Diabetes mellitus (DM) is the most common metabolic disease in humans, and its prevalence is increasing worldwide in parallel with the obesity pandemic. A lack of insulin or insulin resistance, and consequently hyperglycemia, leads to many systemic disorders, among which diabetic encephalopathy (DE) is a long-term complication of the central nervous system (CNS), characterized by cognitive impairment and motor dysfunctions. The role of oxidative stress and neuroinflammation in the pathomechanism of DE has been proven. Fractalkine (CX3CL1) has unique properties as an adhesion molecule and chemoattractant, and by acting on its only receptor, CX3CR1, it regulates the activity of microglia in physiological states and neuroinflammation. Depending on the clinical context, CX3CL1-CX3CR1 signaling may have neuroprotective effects by inhibiting the inflammatory process in microglia or, conversely, maintaining/intensifying inflammation and neurotoxicity. This review discusses the evidence supporting that the CX3CL1-CX3CR1 pair is neuroprotective and other evidence that it is neurotoxic. Interrupting the vicious cycle within neuron-microglia interactions may be a therapeutic goal in DE by limiting the inflammatory response.

A facilitative transport system exists on the blood brain barrier (BBB) that has been tacitly assumed to be a path for glutamate entry to brain. But glutamate is a non-essential amino acid whose brain content is much greater than plasma, and studies in vivo show that glutamate does not enter brain in material quantities except in those small regions with fenestrated capillaries (circumventricular organs). The situation became understandable when luminal (blood facing) and abluminal (brain facing) membranes were isolated and studied separately. Facilitative transport of glutamate and glutamine exist only on the luminal membranes whereas Na+-dependent transport systems for glutamate, glutamine and some other amino acids are present only on the abluminal membrane. The Na+-dependent cotransporters of the abluminal membrane are in a position to actively transport amino acids from the extracellular fluid (ECF) into the endothelial cells of the BBB. These powerful secondary active transporters couple the energy of the Na+-gradient to move glutamate and glutamine into the ECF whereupon glutamate can exit to blood on the luminal facilitative glutamate transporter. Glutamine may also exit brain on a separate facilitative transport system that exists on the luminal membranes or glutamine can be hydrolyzed to glutamate within the BBB thereby releasing ammonia that is freely diffusible. The γ-glutamyl participate cycle participates indirectly by producing oxoproline (pyroglutamate) that stimulates almost all secondary active transporters yet discovered in the abluminal membranes of the BBB.

The blood-brain barrier (BBB), built by brain endothelial cells (BECs), is impermeable to biologics. Liposomes and other nanoparticles are good candidates for delivery of biologics across the BECs, as they can encapsulate numerous molecules of interest in an omnipotent manner. The liposomes need attachment of a targeting molecule, as BECs unfortunately are virtually incapable of uptake of non-targeted liposomes from the circulation. Experiments of independent research groups have qualified antibodies targeting the transferrin receptor as superior for targeted delivery of nanoparticles to BECs. Functionalization of nanoparticles via conjugation with anti-transferrin receptor antibodies leads to nanoparticle uptake by endothelial cells of both brain capillaries and post-capillary venules. Reducing the density of transferrin receptor-targeted antibodies conjugated to liposomes limits uptake in BECs. Opposing the transport of nanoparticles conjugated to high-affine anti-transferrin receptor antibodies, lowering the affinity of the targeting antibodies or implementing monovalent antibodies increase uptake by BECs and allows for further transport across the BBB. The novel demonstration of transport of targeted liposomes in post-capillary venules from blood to the brain is interesting and clearly warrants further mechanistic pursuit. The recent evidence for passing targeted nanoparticles through the BBB shows great promise for future drug delivery of biologics to the brain.

Blood-brain-barrier is a major obstacle in treating brain-related disorders as it does not allow to deliver drugs in the brain. In order to facilitate delivery of drugs in brain, we developed a method for predicting blood-brain-barrier penetrating peptides. These blood-brain barriers penetrating peptides (B3PPs) can act as therapeutic as well as drug delivery agents. We trained, tested, and evaluated our models on blood-brain-barrier peptides obtained from the B3Pdb database. First, we compute a wide range of peptide features then we select relevant peptide features. Finally, we developed numerous machine learning-based models for predicting blood-brain-barrier peptides using selected features. Our model based on random forest performed best on the top 80 selected features and achieved a maximum 85.08% accuracy with 0.93 AUROC. We also developed a web server, B3pred that implements our best models. It has three major modules that allow users to; i) predict B3PPs, ii) scanning B3PPs in a protein sequence, and iii) designing B3PPs using analogs. Our web server and standalone software is freely available at https://webs.iiitd.edu.in/raghava/b3pred/.

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.

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.

Device-mediated, non-invasive drug delivery across the blood-brain barrier (BBB) represents a significant advancement in treating neurological diseases. The BBB is a tightly packed layer of endothelial cells that shields the brain from harmful substances in the blood, allowing necessary nutrients to pass through. It is a highly selective barrier, which poses a challenge to delivering therapeutic agents into the brain. Several non-invasive techniques and devices have been proposed or investigated to enhance drug delivery across the BBB. This paper presents the current state of the art and case studies that address the pharmacology, technology, delivery systems, regulatory approval, ethical concerns, and future possibilities.

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.

Background. Transferrin receptor 1 (TfR1), glucose transporter 1 (GLUT1), and CD98hc are candidates for targeted therapy at the blood-brain barrier (BBB). Our objective was to challenge the expression of TfR1, GLUT1, and CD98hc in brain capillaries by the histone deacetylase inhibitor (HDACi) valproic acid (VPA). Methods. Primary mouse brain capillary endothelial cells (BCECs) and brain capillaries isolated from mice injected intraperitoneally with VPA were examined using RT-qPCR and ELISA. Targeting to the BBB was performed by injecting monoclonal anti-TfR1 (Ri7217)-conjugated gold nanoparticles measured using ICP-MS. Results. In BCECs co-cultured with glial cells, Tfrc mRNA expression was significantly higher after 6 h VPA returning to baseline after 24 h. In vivo Glut1 mRNA expression was significantly higher in males, but not females', receiving VPA, whereas Cd98hc mRNA expression was unaffected by VPA. TfR1 increased significantly in vivo after VPA, whereas GLUT1 and CD98hc were unchanged. Uptake of anti-TfR1-conjugated nanoparticles was unaltered by VPA in spite upregulated TfR expression. Conclusions. VPA upregulates TfR1 in brain endothelium in vivo and in vitro. VPA does not increase GLUT1 and CD98hc proteins. The increase in TfR1 does not result in higher anti-TfR1 antibody targetability, suggesting targeting sufficiently occurs with available transferrin receptors without further contribution from accessory VPA-induced TfR1.

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.

The blood brain barrier (BBB) is an essential component in regulating and maintaining the homeostatic microenvironment of the central nervous system (CNS). During the occurrence and development of glioblastoma (GBM), BBB is pathologically disrupted with markedly increased permeability. Due to the obstruction imposed by the BBB, strategies currently employed for GBM therapeutics still obtain a very low success rate and lead to systemic toxicity. Moreover, chemotherapy could promote pathological BBB functional restoration, accompanied with a prominent decrease of intracerebral therapeutics transportion during GBM multiple administration, resulting in chemotherapy failure for GBM treatment. The effective delivery of therapeutics into the brain still faces with severe challenges. Regulation of pathological BBB for enhanced transporting of therapeutics across the barrier may provide new opportunities for effective and safe treatment of GBM. This article reviews the structure and function of BBB in physiological state, the mechanisms underlying BBB pathological fenestration during the development of GBM, and the therapeutic strategies of GBM based on BBB intervention and therapeutic drugs transporting across the BBB.

Pericytes are increasingly recognized as being important in the control of blood-brain barrier permeability and vascular flow. Research on this important cell type has been hindered by widespread confusion regarding the phenotypic identity and nomenclature of pericytes and other perivascular cell types. In addition, pericyte heterogeneity and mouse-human species differences have contributed to confusion. Herein we summarize our present knowledge on the identification of pericytes and pericyte subsets in humans, primarily focusing on recent findings in humans and nonhuman primates. Precise identification and definition of pericytes and pericyte subsets in humans may help us to better understand pericyte biology and develop new therapeutic approaches specifically targeting disease-associated pericyte subsets.

One of the hallmarks of Alzheimer’s disease (AD) is the accumulation of beta-amyloid peptide (Aβ) leading to formation of soluble neurotoxic Aβ oligomers and insoluble amyloid plaques in various parts of the brain. Aβ undergoes post-translational modifications that alter its pathogenic properties. Aβ is produced not only in brain, but also in the peripheral tissues. Such Aβ, including its post-translationally modified forms, can enter the brain from circulation by binding to RAGE and contribute to the pathology of AD. However, the transport of modified forms of Aβ across the blood–brain barrier (BBB) has not been investigated. Here, we used a transwell BBB model as a controlled environment for permeability studies. We found that Aβ42 containing isomerized Asp7 residue (iso-Aβ42) and Aβ42 containing phosphorylated Ser8 residue crossed the BBB better than unmodified Aβ42, which correlated with different contribution of endocytosis mechanisms to the transport of these isoforms. Using microscale thermophoresis, we observed that RAGE binds to iso-Aβ42 an order of magnitude weaker than to Aβ42. Thus, post-translational modifications of Aβ increase the rate of its transport across the BBB and modify the mechanisms of the transport, which may be important for AD pathology and treatment.

