBM or GCG from the years 1985-2014 in the U.S. Data were collected from the Surveillance, Epidemiology, and End Results Program (SEER) database. The study exposure was GBM or GCG and the outcome was mortality. The potential confounders were age, sex, race, ethnicity, year of diagnosis, primary site, and surgery. A chi-square test was used for categorical data. A univariate analysis was used for variables having a p-value < 0.05. Potential confounders were selected and evaluated using multivariate logistic regression models to calculate the odds ratio with stepwise selection. The study sample was 25,117. The incidences of GBM and GCG were not similar in relation to age group. Also, Spanish-Hispanic ethnicity was independently protective of GBM and GCG as compared to Non-Spanish-Hispanic ethnicity patients with GBM have a higher mortality rate than do GCG patients. The mortality rate was higher among patients diagnosed before 2010. In conclusion, GCG was not statistically significant in association to reduced mortality. Non-Spanish-Hispanics with GBM or GCG had a higher mortality rate than did Spanish-Hispanics. Factors such as being female, being age >59, and having a year of diagnosis before 2010 were independently associated with increased mortality.

A growing body of evidence indicates that aging of the brain is strictly related to the decline of energy metabolism. In particular, in older adults, the neuronal metabolism of glucose declines steadily resulting in a growing deficit of ATP production. The decline is evoked by deficient NAD recovery in the salvage pathway and subsequent impairment of the Krebs cycle. NAD deficit impairs also the activity of NAD-dependent enzymes. All these open vicious circles of neurodegeneration and neuronal death. Some brain structures are particularly prone to aging and neurodegeneration. These are pathological foci of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. This review article summarizes the impacts and mutual relationships between metabolic processes both on neuronal and brain levels. It also provides directions on how to reduce the risk of neurodegeneration and protect the elderly against neurodegenerative diseases.

Antibiotic inefficacy in treating bacterial infections is largely studied in the context of developing resistance mechanisms. However, little attention has been paid to combined diseases mechanisms, interspecies pathogenesis and the resulting impact on antimicrobial treatment. This review will consider the co-infections of Salmonella and Schistosoma mansoni. It summarises the protective mechanisms that the pathophysiology of the two infections confer, which leads to an antibiotic protection phenomenon. This review will elucidate the functional characteristics of the gut microbiota in the context of these co-infections, the pathogenicity of these infections in infected mice, and the efficacy of the antibiotics used in treatment of these co-infections over time. Salmonella-Schistosoma interactions and the mechanism for antibiotic protection are not well established. However, antimicrobial drug inefficacy is an existing phenomenon in these co-infections. The treatment of schistosomiasis to ensure the efficacy of antibiotic therapy for bacterial infections should be considered in co-infected patients.

Adult neurogenesis is an evolutionary conserved process occurring in all vertebrates. However, striking differences are observed between the taxa, considering the number of neurogenic niches, the neural stem cell (NSC) identity and brain plasticity under constitutive and injury-induced conditions. Zebrafish has become a popular model for the investigation of the molecular and cellular mechanisms involved in adult neurogenesis. Compared to mammals, the adult zebrafish displays a high number of neurogenic niches distributed throughout the brain. Furthermore, it exhibits a strong regenerative capacity without scar formation or any obvious disabilities. In this review, we will first discuss the similarities and differences regarding (i) the distribution of neurogenic niches in the brain of adult zebrafish and mammals (mainly mouse) and (ii) the nature of the neural stem cells within the main telencephalic niches. In the second part, we will describe the cascade of cellular events occurring after telencephalic injury in zebrafish and mouse. Our study clearly shows that most early events happening right after the brain injury are shared between zebrafish and mouse including cell death, microglia and oligodendrocyte recruitment, as well as injury-induced neurogenesis. In mammals one of the consequences following an injury is the formation of a glial scar that is persistent. This is not the case in zebrafish, which may be one of the main reasons that zebrafish display a higher regenerative capacity.

The makeup of human microbiota has been linked to a number of autoimmune disorders. Recent developments in whole metagenome sequencing and 16S rRNA sequencing technology have considerably aided research into the microbiome and its relationship to disease. Due to the inherent high dimensionality and complexity of data generated by high-throughput platforms, conventional bioinformatics techniques could only provide an inadequate explanation for the most relevant changes and seldom provide correct predictions. Machine learning, on the other hand, is a subset of artificial intelligence applications that enable the untangling of high-dimensional systems and intricate knots in correlation by learning complex patterns and improving automatically from training data without being explicitly programmed. Machine learning is increasingly being utilized to research the influence of microbes on the onset of illness and other clinical features since computer power has increased dramatically in the last few decades. In this review paper, we focused on emerging methodological approaches of supervised machine learning algorithms for identification of autoimmune disorders utilizing metagenomics data, as well as the potential benefits and limitations of machine learning models in clinical applications.

The tumor suppressor protein p53 is considered a guardian of genome integrity, regulating the induction of apoptosis and cell cycle arrest in response to irradiation to block the transmission of teratogenic mutations to progeny cells. We examined the function of p53 in highly radiosensitive tissues, the developing brain and mature testis, using a small fish model, medaka (Oryzias latipes). Medaka offer advantages as a vertebrate model system, as the transparency and small size of the embryos enables clear detection of apoptotic cells in the developing brain. In addition, the simple architecture of medaka testes enables more precise identification of the differentiating spermatogenic stages compared with mammals. We found that in irradiated p53-deficient embryonic brain, diminished induction of apoptosis facilitated tissue regeneration earlier compared to irradiated wild-type embryos, which remained structural abnormalities in the retina at hatching. Moreover, the prominent delay in apoptotic induction in irradiated p53-deficient testes could induce transient mis-differentiation during spermatogenesis, such as the formation of ovum-like cells (testis-ova). However, all testis-ova cells were eliminated via p53-independent apoptosis, and spermatogenesis was completely restored within 1 month after irradiation. Collectively, these data indicate that p53 is not indispensable for the restoration of irradiation-induced damaged tissues.

Abstract—Low-frequency Fahræus–Lindqvist-driven (not blood pressure-driven) oscillations in the small vessels are crucial because oscillations in small vessels support nutrient supply. Understanding of this is critical in type 2 diabetes mellitus (T2DM) to develop therapeutic measures to prevent Alzheimer's Disease Related Dementias: vascular factors contribute to cerebrovascular disease as well as mild cognitive impairment and dementia, which are predicted to affect 152 million people by 2050 (Alzheimer's Disease International London, UK, 2019). In this clinical study, we performed functional near-infrared spectroscopy (fNIRS) of the forehead to investigate the effect of the Mini-Cog with three-item recall test on the prefrontal cortex (PFC) activation and the relative oscillatory power in the 0.01–0.02-Hz (Fahræus–Lindqvist effect) and 0.021–0.052 Hz (smooth muscle autonomic innervation) frequency bands in elderly (60 years and older) T2DM and age-matched controls. We found a significant (p<0.01) difference in the PFC activation between elderly subjects with T2DM and age-matched elderly controls. Moreover, power spectral density (PSD) analysis revealed a significantly lower relative power in 0.021–0.052 Hz (smooth muscle autonomic innervation) frequency band in elderly subjects with T2DM during the Mini-Cog three-item recall test. Furthermore, a drop in the oscillatory power in the 0.01–0.02-Hz frequency band during Mini-Cog three-item recall test was found more pronounced in the elderly subjects with T2DM. Therefore, our study highlighted portable brain imaging to capture cerebrovascular reactivity to cognitive load that may provide a biomarker of cerebrovascular dysfunction in T2DM.Clinical Relevance— Our study establishes forehead portable brain imaging for monitoring cerebrovascular function in T2DM under cognitive load.

With the ever-increasing rate, obesity has become an epidemiological problem throughout the globe comprising about 39% of the world population as of now. Among several reasons, disruption of the gut microbial ecosystem might contribute to the pathogenesis of metabolic disorders, including obesity, metabolic syndrome, type 2 diabetes, and other associated comorbidities. Though the mechanisms related to dysbiosis are unclear, diet might play a modulating role where different dietary approaches manipulate microbial richness and abundance as well as stability. For instance, shifting of Firmicutes and Bacteroidetes ratio in the gut might have a role in association with the dietary approaches and ingestion duration. Along with altered gut microbial composition, microbial metabolites such as short-chain fatty acids (SCFA) after ingestion of non-digestible dietary starches may have an impact on host metabolism by regulating lipogenesis, gluconeogenesis, and inflammation with potential associations to health and obesity. The dietary approaches like carbohydrates, fibre, protein, and/or fat diet at various arrangements can make a shift in the composition of gut microbiota if introduced for a short period. However, the unique pattern of the gut microbes usually remains the same along with the longer period of habitual diet. Though the short-term dietary intervention or circadian rhythm influences a transient change in gut microbes, other than habitual diet, the understanding related to long-term dietary change-induced permanent alterations is minimum. Alternatively, the usage of prebiotics, probiotics as well as postbiotics could be beneficial to overcome dysbiosis. This review highlights the current knowledge and the interaction between the human intestinal microbiota and diet as a modifying factor, in obesity allowing the scientists to uncover novel targets and tools to use as customized therapy.