Over past decades, a frequent co-morbidity of cerebrovascular pathology and Alzheimer's disease pathology has been observed. Numerous published studies indicate that preservation of healthy cerebrovascular endothelium can be an important therapeutic target. 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 1 (i.e., SR-BI), and crosses the blood-brain barrier. This targeting allows for various Alzheimer’s-related cell types to be simultaneously searched out for localized drug treatment in vivo.

Breast cancer brain metastasis (BCBM) is a challenging condition with limited treatment options and poor prognosis. Understanding the interactions between tumor cells and the blood-brain barrier (BBB) is critical for developing novel therapeutic strategies. One promising target is estrogen receptor β (ERβ), which promotes the expression of key tight junction proteins, sealing the BBB and reducing its permeability. In this study, we investigated the effects of 17β-estradiol (E2) and the selective ERβ agonist diarylpropionitrile (DPN) on endothelial and cancer cells. Western blot analysis revealed the expression patterns of ERs in these cell lines, and estrogen treatment upregulated claudin-5 expression in brain endothelial cells. Using in vitro models of the BBB, we found that DPN treatment significantly increased BBB tightness about suppressed BBB transmigration activity of representative HER2-positive (BT-474) and triple-negative (MDA-MB-231) breast cancer cell lines. However, the efficacy of DPN treatment decreased when cancer cells were pre-differentiated in the presence of E2. Our results support ERβ as a potential target for the prevention and treatment of BCBM and suggest that targeted vector-based approaches may be effective for future preventive and therapeutic implications.

Development of new neurotherapeutics is strongly depending on appropriate animal model chosen in preclinical studies. A cuprizone model is an effective tool for studying demyelination and re-myelination processes in the brain, but BBB integrity in cuprizone model is still a topic for debate. Several publications claim that BBB remains intact during cuprizone-induced demyelination; others demonstrate results that could be explained by the increased BBB permeability. In our work we aim to analyze permeability of BBB for different macromolecules, particularly, antibody-conjugates in cuprizone-intoxicated mice. We compared the traditional approach using Evans blue injection with following dye extraction and detection of antibody-conjugates using magnetic resonance imaging (MRI) and confocal microscopy to analyze BBB permeability in cuprizone model. First, we validated our model of demyelination by detecting changes in gene expression of myelin basic protein and proteolipid protein, and by performing MRI and histological analysis. Our results suggest that the methods with better sensitivity were able to detect the accumulation of macromolecules (such as fluorescent-labeled or gadolinium-labeled antibody conjugates) in the brain, suggesting a local BBB disruption in the demyelinating area. These findings support previous investigations that ques-tioned BBB integrity in cuprizone model and demonstrate possibility for delivery of anti-body-conjugates to demyelinated corpus callosum

Controlling CD4+ immune cells infiltration of the brain is a leading aim in designing therapeutic strategies for a range of neuropathological disorders such as; multiple sclerosis, Alzheimer and depression. CD4+ T cells are a highly heterogeneous and reprogrammable family, that includes various distinctive cell types such as Th17, Th1, and Tregs. Interestingly Th17 and Tregs share a related transcriptomic profile, where the TGFβ-SMADS pathway plays a fundamental role in regulating the differentiation of both of these cell types. However, Th17 could be highly pathogenic and was shown to promote inflammation in various neuropathological disorders. Conversely, Treg is anti-inflammatory and is known to inhibit Th17. It could be noticed that Th17 frequencies of infiltration of the blood-brain barrier (BBB) in various neurological disorders are significantly upregulated. However, Treg infiltration numbers are significantly low. The reasons behind these contradicting observations are still unknown. In this perspective, we propose that the difference in the TCR repertoire diversity, diapedesis pathways, chemokine expression and mechanical properties of these two cell types could be contributing to answering this intriguing question.

The blood-brain barrier (BBB) acts as a specialized structure separating the brain from peripheral blood circulation and plays an important role in brain function. Following an ischaemic stroke or cerebral ischaemia, the BBB is damaged leading to degraded proteins being released into blood circulation. However, little is known about cerebral ischaemia and reperfusion (I/R) induced BBB damage and changes in circulatory biomarkers. This study aims to use both immunohistochemistry and western blotting (WB) to examine neuronal death, glial cell alterations and changes in BBB tight junction (TJ) proteins such as zonula occludens-1 (ZO-1), Occludin and Claudin-5 in the hippocampus in a murine model of cerebral I/R. The changes in these proteins in the blood serum of this model were assessed by enzyme-linked immunosorbent assay. The results showed neuronal death and a significant increase in glial fibrillary acidic protein (GFAP), a protein primarily expressed in astrocytes and a significant decrease in TJ proteins, ZO-1, Occludin and Claudin-5 in the hippocampus of occluded mice as compared to sham-operated mice. These changes are associated with an increased level of these proteins in blood serum in ischaemic mice, suggesting that these proteins can be used as potential biomarkers for determining ischaemic stroke.

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.

Telomeres, located at the ends of each chromosome play a vital role in determining cellular fate and aging. Accelerated shortening of telomeres may also result in accelerated aging and occurrence of age-related degenerative diseases. Anti-aging treatments may help in increasing the telomere length along with improving quality of life, reducing dependency for daily life activities, increasing life expectancy and reducing the risks associated with aging. In this study, we evaluated the effect of anti-aging integrative therapy in 36 individuals. The treatment included a combination of HBOT, ozone therapy, colon hydrotherapy, etc. Telomere length was used as a biomarker for objectively quantifying the outcome of the treatment. The effect of treatment was also assessed on various aging symptoms. At the end of the treatment, it was found that that 97.22% individuals showed an increase in telomere length with an average increase of 0.43 Kbp and 94.44% individuals showed reduced biological age with an average decrease of 3.8 years. These improvements were statistically significant. Improvements were also recorded in the majority of the symptoms. No major adverse events were observed. These results indicate that antiaging integrative therapy has the potential to reverse aging symptoms, cellular aging and improve quality of life.

Diabetes mellitus is one of the most common metabolic diseases worldwide, and its long-term complications include neuropathy, referring both to the peripheral and to the central nervous system. Detrimental effects of dysglycemia, especially hyperglycemia, on the structure and function of blood-brain barrier (BBB) seem to be a significant backgrounds of diabetic neuropathy pertaining to the central nervous system (CNS). Effects of hyperglycemia, including excessive glucose influx to insulin independent cells, may induce oxidative stress and secondary innate immunity dependent inflammatory response which can damage cells within the CNS, thus promoting neurodegeneration and dementia. Advanced glycation end products (AGE) may exert similar, pro-inflammatory effects through activating receptors for advanced glycation end products (RAGE), as well as some pattern-recognition receptors (PRR). Moreover, long-term hyperglycemia can promote brain insulin resistance, which may in turn promote Aβ aggregate accumulation and tau hyperphosphorylation. This review is focused on a detailed analysis of the effects mentioned above towards the CNS, with special regard to mechanisms taking part in the pathogenesis of central long-term complications of diabetes mellitus initiated by the loss of BBB integrity.

The neurovascular niche is crucial for constant blood supply and blood-brain barrier (BBB) function and is altered in a number of different neurological conditions, making this an intensely active field of research. Brain vasculature is unique for its tight association of endothelial cells with astrocytic endfeet processes. Separation of the vascular compartment by centrifugation-based methods confirmed enrichment of astrocytic endfeet processes, making it possible to study the entire vascular niche with such methods. Several centrifugation-based separation protocols are found in the literature; however, with some constraints which limit their applicability and the scope of the studies. Here, we describe and validate a protocol for physically separating the neurovascular niche from the parenchyma, which is optimized for smaller tissue quantities. Using endothelial, neuronal and astrocyte markers, we show that quantitative Western blot-based target detection can be performed of both the vascular and parenchymal fractions using as little as a single mouse brain hemisphere. Validation of our protocol in rodent stroke models by detecting changes in serum albumin signals and astrocyte activation, i.e. increased glial fibrillary acidic protein expression, between the ipsilateral and the lesion-free contralateral hemisphere demonstrates this protocol as a new way of detecting BBB breakdown and astrogliosis, respectively.

A central hypothesis on brain functioning is that plasticity regulates the signals transfer function by modifying the efficacy of synaptic transmission. In the cerebellum, granular layer has been shown to control the gain of signals transmitted through the mossy fiber pathway. Until now, the impact of plasticity on incoming activity patterns was analyzed by combining electrophysiological recordings in acute cerebellar slices and computational modeling, unraveling a broad spectrum of different forms of synaptic plasticity in the granular layer, often along with forms of intrinsic excitability changes. Here, we attempt to provide a brief overview of the most prominent forms of plasticity at excitatory synapses formed by mossy fibers onto principal neurons (granule cells, Golgi cells and unipolar brush cells) in the granular layer. Specifically, we will highlight current understanding of the mechanisms and their functional implications of the synaptic and intrinsic plasticity, providing valuable insights into how inputs are processed and reconfigured at the cerebellar input stage.

Obstructive sleep apnea (OSA) is a chronic condition characterized by intermittent hypoxia (IH) and sleep fragmentation (SF). In murine models, chronic SF can impair endothelial function and induce cognitive declines. These deficits are likely mediated, at least in part, by alterations in Blood-Brain Barrier (BBB) integrity. Male C57Bl/6J mice were randomly assigned to SF or sleep control (SC) conditions for 4 or 9 weeks, and in a subset 2 or 6 weeks of normal sleep recovery. Presence of inflammation and microglia activation were evaluated. Explicit memory function was assessed with the novel object recognition (NOR) test, while BBB permeability was determined by systemic dextran-4kDA-FITC injection and Claudin 5 expression. SF exposures resulted in decreased NOR performance and in increased inflammatory markers and microglial activation as well as enhanced BBB permeability. Explicit memory and BBB permeability were significantly associated. BBB permeability remained elevated after 2 weeks of sleep recovery (p<0.01) and returned to baseline values only after 6 weeks. Chronic SF exposures mimicking the fragmentation of sleep that characterizes patient with OSA elicits evidence of inflammation in brain regions and explicit memory impairments in mice. Similarly, SF is also associated with increased BBB permeability, the magnitude of which is closely associated with cognitive functional losses. Despite normalization of sleep patterns, BBB functional recovery is a protracted process that merits further investigation.

Angiostrongylus cantonensis, a zoonotic parasite, can invade the human central nervous system (CNS) and cause acute eosinophilic meningitis or eosinophilic meningoencephalitis. Mice infected with A. cantonensis show elevated levels of pro-inflammatory cytokines, plasminogen activators, and matrix metalloproteinase-9, resulting in disruption of the blood-brain barrier (BBB) and immune cell infiltration into the CNS. Caveolin-1 (Cav-1) regulates the permeability of the BBB, which affects immune cells and cerebrospinal fluid. This intricate interaction ultimately fuels the progression of brain damage and edema. This study aims to investigate the regulatory role of Cav-1 in the pathogenesis of meningoencephalitis induced by A. cantonensis infection. We investigate pathological alterations by triphenyl-tetrazolium chloride, brain water content, BBB permeability, Western blot analysis, and gelatin zymography in BALB/c mice after A. cantonensis. The study evaluates the critical role of Cav-1 regulation through the TLR4 / MyD88 signaling pathway, modulates tight junction proteins, influences BBB permeability, and contributes to brain damage in A. cantonensis-induced meningoencephalitis.

Neurodegenerative diseases encompass a broad spectrum of profoundly disabling disorders that impact millions of individuals globally. While their underlying causes and pathophysiol-ogy display considerable diversity and remain incompletely understood, a mounting body of evidence indicates that the disruption of blood-brain barrier (BBB) permeability, resulting in brain damage and neuroinflammation, constitutes a shared characteristic among them. Con-sequently, targeting the BBB has emerged as an innovative therapeutic strategy for address-ing neurological diseases. Within this review, we not only explore the neuroprotective, neu-rotrophic, and immunomodulatory benefits of mesenchymal stem cells (MSCs) in combating neurodegeneration but also delve into their recent role in modulating the BBB. We will delve into the cellular and molecular mechanisms through which MSC treatment impacts primary age-related neurological disorders like Alzheimer’s disease, Parkinson’s disease, and stroke as well as immune-mediated conditions such as multiple sclerosis. Our focus will center on how MSCs participate in the modulation of cell transporters, matrix remodeling, stabilization of cell-junction components, and restoration of BBB network integrity in these pathological con-texts.

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.

The blood-brain barrier (BBB) is a selectively permeable boundary that separates the circulating blood from the extracellular fluid of the brain and is an essential component for brain homeostasis. In glioblastoma (GBM), the BBB of peritumoral vessels is often disrupted. Pericytes, being important to maintain the BBB integrity, can be functionally modified by GBM cells by inducing proliferation and cell motility via the TGF-β-mediated induction of central epithelial to mesenchymal transition (EMT) factors., We demonstrate that pericytes strengthen the integrity of the BBB in primary endothelial cell/pericyte co-cultures as in vitro BBB model, using TEER measurement of the barrier integrity. In contrast, this effect was abrogated by TGF-β or conditioned medium from TGF-β secreting GBM cells, finally leading to the disruption of a so far intact and tight BBB. TGF-β dramatically changed the metabolic behavior of pericytes, such as shutting down the TCA cycle, driving energy generation from oxidative phosphorylation towards glycolysis, and by shifting the cells towards the activation of pathways that are necessary to produce molecules used for proliferation and cell division. Furthermore, combined metabolomics and RNASeq analyses indicated that the observed functional changes of TGF-β-treated pericytes are closely connected with their behavior.

Dynamic contrast-enhanced MRI (DCE-MRI) is increasingly used to quantify and map the spatial distribution of blood-brain barrier (BBB) leakage in neurodegenerative disease, including cerebral small vessel disease and dementia. However, the subtle nature of leakage and resulting small signal changes make quantification challenging. While simplified one-dimensional simulations have probed the impact of noise, scanner drift, and model assumptions, the impact of spatio-temporal effects such as gross motion, k-space sampling and motion artefacts on parametric leakage maps has been overlooked. Moreover, evidence on which to base the design of imaging protocols is lacking due to practical difficulties and the lack of a reference method. To address these problems, we present an open-source computational model of the DCE-MRI acquisition process for generating four-dimensional Digital Reference Objects (DROs), using a high-resolution brain atlas and incorporating realistic patient motion, extra-cerebral signals, noise and k-space sampling. Simulations using the DROs demonstrated a dominant influence of spatio-temporal effects on both the visual appearance of parameter maps and on measured tissue leakage rates. The computational model permits a greater understanding of the sensitivity and limitations of subtle BBB leakage measurement and provides a non-invasive means of testing and optimising imaging protocols for future studies.

Short video addiction refers to a psychological dependency on short video applications, characterized by an intense attachment and an inability to control usage, leading to typical addiction symptoms. While its definition bears similarities to substance addiction, significant differences also exist. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), published in 2013, short video addiction has not yet been officially classified as an addiction disorder. To facilitate more in-depth and standardized research on short video addiction, it is essential to synthesize and organize existing studies on its theoretical foundations and mechanisms.

There is a huge interest in developing novel hollow fiber (HF) membranes able to modulate neural differentiation to produce in vitro blood-brain barrier (BBB) models for biomedical and pharmaceutical research, due to the low cell-inductive properties of the polymer HFs used in current BBB models. In this work, poly(ε-caprolactone) (PCL) and composite PCL/graphene (PCL/G) HF membranes were prepared by phase inversion and were characterized in terms of mechanical, electrical, morphological, chemical, and mass transport properties. The presence of graphene in PCL/G membranes enlarged the pore size and the water flux and presented significantly higher electrical conductivity than PCL HFs. Biocompatibility assay showed that PCL/G HFs significantly increased C6 cells adhesion and differentiation towards astrocytes, may be attributed to their higher electrical conductivity in comparison to PCL HFs. On the other hand, PCL/G membranes produced a cytotoxic effect on the endothelial cell line HUVEC presumably related with a higher production of intracellular reactive oxygen species induced by the nanomaterial in this particular cell line. These results prove the potential of PCL HF membranes to grow endothelial cells and PCL/G HF membranes to differentiate astrocytes, the two characteristic cell types that could develop in vitro BBB models in future 3D co-culture systems.

Therapeutic antibodies targeting immune checkpoints have shown limited efficacy in clinical trials in glioblastoma (GBM) patients. Ultrasound-mediated blood-brain barrier opening (UMBO) using low-intensity pulsed ultrasound improved drug delivery to the brain. We explored the safety and the efficacy of UMBO plus immune checkpoint inhibitors in preclinical models of GBM. A Blood-brain barrier (BBB) opening was performed using a 1 MHz preclinical ultrasound system in combination with 10µl/g microbubbles. Brain penetration of immune checkpoint inhibitors was determined, and immune cell populations were evaluated using flow cytometry. The impact of repeated treatments on survival was determined. In syngeneic GL261-bearing immunocompetent mice, we showed that UMBO safely and repeatedly open the BBB. BBB opening was confirmed visually and microscopically using Evans’s blue dye and magnetic resonance imaging. UMBO plus anti-PDL-1 was associated with a significant improvement of the overall survival compared to anti-PD-L1 alone. Using mass spectroscopy, we showed that the penetration of therapeutic antibodies can be increased when delivered intravenously compared to non-sonicated brains. Furthermore, we observed an enhancement of activated microglia percentage when combined with anti-PD-L1. Here, we report that the combination of UMBO and anti-PD-L1 dramatically increases GL261-bearing mice's survival compared to their counterparts treated with anti-PD-L1 alone. Our study highlights the BBB as a limitation to overcome to increase the efficacy of anti-PD-L1 in GBM and supports clinical trials combining UMBO and in GBM patients.