Eukaryotic enteric pathogens (EEP) are a public health issue in tropical areas. Yet, their interactions with the gut mycobiota remain poorly understood. We conducted a cross-sectional study in Malian children to analyze the impact of EEP on the gut fungal community. EEP were assessed by qPCR and the gut mycobiota was characterized by ITS1-2 metabarcoding in stool samples collected from 296 children. The 100 controls, in whom no EEP was detected, were compared to: a) 196 children with ≥1 EEP; b) 91 with only Blastocystis; c) 35 with only Giardia intestinalis; and d) 12 with another (&lt;1% each) EPP. The gut fungal community structure was homogenous in each children’s group. Linear size-effect discriminant analysis highlighted five relatively more abundant species, including Fusarium longipes and Penicillium caseifulvum, in children with ≥1 EEP, whereas 28, including Aspergillus sydowii and Microdochium colombiense were more abundant in controls. Fusarium, Pyxidiophora, and Stereum abundance was higher in Blastocystis-infected children, whereas Ogataea and Allocryptovalsa were more abundant in controls. Sordariales and Mortierellales abundance was higher in Giardia intestinalis-infected children, whereas Agaricales and Capnodiales abundance was higher in controls. In conclusion, EEP do not significantly alter the gut fungal community structure, and further studies are warranted to confirm our findings that particular taxa are associated with susceptibility or resistance to specific EEP.

Non-pharmacologic options like the ketogenic diet (KD) and intermittent fasting (IF) are practical nutritional interventions with minor reported side effects like gastrointestinal symptoms, dyslipidemia, and hypomagnesemia for various medical ailments. In conjunction with IF, KD shows promise in weight loss, diabetes management, cardiovascular disorders, polycystic ovarian syndrome, cancer, and chronic neurological disorders. Based on prior research, we have examined the mechanism of action of KD and IF and their effect on neurological diseases, cancer, and obesity. We have also suggested evidence-based recommendations for the safer practice of KD and IF. Despite potential benefits, long-term adherence to KD poses challenges. Periodic KD implementation may thus benefit newly diagnosed overweight or obese patients with type 2 diabetes mellitus, aiding blood glucose and lipid management while promoting weight loss. KD is a high-fat and low-carbohydrate diet with a ratio of fat to carbohydrates and protein being 4:1 or 3:1, and thus, for peripheral tissues and the brain, fatty acids become the mandatory source of cellular energy. Ketone bodies have been used as the primary energy source during fasting. KD has been utilized as an effective treatment for refractory epilepsy since the 1920s. Evidence of the neuroprotective role of KD in diseases like epilepsy, stroke, traumatic brain injury, Alzheimer’s disease, and other neurological diseases has been noted. Since the 1960s, KD has become a popular method for obesity treatment. In addition, KD has been suggested as a potent anticancer therapy when used alone or as an adjuvant. KD may increase tumor cell sensitivity when combined with classic chemotherapy and radiotherapy. Thus, the probability that modifying the diet can help manage obesity, cancer, and chronic neurological disease without depending on pharmacological treatment and their serious side effects for a lifetime is promising and requires further investigation. KD holds promise as a potential adjunctive therapy in various neurological disorders, offering new avenues for treatment and neuroprotection. IF has shown potential in slowing the progression of neurodegenerative diseases such as Alzheimer's and Parkinson's by promoting antioxidant defense and suppressing inflammation. KD and IF show promise in cancer therapy by targeting altered cancer cell metabolism. Additionally, KD may enhance the effects of standard treatments like chemotherapy and radiotherapy. Some of the most robust reports of keto's possible benefits have come from glioblastoma, a very aggressive brain cancer. KD has also shown strong evidence for its effectiveness in weight loss, mainly attributed to its appetite-suppressing action in ketosis. However, long-term adherence to KD can be challenging, and periodic KDs may help manage blood glucose and lipid levels in overweight or obese patients with type 2 diabetes mellitus. Likewise, IF may be more effective than regular calorie restriction for achieving weight loss goals when combined with exercise programs. More prospective human studies are warranted to evaluate both KD and IF's potential therapeutic effectiveness and safety.