Abstract Cerebral microbleed(s) (CMBs) are increasingly being viewed not only as a marker for cerebral small vessel disease (SVD) but also as having an increased risk for the development of stroke (hemorrhagic/ischemic) and aging-related dementia. Recently, brain endothelial cell activation and dysfunction and blood-brain barrier dysfunction and/or disruption have been shown to be associated with SVD, enlarged perivascular spaces, and the development and evolution of CMBs. CMBs are a known disorder of cerebral microvessels that are visualized as 3-5mm, smooth, round or oval, and hypointense (black) lesions seen only on T2*-weighted gradient recall echo or susceptibility-weighted sequences on MRI images. CMBs (a global problem) are known to occur with high prevalence in community-dwelling older individuals. Since our current global population is the oldest recorded in history and only expected to continue to grow, we can only expect the health care burdens associated with CMBs to also grow. CMBs should raise a red flag regarding the increased risk of large symptomatic neurologic intracerebral hemorrhages. Importantly, CMBs are also currently regarded as markers of diffuse vascular and neurodegenerative brain damage. Thus, it is essential that we try to learn as much as we can about their development, evolution, and their relation to impaired cognition, dementia, and neurodegeneration.

The lymphatic system of the brain meninges and head plays a crucial role in the clearance of amyloid-β protein (Aβ), a peptide thought to be pathogenic in Alzheimer’s disease (AD), from the brain. The development of methods to modulate lymphatic clearance of Aβ from the brain coild be a revolutionary step in the therapy of AD. The opening of the blood-brain barrier (OBBB) by focused ultrasound is considered as a possible tool for stimulation of clearance of Aβ from the brain of humans and animals. Here, we propose an alternative method of non-invasive music-induced OBBB that is accompanied by the activation of clearance of fluorescent Aβ (Fαβ) from the mouse brain. Using confocal imaging, fluorescence microscopy and magnetic resonance tomography, we clearly demonstrate that OBBB by music stimulates the movement of Fαβ and Omniscan in the cerebrospinal fluid and lymphatic clearance of Fαβ from the brain. We propose the extended detrended fluctuation analysis (EDFA) as a promising method for the identification of OBBB markers in the electroencephalographic (EEG) patterns. These pilot results suggest that music-induced OBBB and the EDFA analysis of EEG can be a non-invasive, low cost, labelling free, clinical perspective and completely new approach for the treatment and monitoring of AD.

Targeting drugs to the central nervous system (CNS) is challenging due to the presence of the blood-brain barrier. (BBB). The cutting edge in nanotechnology generates optimism to overcome the growing challenges in biomedical sciences through effective engineering of nanogels. The primary objective of the present report was to develop and characterize biocompatible natural chitosan (CS)-based NG that can be tracked thanks to the tricarbocyanine (CNN) fluorescent probe addition of the biopolymer backbone. FTIR shed light on the chemical groups involved in the CS and CNN interactions and between CNN-CS with tripolyphosphate, the cross-linking agent. Both in vitro and in vivo experiments were carried out to determine if CS-NG can be utilized as therapeutic delivery vehicles directed towards the brain. An ionic gelation method was chosen to generate cationic CNN-CS-NG. DLS and TEM confirmed that these entities size fell into nanoscale. CNN-CS-NG was found to be non-cytotoxic as determined in the SH-SY5Y neuroblastoma cell line through biocompatibility assays. After cellular internalization, the occurrence of an endo-lysosomal escape (a crucial event for an efficient drug delivery) of CNN-CS-NG was detected. Furthermore, CNN-CS-NG administered intraperitoneally to female CF-1 mice were detected in different brain regions after 2 h of administration using fluorescence microscopy. To conclude, the obtained findings in the present report can be useful in the field of neuro-nanomedicine when designing drug vehicles with the purpose of delivering drugs to the CNS.

The appearance of brain metastasis is the most serious complication of breast cancer with mostly fatal outcomes. To reach the brain, tumor cells need to pass the blood-brain barrier (BBB). The molecular mechanisms underlying penetration of the BBB are largely unknown. Previously we found that tumor-infiltrating T lymphocytes enhance the development of brain metastasis of estrogen receptor-negative (ER-) breast cancer. In the current study, we investigate the contribution of T lymphocytes and the IFN- pathway in enabling breast cancer cells to pass the in vitro BBB. CD8+ cells display the strongest stimulatory effect on breast cancer cell passage. We show that inhibition of the IFN- receptor in MDA-MB-231 breast cancer cells, or neutralization of soluble IFN-, impairs the in vitro trespassing of breast cancer cells. Importantly, we validated our findings using gene expression data of breast cancer patients. CXCL-9,-10,-11/CXCR3 axis, dependent on IFN- signaling activity, was overexpressed in primary breast cancer samples of patients who developed brain metastasis. The data support a role for T-lymphocytes and the IFN- pathway in the formation of brain metastasis of ER- breast cancer, and offer targets to design future therapies for preventing breast cancer cells to cross the BBB.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a single stranded RNA virus which has resulted in the Coronavirus Disease 2019 (COVID-19) pandemic and has infected millions of people all over the world. SARS-CoV-2 has been mutating rapidly resulting in the emergence of multiple variants to escape the host immune system mainly by mutations in its receptor binding domain (RBD) of the spike protein. This rapid evolution of the SARS-CoV-2 posed a great challenge regarding the efficacy and effectiveness of the current SARS-CoV-2 vaccines. The RBD and full-length spike of SARS-CoV-2 is the main target of the neutralizing antibodies. Many SARS-CoV-2 variants are considered to have the potential to escape from the host immune system. In this study, the RBD of Alpha, Beta, Gamma, Kappa and Omicron and the full-length spike of BA.1, BA.2, BA.3, BA.4/5, BQ.1.1 and XBB.1.5 Omicron variants were used as coating antigens in Enzyme Linked Immuno-Sorbent Assay (ELISA) to check the neutralization capability of COVID-19 convalescent sera from patients of first wave of infection occurring in Wuhan. Our results show that the currently circulating Omicron BQ.1.1, XBB.1.5 and previous Omicron BA.1, BA.2 and BA.4/5 do not show significant reduction in neutralization, while Omicron BA.3 and previous variants Alpha, Beta, Gamma, Kappa, and Omicron showed a significantly reduced neutralization when compared to the wild-type Wuhan strain. These results indicate patients recovering from natural infection of early original Wuhan strain may have the potential to resist infection of current circulating variants and the vaccines using the prototype antigen may still working for newly emerged variants.

Macrophages as a source and target of GDF-15

Brain aging causes a wide variety of changes at molecular and cellular levels, leading to the decline of cognitive functions and increased vulnerability to neurodegenerative disorders. The research aimed at understanding the aging of the brain has made much progress in recent decades. Technological innovations such as single-cell RNA-sequencing (scRNA-seq), proteomic analyses, and spatial transcriptomic analyses have facilitated the research on the dynamic changes occurring within neurons, glia, and other cells along with their impacts on intercellular communication during aging. In this review, we introduce recent trends of how neurons and glia change during aging and discuss the impact of the brain microenvironment such as the blood-brain barrier (BBB).

Clustered regularly interspaced short palindromic repeats (CRISPR) based gene-editing has begun to transform the treatment landscape of genetic diseases. The history of the discovery of CRISPR/CRISPR-associated (Cas) proteins/single guide RNA (sgRNA)-based gene-editing since the first report of repetitive sequences of unknown significance in 1987 is fascinating, instructive, and inspiring for future advances. The recent approval of CRISPR-Cas9-based gene therapy to treat patients with severe sickle cell anemia and transfusion-dependent beta thalassemia has renewed hope for treating other hematologic diseases, including patients with germline predisposition to hematologic malignancies, who would benefit greatly from the development of CRISPR-based gene therapies. The purpose of this manuscript is three-fold: first, a chronological description of the history of CRISPR-Cas9-sgRNA-based gene editing; second, a brief description of the current state of clinical research in hematologic diseases, including selected applications in treating hematologic diseases with CRISPR-based gene therapy; and third, the current progress in gene therapies in inherited hematologic diseases and bone marrow failure syndromes, to hopefully stimulate efforts towards developing these therapies for patients with inherited bone marrow failure syndromes and other inherited conditions with germline predisposition to hematologic malignancies.

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.