As the world endures the coronavirus disease 2019 (COVID-19) pandemic, conditions of 35 million vulnerable individuals struggling with substance use disorders (SUDs) worldwide have not received sufficient attention for their special health and medical needs. Many of these individuals are complicated by underlying health conditions, such as cardiovascular and lung diseases and undermined immune systems. During the pandemic, access to the healthcare systems and support groups is greatly diminished. Current research on COVID-19 has not addressed the unique challenges facing individuals with SUDs, including the heightened vulnerability and susceptibility to the disease. In this systematic review, we will discuss the pathogenesis and pathology of COVID-19, and highlight potential risk factors and complications to these individuals. We will also provide insights and considerations for COVID-19 treatment and prevention in patients with SUDs.

Traumatic brain injury (TBI) is a major source of worldwide morbidity and mortality. Patients suffering from TBI exhibit a higher susceptibility to bone loss and an increased rate of bone fractures; however, the underlying mechanisms remain poorly defined. Herein, we observed significantly lower bone quality and elevated levels of inflammation in bone and bone marrow niche after controlled cortical impact-induced TBI in in-vivo CD-1 mice. Further, we identified dysregulated NFB signaling, an established mediator of osteoclast differentiation and bone loss, within the bone marrow niche of TBI mice. Ex vivo studies revealed increased osteoclast differentiation in bone marrow-derived cells from TBI mice, as compared to sham injured mice. Finally, we found bone marrow derived extracellular vesicles (EVs) from TBI mice enhanced the colony forming ability and osteoclast differentiation efficacy of bone marrow cells and activated NFB signaling genes in bone marrow-derived cells. Taken together, we provide evidence that TBI-induced inflammatory stress on bone and the bone marrow niche may activate NFB leading to accelerated bone loss. Targeted inhibition of these signaling pathways may reverse TBI-induced bone loss and reduce fracture rates.

There is evidence that spaceflight poses acute and late risks on the central nervous system. To explore possible mechanisms, the proteomic changes following spaceflight in mouse brain were characterized. Space Shuttle Atlantis (STS-135) was launched at the Kennedy Space Center on a 13-day mission. Within 3–5 hours after landing, brain tissue was collected to evaluate protein expression profiles using quantitative proteomic analysis. Our results showed that there were 26 proteins that were significantly altered after spaceflight in the grey and/or white matter. While there was no overlap between the white and grey matter in terms of individual proteins, there was overlap in terms of function, synaptic plasticity, vesical activity, protein/organelle transport, and metabolism. Our data demonstrate that exposure to the spaceflight environment induces significant changes in protein expression related to neuronal structure and metabolic function. This might lead to a significant impact on brain structural and functional integrity that could affect the outcome of space missions.

Dynamical system tools offer a complementary approach to detailed biophysical seizure modeling, with a high potential for clinical applications. This review describes the theoretical framework that provides a basis for theorizing certain properties of seizures and for their classification according to their dynamical properties at onset and offset. We describe various modeling approaches spanning different scales, from single neurons to large-scale networks. This narrative review provides an accessible overview of this field, including non-exhaustive examples of key recent works.

Equine fecal microbiota transplantation (FMT) is an emerging therapy for restoring gut microbiome balance in horses. An imbalance in the gut microorganisms, known as dysbiosis, can cause inflammation and metabolic disruptions. FMT, which involves transferring gut bacteria from a healthy donor to a diseased recipient, has shown positive results in treating gastrointestinal diseases in horses, but is still largely limited to research purposes due to safety concerns and lack of understanding of its mechanisms. This paper aims to shed light on the possible mechanisms of FMT in horses and discuss future perspectives for its clinical application. Further research is needed to develop more effective and safer FMT techniques for horses.

The effect of Alzheimer's disease (AD) medications on CD4+ T cells homing has not been thoroughly investigated. Alzheimer's disturbs the life of at least five million persons in the USA. CD4+ T cells could both exacerbate and reduce AD symptoms. Regulating CD4+ T cells homing to the leaky blood-brain barrier (BBB) constitutes a new hope for enhancing AD prognosis. Alzheimer's drugs such as Donepezil (Aricept), Rivastigmine (Exelon), Galantamine (Razadyne) and memantine are known to play an important part in regulating the neurotransmitters mechanisms. However, little is known about the effect of these drugs on CD4+ T cells homing. In this review, we focus on current and new drugs that could modulate CD4+ T cells interactions with the BBB in AD.

The noradrenergic theory of Cognitive Reserve (Robertson, 2013-2014) postulates that the upregulation of the Locus Coeruleus - Noradrenergic System (LC-NA) originating in the Brainstem might facilitate cortical networks involved in attention, and protracted activation of this system throughout the lifespan may enhance cognitive stimulation contributing to Reserve. To test the above-mentioned theory, a study was conducted on a sample of 686 participants (395 controls, 156 Mild Cognitive Impairment, 135 Alzheimer’s Disease) investigating the relationship between LC volume, attentional performance and a biological index of brain maintenance (BrainPAD – an objective measure which compares an individual’s structural brain health, reflected by their voxel-wise grey matter density, to the state typically expected at that individual’s age). Further analyses were carried out on Reserve indices including education and occupational attainment. Volumetric variation across groups was also explored along with gender differences. Control analyses on the Serotoninergic (5-HT), Dopaminergic (DA) and Cholinergic (Ach) systems were contrasted with the Noradrenergic (NA) hypothesis. The antithetic relationships were also tested across the neuromodulatory subcortical systems.Results supported by bayesian modelling showed that LC volume disproportionately predicted higher attentional performance as well as biological brain maintenance across the three groups. These findings lend support to the role of the noradrenergic system as a key mediator underpinning the neuropsychology of Reserve, and they suggest that early prevention strategies focused on the noradrenergic system (e.g. cognitive-attentive training, physical exercise, pharmacological and dietary interventions) may yield important clinical benefits to mitigate cognitive impairment with age and disease.

The heterogeneity of tumor infiltrating lymphocytes is not well characterized in brain metastasis. To address this, we performed a targeted analysis of immune cell subsets in brain metastasis tissues to test which immunosuppressive routes are involved in brain metastasis. We performed multiplex immunofluorescence (mIF), using commercially available validated antibodies on twenty formalin-fixed paraffin embedded whole sections. We quantitated the subsets of immune cells utilizing a targeted panel of proteins including PanCK, CD8, CD4, VISTA and Iba1, and analyzed an average of 15000 cells per sample. We classified tumours as either high (>30%) or low (<30%) tumour infiltrating lymphocytes (TILs) and found that increased TILs density correlated with survival. We next sought out to phenotype these TILs using mIF. The tumours with low TILs (n=9) had significantly higher expression of the immune-checkpoint molecule VISTA in tumor cells (p<0.01) as well as in their microenvironment (p<0.001). Contrastingly, the brain metastatic tumours with high TILs (n=8) displayed higher levels of activated microglia, as measured by Iba1 expression. Low TILs-tumours displayed CD8+ T-cells that co-express VISTA (p<0.01) significantly more compared to high TILs group, where CD8+ T-cells significantly co-express Iba1 (p<0.05). Interestingly, no definite phenotypes of CD4+ subsets were observed. These results were supported by RNA analysis of a publicly available, independent cohort. In conclusion, our work contributes to a growing understanding of the immune surveillance escape routes active in brain metastasis.

Background: Morphological alterations in intracranial pressure pulse waveform (ICPPW) secondary to intracranial hypertension (ICP >20 mmHg) and reduction in intracranial compliance (ICC) are well known indicators of neurological severity. To date, no studies have documented the ICPPW modifications after intracranial hypertension resolution with decompressive craniectomy (DC). The present study aimed to assess the morphological alterations in ICPPW among neurocritical care patients with and without DC, by comparing the variations of ICPPW features according to elevations in mean ICP values. Methods: Patients requiring ICP monitoring because of severe traumatic or spontaneous conditions were included. Mean ICP values were compared with ICPPW features (P2/P1 ratio, TTP and pulse amplitude). Elevation in ICP was produced by means of ultrasound-guided manual internal jugular veins compression. Results were distributed for three groups: intact skull (exclusive burr hole for ICP monitoring), craniotomy/large fractures (group 2) or DC (group 3). Results: 57 patients were analyzed. 21 (36%) presented no skull defects, whereas 15 (26%) had DC. ICP was not significantly different between groups: ±13.59 for intact and ±17.66 mmHg for DC, with ICP induced elevation also similar between groups (p= 0.56). Significant elevation was observed for P2/P1 ratio for groups 1 and 2, whereas reduction was observed in group 3 (elevation of ±0.09 for groups 1 and 2, whereas reduction of 0.03 for group 3, p=0.01). Conclusion: In the present study, intracranial pressure pulse waveform analysis indicated that intracranial compliance was significantly more impaired among decompressive craniectomy patients, although ICPPW indicated DC to be protective for further influences of ICP elevations over the brain. Analysis of ICPPW seems to be an alternative to real time ICC assessment.