Sparse training (ST) aims to ameliorate deep learning by replacing fully connected artificial neural networks (ANNs) with sparse or ultra-sparse ones, such as brain networks are, therefore it might benefit to borrow brain-inspired learning paradigms from complex network intelligence theory. Here, we launch the ultra-sparse advantage challenge, whose goal is to offer evidence on the extent to which ultra-sparse (around 1% connection retained) topologies can achieve any leaning advantage against fully connected. Epitopological learning is a field of network science and complex network intelligence that studies how to implement learning on complex networks by changing the shape of their connectivity structure (epitopological plasticity). One way to implement Epitopological (epi- means new) Learning is via link prediction: predicting the likelihood of non-observed links to appear in the network. Cannistraci-Hebb learning theory inspired the CH3-L3 network automata rule for link prediction which is effective for general-purpose link prediction. Here, starting from CH3-L3 we propose Epitopological Sparse Meta-deep Learning (ESML) to apply Epitopological Learning to sparse training. In empirical experiments, we find that ESML learns ANNs with ultra-sparse hyperbolic (epi-)topology in which emerges a community layer organization that is meta-deep (meaning that each layer also has an internal depth due to power-law node hierarchy). Furthermore, we discover that ESML can in many cases automatically sparse the neurons during training (arriving even to 30% neurons left in hidden layers), this process of node dynamic removal is called percolation. Starting from this network science evidence, we design Cannistraci-Hebb training (CHT), a 4-step training methodology that puts ESML at its heart. We conduct experiments on 7 datasets and 5 network structures comparing CHT to dynamic sparse training SOTA algorithms and the fully connected counterparts. The results indicate that, with a mere 1% of links retained during training, CHT surpasses fully connected networks on VGG16, GoogLeNet, ResNet50, and ResNet152. This key finding is an evidence for ultra-sparse advantage and signs a milestone in deep learning. CHT acts akin to a gradient-free oracle that adopts CH3-L3-based epitopological learning to guide the placement of new links in the ultra-sparse network topology to facilitate sparse-weight gradient learning, and this in turn reduces the convergence time of ultra-sparse training. Finally, CHT offers the first examples of parsimony dynamic sparse training because, in many datasets, it can retain network performance by percolating and significantly reducing the node network size. Our code is available at: https://github.com/biomedical-cybernetics/Cannistraci-Hebb-training.

This review article focuses on the upstream pertinent pathophysiology leading to neurodegenerative disease. Specifically, the nexus appears to be blood brain barrier (BBB) leakiness resulting in a two-prong inflammatory disease spectrum damaging the microvasculature and corrupted protein synthesis and degradation with accumulating misfolded toxic proteins. The suboptimal results of removing misfolded proteins means a new approach to disease in the preclinical state is required aimed at other targets.Validated noninvasive imaging and serologic biomarkers of early preclinical disease implemented in the high-risk patient cohort along with periodic surveillance once effective treatments are developed will be required.This review discusses the physiology and pathophysiology of the BBB, new MRI imaging techniques identifying the leak and altered fluid dynamic effects in the preclinical state. The risk factors for disease development, preventative measures, and potential treatment targets are also discussed.

Dynamic sparse training is an effective strategy to alleviate the training and inference demands of artificial neural networks. However, current sparse training methods face a challenge in achieving high levels of sparsity while maintaining performance comparable to that of their fully connected counterparts. The Cannistraci-Hebb training (CHT) method produces an ultra-sparse advantage compared to fully connected training in various tasks by using a gradient-free link regrowth method, which relies solely on the network topology. However, its rigid selection based on link prediction scores may lead to epitopological local minima, especially at the beginning of the training process when the network topology might be noisy and unreliable. In this article, we introduce the Cannistraci-Hebb training soft rule (CHTs), which applies a flexible approach to both the removal and regrowth of links during training, fostering a balance between exploring and exploiting network topology. Additionally, we investigate the network topology initialization using several approaches, including the bipartite scale-free and bipartite small-world network models. Empirical results show that CHTs can surpass the performance of fully connected networks with MLP architecture by using only 1% of the connections (99% sparsity) on the MNIST, EMNIST, and Fashion MNIST datasets and can provide remarkable results with only 0.1% of the links (99.9% sparsity). In some MLPs for image classification tasks, CHTs can reduce the active neuron network size to 20% of the original nodes (neurons), demonstrating a remarkable ability to generalize better than fully connected architectures, reducing the entire model size. This represents a relevant result for dynamic sparse training. Finally, we present evidence from larger network models such as Transformers, with 10% of the connections (90% sparsity), where CHTs outperform other prevalent dynamic sparse training methods in machine translation tasks.

Elizabethkingia anophelis is an opportunistic pathogen causing lifethreatening infections in humans, particularly in immunocompromised patients, neonates and elderly. Infections caused by this species are exceptionally challenging to treat due to its multiresistance to antimicrobials. We report a case of central line-associated bloodstream infection by E. anophelis in a 2.5-year-old girl with acute lymphoblastic leukemia successfully treated with a combination of piperacillin/tazobactam and amikacin. The literature was also reviewed on paediatric infections caused by E. anophelis. Accurate identification with MALDI-TOF, or using molecular techniques, is crucial because of varying susceptibilities among species. Early, accurate diagnosis and prompt effective treatment optimize outcomes.

The origin of neurodegenerative diseases is linked to the abnormal folding of disease-associated proteins. The traditional amyloid hypothesis has been a focal point of research, but recent findings suggest a more complex picture. This review explores the role of physiological conformation of aggregation-prone domain (also known as prion-like low complexity domain) and multiple co-misfolded proteins in neurodegenerative diseases. We highlight the importance of targeting multi-heterotypic misfolded proteins for effective treatments and emphasize the irreversible neurodegeneration stemming from the loss of physiological folding in prion-like disease-causing proteins underscores the criticality of refolding. Additionally, we introduce the concept of ReproFold Therapeutics, a novel approach aimed at restoring the cellular prion-like folding of disease-causing proteins to rebuild normal cross-β interactomes and mitigate neurodegeneration. Baicalein, a potential drug candidate for this approach, shows promise in vitro and in animal models. Moreover, prion-like low complexity domains implicated in neurodegeneration are also associated with other disorders such as diabetes, cancers, and mental illnesses. Understanding the core pathology of neurodegenerative diseases and the broader implications of prion-like LC domains could revolutionize healthcare approaches and policies worldwide.

The neurodegenerative diseases (Alzheimers, Parkinsons, amyotrophic lateral sclerosis, Huntingdons) and the prion disorders, have in common a dysregulation of metalloprotein chemistry involving redox metals (Cu,Fe,Mn). The consequent oxidative stress gives rise to protein plaques and neuronal cell death. An equilibrium exists between the functional requirement of the brain for Cu and Fe and their destructive potential with the production of reactive oxygen species. The importance of the brain barrier is highlighted in regulating the import of these metals. Upregulation of key transporters occurs in foetal and neonatal life when brain metal requirement is high and is down-regulated in adult life when need is minimal. By contrast a neonatal mode of CTR1 upregulation persists in feral N.Ronaldsay sheep. This has led to the premise that metal regulation may return to the default setting in ageing with implications for neurodegenerative disease.

Regardless of the SARS-CoV-2 pandemic containment, it remains paramount to comprehensively understand its underlying mechanisms to mitigate potential future health and economic impacts, comparable to those experienced throughout the course of the pandemic. The angiotensin-converting enzyme 2 (ACE2) provide anchorage for SARS-CoV-2 binding, thus implicating that ACE and ACE2 might contribute to the variability in infection severity. This study aimed to elucidate predisposing factors influencing the disease course among people infected by SARS-CoV-2, focusing on angiotensin-converting enzyme (ACE) and ACE2 polymorphisms. Notably, despite similar demographics and comorbidities, COVID-19 patients exhibit substantial differences in prognosis. Genetic polymorphisms in ACE and ACE2 have been implicated in disease progression, prompting our investigation into their role in COVID-19 evolution. Using next-generation sequencing (NGS), we analyzed ACE and ACE2 genes in a sample group comprising six subjects infected by SARS-CoV-2. Our findings revealed a correlation between specific polymorphisms and COVID-19 outcomes. Specifically, ACE and ACE2 intronic deletions were observed in all deceased patients, suggesting a potential association with mortality. These results highlight the significance of genetic factors in shaping the clinical course of COVID-19, emphasizing the importance of further research into the impact of genetic variations on COVID-19 severity.

Molecular analysis of growing teratoma syndrome has not been extensively studied. Here, we report a 14-year-old boy with a growing mass during treatment for a mixed germ cell tumor of the pineal region. Tumor markers were negative; thus, growing teratoma syndrome was suspected. A radical resection via the occipital transtentorial approach was performed, and histopathological examination revealed a teratoma with malignant features. Methylation classifier analysis confirmed the diagnosis of teratoma, and DMRT1 loss and 12p gain were identified by copy number variation analysis, potentially elucidating the cause of growth and malignant transformation of the teratoma. The patient remains in remission after intense chemoradiation treatment as a high-risk germ cell tumor.

Autoimmune hemolytic anemias (AIHAs) are conditions whereby a person produces an antibody to their own red blood cells (RBCs). These conditions can be primary with unknown cause or secondary, associated with diseases or infections. There are seven different categories of AIHA, warm-antibody AIHA (wAIHA); cold-antibody AIHA that includes cold agglutinin syndrome (CAS) and cold agglutin disease (CAD); mixed AIHA, also called combined cold and warm AIHA; paroxysmal cold hemoglobinuria (PCH) also termed Donath-Lansteiner test-positive AIHA; direct antiglobulin test-negative AIHA (DAT-neg AIHA); drug-induced immune hemolytic anemia (DIIHA); and passenger lymphocyte syndrome. This review will discuss each of these AIHAs and provide information on diagnosis and treatment.

This study explores innovative strategies to enhance hands-on learning experiences in a Database Management Systems (DBMS) course while addressing challenges related to software installation complexities and financial barriers. The investigation focuses on an online course format catering to students majoring in information systems, healthcare administration, business administration, and marketing. Traditional software installation hurdles, especially for complex systems like Microsoft Access and MySQL, can impede students' engagement and access. To overcome these challenges, the study proposes leveraging cloud-based solutions and clientless remote desktop gateways like Apache Guacamole. Results indicate that these approaches effectively eliminate software installation obstacles, ensuring seamless access to essential tools for all students. The study underscores the importance of innovative technological solutions in promoting inclusive and impactful learning environments in higher education.

The landscape of business intelligence (BI) is marked by rapid growth, extensive research, and practical implementations, reflecting its sustained relevance in modern business strategies. This paper delves into the dynamics of BI, particularly focusing on the interplay between maturity and agility. While BI maturity emphasizes optimization and predefined goals, BI agility prioritizes adaptability and response to change. The paper highlights the contradictions between these concepts, emphasizing the need for a balanced approach in BI strategy formulation.The role of organizational culture in fostering BI agility is explored through literature review and interviews with BI professionals. Key insights include the necessity of an open culture for effective BI utilization, clear strategic vision, decision delegation, information sharing, business-IT cooperation, and a learning-oriented mindset. These cultural factors contribute significantly to BI effectiveness and the ability to navigate dynamic business landscapes. The paper proposes pillars of agile maturity supported by an open organizational culture, including efficient communication, information integration, creative problem-solving, and close collaboration between business and IT. These pillars underscore the importance of a flexible and open mindset in navigating BI challenges and ensuring sustained value. Empirical validation and further research are suggested to deepen our understanding of the impact of organizational culture on BI agility and effectiveness.

The representation of intelligence is achieved by patterns of connections among neurons in brains and machines. Brains grow continuously, such that their patterns of connections develop through activity-dependent specification with the continuing ontogenesis of individual experience. The theory of active inference proposes that the developmental organization of sentient systems reflects general processes of informatic self-evidencing, through the minimization of free energy, that may be described in information terms that are not dependent on a specific physical substrate. At a certain level of complexity, self-evidencing of living (self-organizing) information systems becomes hierarchic and reentrant, such that effective consciousness emerges as the consequence of a good regulator. These principles imply that an adequate reconstruction of the computational dynamics of an individual human brain is possible with a sufficient neuromorphic emulation.

Temporal lobe epilepsy (TLE) is associated with reorganization of hippocampal neuronal net-works, gliosis, neuroinflammation, loss of integrity of the blood-brain barrier (BBB) in humans and animal models. More than 30% of epilepsies remain intractable and characterization of the molecular mechanisms involved in BBB dysfunction is essential to the identification of new thera-peutic strategies. In this work, we induced status epilepticus in rats by injection of the proconvul-sant drug pilocarpine that leads to TLE. Using RT-qPCR, double immunohistochemistry and con-focal imaging, we studied at different time points of epileptogenesis (latent phase, 3, 7, 14 days; chronic phase, 1 and 3 months) the regulation of reactive glia and vascular markers. In the hippo-campus, increased expression of mRNA encoding the glial proteins GFAP and Iba1 confirmed neu-roinflammatory status. We report for the first time the concomitant induction in endothelial cells, pericytes and basement membrane of the BBB of specific proteins CD31, PDGFR and ColIV, that peaks at the same time points as inflammation. The altered expression of these proteins occurs ear-ly in TLE, during the latent phase, suggesting that they could be associated with early rupture and pathogenicity of the BBB that will contribute to the chronic phase of epilepsy.

With the rapid growth of large language models (LLMs), there is increasing demand for memory and computation in LLMs. Recent efforts on post-training pruning of LLMs aim to reduce the model size and computation requirements, yet the performance is still sub-optimal. In this paper, we present a plug-and-play solution for post-training pruning of LLMs. The proposed solution has two innovative components: 1) Relative Importance and Activations (RIA), a new pruning metric that jointly considers the weight and activations efficiently on LLMs; and 2) Channel Permutation, a new approach to maximally preserve important weights under N:M sparsity. The two proposed components can be readily combined to further enhance the N:M semi-structured pruning of LLMs. Our empirical experiments show that RIA alone can already surpass all existing post-training pruning methods on prevalent LLMs, e.g., LLaMA ranging from 7B to 65B. Furthermore, N:M semi-structured pruning with channel permutation can even outperform the original LLaMA2-70B on zero-shot tasks, together with practical speed-up on specific hardware. Our code is available at: https://github.com/biomedical-cybernetics/Relative-importance-and-activation-pruning

As the most serious of the many worse new pathological changes caused by diabetes, there are many risk factors for the occurrence and development of DR. It mainly includes hyperglycemia, hypertension, hyperlipidemia and so on. Among them, hyperglycemia is the most critical cause, which plays a key role in the pathological changes of DR.High-sucrose diets(HSDs) lead to elevated blood glucose levels in vivo, which, through oxidative stress, inflammation, the production of AGEs and VEGF, causes plenty of pathological damages to the retina and ultimately bring about loss of vision. The existing therapies for DR primarily target the terminal stage of the disease, when irreversible visual impairment has appeared. Therefore, early prevention is particularly critical. Early prevention of DR-related vision loss requires adjustments to dietary habits, mainly by reducing sugar intake. This article primarily discusses the risk factors, pathophysiological processes, and molecular mechanisms associated with the development of DR caused by HSDs. It aims to raise awareness of the crucial role of diet in the occurrence and progression of DR, promote timely changes in dietary habits, prevent vision loss, and improve the quality of life. The aim is to make people aware of the importance of diet in the occurrence and progression of DR. According to the dietary modification strategies we give, patients can change their poor eating habits timely, avoid the retinopathy that can be avoided theoretically, and obtain a excellent outcome.

This study examines the contribution of early executive functions (EFs) in the association between fluency in reading and arithmetic. Kindergarten children (N = 1,185) were assessed on Executive Functions skills and on reading and arithmetic fluency in Grade 1 and Grade 3. The analysis revealed that beyond the connection within each domain there is a unidirectional effect between fluency measures, with Grade 1 reading fluency significantly influencing the development of arithmetic fluency in Grade 3. Furthermore, the findings indicate that kindergarten EFs significantly contribute to arithmetic fluency at both time points and to reading fluency in the first grade. Early EF skills also emerged as a mediator of associations between fluency performance in reading and arithmetic, suggesting that the influence of EFs extends beyond individual academic domains. These findings have implications for understanding the cognitive mechanisms that underlie the relations between these academic skills.

Background: Several kinds of research say that adjuvant blood glucose and blood pressure are usual, but an efficient solution for medical application count remains. This review analyzes the pandemic blood pressure and blood glucose to identify the publications which tell about the clinical practices and research gaps in systematic research.Methods: A study guides to identify the research of Blood Pressure (BP) and Blood Glucose. In order to analyze the recent innovations and research on BP and Blood glucose, the relevant publications and literature from journals were identified.Results: Co-morbidity of BP and Blood glucose is reported as very high. The commonness of blood pressure is thrice as high in type I diabetes patients and almost two times higher in type II diabetes patients when compared to others without Diabetes. The pervasiveness of getting depression is more in the female when compared with men. A detailed study about the linkage of BP and blood glucose tells that the relationship between them is not exactly clear.Limitations: Nearly all reviews providing the linkage of BP and blood glucose are with some limitations and they are not providing any clear conclusion.Conclusions: Present research tells that people having high blood glucose will have a greater chance of getting high blood pressure. More research is needed to state the linkage between BP, blood glucose, and the growth of diabetes mellitus issues and to provide support for managing Diabetes.

Complexity science studies physical phenomena that cannot be explained by the mere analysis of the single units of a system but requires to account for their interactions. A feature of complexity in connected systems is the emergence of mesoscale patterns in a geometric space, such as groupings in bird flocks. These patterns are formed by groups of points that tend to separate from each other, creating mesoscale structures. When multidimensional data or complex networks are embedded in a geometric space, some mesoscale patterns can appear respectively as clusters or communities, and their geometric separability is a feature according to which the performance of an algorithm for network embedding can be evaluated. Here, we introduce a framework for the definition and measure of the geometric separability (linear and nonlinear) of mesoscale patterns by solving the travelling salesman problem (TSP), and we offer experimental evidence on embedding and visualization of multidimensional data or complex networks, which are generated artificially or are derived from real complex systems. For the first time in literature the TSP’s solution is used to define a criterion of nonlinear separability of points in a geometric space, hence redefining the separability problem in terms of the travelling salesman problem is an innovation which impacts both computer science and complexity theory.