Background: The gut microbiome plays a major role in chronic diseases, of which several are characterized by an altered composition and diversity of bacterial communities. Large-scale sequencing projects allowed characterizing the perturbations of these communities. However, translating these discoveries into clinical applications remains a challenges. To facilitate routine implementation of microbiome profiling in clinical settings, portable, real-time, and low-cost sequencing technologies are needed. Results: Here, we propose a computational and experimental protocol for whole genome quantitative metagenomics studies of human gut microbiome with Oxford Nanopore sequencing technology (ONT) that could be applied to other microbial ecosystems. We developed a bioinformatic protocol to analyse ONT sequences taxonomically and functionally and optimized pre-analytic protocols including stool collection and DNA extraction methods to maximize read length. This is a critical parameter for the sequence alignment and classification. Our protocol was evaluated using simulations of metagenomic communities which reflect naturally occuring compositional variations. Next, we validated both protocols using stool samples from a bariatric surgery cohort, sequenced with ONT, Illumina and SOLiD technologies. Results revealed similar diversity and microbial composition profiles. Conclusion: This protocol can be implemented in the clinical or research setting, bringing rapid personalized whole genome profiling of target microbiome species.

Background: Plasma metabolites are associated with cognitive and physical function in the elderly. Because cerebral small vessel disease (SVD) and neurodegeneration are common causes of cognitive and physical function decline, the primary objective of this study was to investigate the associations of six plasma metabolites (two plasma phosphatidylcholines [PCs]: PC aa C36:5 and PC aa 36:6 and four sphingomyelins [SMs]: SM C26:0, SM [OH] C22:1, SM [OH] C22:2, SM [OH] C24:1) with magnetic resonance imaging (MRI) features of cerebral SVD and neurodegeneration in older adults. Methods: This study included 238 older adults in the Atherosclerosis Risk in Communities study at the fifth exam. Multiple linear regression was used to assess the association of each metabolite (log-transformed) in separate models with MRI measures except lacunar infarcts, for which binary logistic regression was used. Results: Higher concentrations of plasma PC aa C36:5 had adverse associations with MRI features of cerebral SVD (odds ratio of 1.69 [95% confidence interval: 1.01, 2.83] with lacunar infarct, and beta of 0.16 log [cm³] [0.02, 0.30] with log [White Matter Hyperintensities (WMH) volume]) while higher concentrations of 3 plasma SM (OH)s were associated with higher total brain volume (beta of 12.0 cm³ [5.5, 18.6], 11.8 cm³ [5.0, 18.6], and 7.3 cm³ [1.2, 13.5] for SM [OH] C22:1, SM [OH] C22:2, and SM [OH] C24:1, respectively). Conclusions: This study identified associations between certain plasma metabolites and brain MRI measures of SVD and neurodegeneration in older adults, particularly higher SM (OH) concentrations with higher total brain volume.

Lewis et al. published an important and timely necessary article about the determination of death by neurological criteria, revising the Uniform Determination of Death.The acceptance of brain death (BD) has been progressively accepted beginning at the late 1950s. Nonetheless, contentious brain-death cases have recently raised new controversies about the diagnosis of BD, such as the Jahi McMath case, extensively covered by the US and international press. Jahi McMath meant a terrible tragedy for her and her family. But further than this gloomy story, the case has also raised confusion and challenging qualms about a fundamental query: how we confirm whether a person is dead or alive? Since 1981, the Uniform Determination of Death Act (UDDA) has served as the legal foundation for the medical practice of determining death. But, although death by neurologic criteria is considered legal death throughout the United States, several recent lawsuits have quizzed the rightfulness the authority of the UDDA to declare death by neurological criteria. This issue explains the importance of Lewis’s et al. paper. In this article I want to present the historical procedure for issuing a law in Cuba for the determination and certification of death. Of course, it is impossible to compare our country with USA. Cuba is a small and developing country, in which a law encompasses a national scenery, in contrast with USA, a multistate nation.