: Background: Brain-derived neurotrophic factor (BDNF) is a crucial mediator of neuronal plasticity. Here, we investigated the effects of controlled normobaric hypoxia (NH) combined with physical inactivity on BDNF blood levels and executive functions. Methods: Twenty-five healthy adults (25.8±3.3 years, 15 female) were analyzed in a randomized, controlled cross-over study. Each intervention began with a 30 min resting phase under normoxia (NOR), followed by a 90 min continuation of NOR or NH (peripheral oxygen saturation [SpO₂] 85-80%). Serum and plasma samples were collected every 15 min. Heart rate and SpO₂ were continuously measured. Before and after each exposure, cognitive tests were performed and after 24 h another follow-up blood sample was taken. Results: NH decreased SpO₂ (p<.001, η_p²=.747) and increased heart rate (p=.006, η_p²=.116) significantly. The 30-min resting phase under NOR led to a significant BDNF reduction in serum (p <.001, η_p²=.581) and plasma (p <.001, η_p²=.362). Continuation of NOR further significantly reduced BDNF after another 45 min (p=.018) in serum and after 30 min (p=.040) and 90 min (p=.005) in plasma. There was no significant BDNF decline under NH. 24 h Follow-up examination showed a significant decline of serum BDNF, both after NH and NOR. Conclusion: Our results show that NH has the potential to counteract physical inactivity-induced BDNF decline. Therefore, our study emphasizes the need for a physically active lifestyle and its positive effects on BDNF. This study also demonstrates the need for a standardized protocol for future studies to determine BDNF in serum and plasma.

Background: Mounting evidence supports the role of the endocannabinoid system in neurophysiology, includ-ing blood-brain barrier (BBB) function. Recent work has demonstrated that activation of endocannabinoid re-ceptors can mitigate insults to the BBB during neurological disorders, like traumatic brain injury, cortical spreading depression and stroke. As alterations to the BBB are associated with worsening clinical outcomes in these conditions, studies herein sought to examine the impact of endocannabinoid depletion on BBB integrity. Methods: Barrier integrity was investigated in vitro via bEnd.3 cell monolayers to assess endocannabinoid syn-thesis, barrier function, calcium influx, junctional protein expression, and proteome-wide changes. Results: In-hibition of 2-AG synthesis using DAGLα inhibition and siRNA inhibition of DAGLα led to loss of barrier in-tegrity via altered expression of VE-cadherin, which could be partially rescued by exogenous application of 2-AG. Moreover, the deleterious effects of DAGLα inhibition on BBB integrity showed both calcium and PKC (protein kinase C)-dependency. Conclusions: These data indicate that disruption of 2-AG homeostasis in brain endothelial cells, in the absence of insult, is sufficient to disrupt BBB integrity thus supporting the role of the endocannabinoid system in neurovascular disorders.

To elucidate mesenchymal stromal cells (MSC)-tumor intricate and ambiguous interactions, the reliable cell labeling and tracking techniques are imperative. Traditional methods of cell labelling have limitations mostly relevant to need for genetic modification what demands the exploration for alternative strategies. Here, we propose using fluorescent photoconvertible microcapsules containing Rhodamine B (RhB) to study mMSC migration in brain tumors. These 3 μm sized microcapsules are readily internalised by cells and undergo photoconversion under 561 nm laser exposure with fluorescence blue shift on demand. Optimal photoconversion was achieved with a laser irradiation duration of 0.4 ms, which provide a maximal brightness of photoconverted label without an excessive laser exposure on cells. Capsules modified with polyallylamine hydrochloride demonstrated the best potential for intracellular uptake without significantly affecting cell viability, motility, or proliferation. The optimal ratio of 20 capsules per mMSC was determined for labeling. Moreover, migration of individual mMSCs within 2D and 3D glioblastoma cell (EPNT-5) colonies over 2 days and in vivo tumor settings over 7 days was tracked. Our study unveils a robust platform for investigating MSC-tumor dynamics, offering insights into therapeutic strategies. Photoconvertible microcapsules could also become an indispensable tool for studying complex fundamental processes of cell-cell interactions for a wide range of problems in biology and medicine.

Arguably the most important parameter in treating cognitive decline associated with Alzheimer’s disease is the length of time in which improvement, if achieved at all, is sustained. However, monotherapies such as donepezil and memantine are associated with a more rapid decline than no treatment in patients over multi-year follow-ups {Kennedy, 2018 #535}. Furthermore, anti-amyloid antibody treatment, which at best simply slows decline, is associated with accelerated cerebral atrophy [2], resulting in earlier dementia-associated brain volumes for those treated at the MCI stage than untreated patients. In contrast, a precision medicine approach, in which the multiple potential drivers of cognitive decline are identified for each patient and then targeted with a personalized protocol (such as ReCODE), has led to documented improvement in patients with cognitive decline [3]; [4]; [5], but long-term follow-up (>5 years) has not been reported previously. Therefore, we report here sustained cognitive improvement, in some cases for over a decade, in patients treated with a precision medicine protocol—something that has not been reported in patients treated with anti-cholinesterase, glutamate receptor inhibitory, anti-amyloid, or other therapeutic methods. These case studies warrant long-term cohort studies to determine how frequently such sustained cognitive improvements occur in patients treated with precision medicine protocols.

(1) Background: Alzheimer’s disease (AD) presents a significant challenge in terms of discovering novel diagnostic methods and therapies. Previous research has shed light on the neuroprotective properties of Apelin-13 in neurodegenerative disorders. However, elucidating the mechanism underlying its efficacy in combating AD-related nerve injury is imperative. In this study, we aimed to investigate the mechanism of action of Apelin-13 in an in vivo model of AD induced by streptozocin (STZ); (2) Methods: We utilized an STZ-induced nerve injury model of AD in mice to investigate the effects of Apelin-13 administration. The Apelin-13 was administered intranasally, and cognitive impairment was assessed using standardized behavioral tests. The main methods included behavioral assessment, histological analysis, and biochemical assays to evaluate synaptic plasticity and oxidative stress signaling pathways; (3) Results: Our findings indicate that intranasal administration of Apelin-13 ameliorated cognitive impairment in the STZ-induced AD model. Furthermore, we observed that this effect was potentially mediated through the enhancement of synaptic plasticity and attenuation of oxidative stress signaling pathways; (4) Conclusions: The results of this study suggest that intranasal administration of Apelin-13 holds promise as a therapeutic strategy for preventing neurodegenerative diseases such as AD. By improving synaptic plasticity and mitigating oxidative stress, Apelin-13 may offer a novel approach to neuroprotection in AD and related conditions.

BACKGROUND Detecting total cholesterol in dried blood spots could aid in identifying individuals with a high likelihood of familial hypercholesterolemia and could be used as a screening measure. This study aims to assess the diagnostic accuracy of dried blood spots on Whatman 903 paper cards using a manual enzymatic technique. METHODS A total of 394 samples collected as serum and dried blood spots were compared. Cholesterol was determined in serum using the automated reference method, while cholesterol on paper was measured using a manual enzymatic method. Within- and between-day diagnostic variability were analyzed. The correlation between both methods was assessed using Passing-Bablok regression and Bland-Altman plot. Internal validation of our correlation formula was performed on 149 samples, along with external validation of the formula proposed by Corso et al. RESULTS The within- and between-day coefficient of variation was found to be lower than 10.14% and 14.09%, respectively. Method comparison yielded an area under the curve of 0.976, with a standard error of 0.009. Passing-Bablok regression indicated a precision of 0.803 and an accuracy of 0.96. Internal validation precision was measured at 0.716. Regarding internal validation, calculated cholesterol with our regression line did not differ from serum cholesterol analysis, while significant differences were observed in calculated cholesterol levels using the external formula. CONCLUSIONS Total cholesterol analysis in dot blood spots demonstrates high precision and reproducibility. This method reliably enables the incorporation of this biological marker into neonatal screening for familial hypercholesterolemia detection.

This study aimed to investigate the relationship between sleep duration, dementia severity, age, and ANS regulation. This cross-sectional pilot study included 27 older patients with probable Alzheimer’s disease, hospitalized at a psychiatric center. We measured heart rate variability to assess ANS regulation at night, evaluated dementia severity using the Clinical Dementia Rating scale, and obtained sleep duration data from sleep diaries maintained by psychiatric nurses. The data were analyzed using repeated-measures generalized linear models with age, sex, dementia severity, and medication (antipsychotics) as covariates. A sleep duration of 7–8 h per night was associated with better ANS regulation than other sleep durations, as indicated by sympathovagal balance (p = 0.005). ANS dysregulation was characterized by a 20.7% increase in sympathetic nervous system activity and a 14.8% decrease in parasympathetic nervous system (PSNS) activity. We found a significant correlation between dementia severity and PSNS activity (p = 0.04) and observed an inverted U-shaped association between sleep duration and ANS regulation. This pilot study demonstrated that a sleep duration of 7–8 h per night may be critical in maintaining optimal ANS regulation. Bidirectional associations between sleep duration, inadequate sleep duration, aging, and ANS regulation warrant further investigation.

Survivors of severe brain injury may require care in a neurointensive care unit (neuro-ICU), where the brain is vulnerable to secondary brain injury. Thus, there is a need for noninvasive, bedside, continuous cerebral blood flow monitoring approaches in the neuro-ICU. Our goal is to address this need through combined measurements of EEG and functional optical spectroscopy (EEG-Optical) instrumentation and analysis to provide a complementary fusion of data about brain activity and function. The present case demonstrates in a patient with traumatic brain injury, noninvasive cerebral blood flow transients can be recorded that correlate with gold-standard invasive measurements and with the frequency content changes in the EEG data during clinical care.

Diarrhoea is a serious cause of mortality worldwide that can lead to dehydration, gut barrier function impairment, nutrient malabsorption, and alterations of the gut microbiota (dysbiosis). Current solutions for its management, such as oral rehydration salts (ORS), inhibitors of the gut motility, antibiotics, and living probiotics only partially counteract the mechanisms of the disease and do not provide a full coverage of the problem. Potential risks of the use of living probiotic strains, particularly in immunocompromised patients, can be eliminated with the use of tyndallized (heat-killed) postbiotic bacteria and yeast. ABB C22® is a postbiotic combination of three tyndallized yeasts, namely Saccharomyces boulardii, Saccharomyces cerevisiae, and Kluyveromyces marxianus. To assess the action of the postbiotic combination on diarrhoea, immune and gut epithelial cell signaling assays, gut barrier formation assay and rotavirus gene expression assay were performed. ABB C22® showed a strong anti-inflammatory effect, an induction of the build-up of the gut epithelium, and a degree of protection against rotavirus infection. These experimental studies support the use of the postbiotic ABB C22® as a solution for the management of diarrhoea and gastrointestinal conditions, alone or in combination with existing but incomplete treatments.

Diarrhoea is a serious cause of mortality worldwide that can lead to dehydration, gut barrier function impairment, nutrient malabsorption, and alterations of the gut microbiota (dysbiosis). Current solutions for its management, such as oral rehydration salts (ORS), inhibitors of the gut motility, antibiotics, and living probiotics only partially counteract the mechanisms of the disease and do not provide a full coverage of the problem. Potential risks of the use of living probiotic strains, particularly in immunocompromised patients, can be eliminated with the use of tyndallized (heat-killed) postbiotic bacteria and yeast. ABB C22® is a postbiotic combination of three tyndallized yeasts, namely Saccharomyces boulardii, Saccharomyces cerevisiae, and Kluyveromyces marxianus. To assess the action of the postbiotic combination on diarrhoea, immune and gut epithelial cell signaling assays, gut barrier formation assay and rotavirus gene expression assay were performed. ABB C22® showed a strong anti-inflammatory effect, an induction of the build-up of the gut epithelium, and a degree of protection against rotavirus infection. These experimental studies support the use of the postbiotic ABB C22® as a solution for the management of diarrhoea and gastrointestinal conditions, alone or in combination with existing but incomplete treatments.

Background: Previous neuroimaging studies have identified brain regions related to respiratory motor control and perception. However, little is known about the resting-state functional connectivity (FC) associated with respiratory impairment. We aimed to determine the FC involved in mild respiratory impairment without changing the saturation of percutaneous oxygen. Methods: We obtained resting-state functional magnetic resonance imaging data from 36 healthy volunteers during normal respiration and mild respiratory impairment induced by resistive load (effort breathing). ROI-to-ROI and seed-to-voxel analyses were performed using Statistical Parametric Mapping 12 and the CONN toolbox. Results: Compared to normal respiration, effort breathing activated FCs within and between the sensory perceptive area of respiration (the postcentral gyrus, anterior insular cortex (AInsula), and anterior cingulate cortex) and visual cortex (the visual occipital, occipital pole (OP), and occipital fusiform gyrus). Graph theoretical analysis showed strong centrality in the visual cortex. A significant positive correlation was observed between the dyspnoea score (modified Borg scale) and FC between the left AInsula and right OP. Conclusions: These results suggested that the FCs within the respiratory sensory area via the network hub may be neural mechanisms underlying effort breathing and modified Borg scale scores.

The nature of the interaction between Th17 cells and the blood-brain barrier (BBB) is critical for the development of autoimmune inflammation in the central nervous system (CNS). TNF-a or IL-17 stimulation is known to enhance the adherence of Th17 cells to the brain endothelium. The brain endothelial cells (bEnd.3) express VCAM-1, the receptor responsible for inflammatory cell adhesion, which binds VLA-4 on migrating effector lymphocytes at the early stage of brain inflammation. The present study examines the effect of the pro-inflammatory cytokines TNF-a and IL-17 on the adherence of Th17 cells to bEnd.3 The bEnd.3 cells were found to increase production of CCL2 and CXCL1 after stimulation by pro-inflammatory cytokines, while CCL2, CCL5, CCL20 and IL17 induced Th17 cell migration through a bEnd.3 monolayer. This interaction between Th17 cells and the brain endothelium appears to be mediated by VCAM-1 and some chemotactic cytokines. This observation may suggest potential therapeutic targets for the prevention of autoimmune neuroinflammation development in the CNS.

Emerging evidence demonstrated that using a new manufacturing technology to produce γ-aminobutyric acid (GABA)-fortified oolong (GO) tea could relieve human stress and exert versatile physiological benefits. The purpose of this human research aims to investigate therapeutic effects of daily GO tea consumption on the improvement of blood pressure, relaxation-related brain waves and quality of life (QOL) during a period of 28 consecutive days. Total polyphenols, major catechins and free amino acids were analyzed via HPLC assay. Changes of heart rate, blood pressure, α-brain wave (index of relaxation) and eight-item QOL score were investigated on day 0, 7, 14, 21 and 28, respectively. The chemical analysis results showed that GO tea contained the most abundant amino acids and GABA, contributing to the relaxation activity. Among all study participants, daily drinking GO tea could reduce systolic blood pressure on day 21 and diastolic blood pressure on day 28 (p &lt; 0.05, respectively). For participants with pre-hypertension, GO tea could effectively reduce heart rate, systolic and diastolic blood pressure on day 28 (p &lt; 0.05). At the end of the study, incremental changes in alpha-brain wave and QOL scores were also demonstrated (p &lt; 0.05, respectively). This study recommended that GO tea might potentially serve as a natural source of alternative therapy to benefit blood pressure, stress-relief and QOL.

In the present study, a multilayer high barrier thin blown film based on a polybutylene adipate terephthalate (PBAT) blend with polyhydroxyalkanoate (PHA), and composed of four layers, including a cellulose nanocrystals (CNC) barrier layer and an electrospun poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) hot-tack layer, was characterized in terms of surface roughness, surface tension, migration, mechanical and peel performance, barrier properties and disintegration rate. The results showed a material with a smooth surface. The overall migration test showed that the material was suitable for its use as a food contact layer. The addition of the CNC interlayer had a significant effect on the mechanical properties of the system, drastically reducing the elongation at break and, thus, the flexibility of the material. However, the material retained its elastic modulus and tensile strength. The CNC coating had a negative impact on the peeling strength, weakening the inherently strong interlayer adhesivity of the electrospun PHBV fibers. The multilayer had a good barrier to water vapor, and especially to oxygen, with its permeance reduced by up to a 90 % when the CNC layer was present. Finally, the monolayer blend film disintegrated in a period of less than 55 days in a laboratory-scale composting experiment, while the multilayer system disintegrated in 60 days. Overall, the multilayer system formed a fully compostable structure with great potential for use in food packaging applications.

Intraprocedural rupture (IPR) is a severe complication of coil embolization (CE) for intracranial aneurysms, yet the clinical and hemodynamic features of rupture risk areas remain unclear. From January 2013 to December 2023, 435 saccular cerebral aneurysms (316 unruptured, 119 ruptured) underwent CE at our institution. Included were cases where extravasation or coil protrusion occurred during CE. The rupture point was determined from postoperative data, and computational fluid dynamics (CFD) analysis was conducted to assess hemodynamic features. IPR occurred in six aneurysms (1.3%; three ruptured, three unruptured; dome size: 4.7±1.8 mm, D/N: 1.5±0.5, locations: four internal carotid artery [ICA], one anterior cerebral artery, one middle cerebral artery). ICA aneurysms were treated using adjunctive techniques (three balloon-assisted, one stent-assisted). Two aneurysms (M1M2 and A1) were treated simply, yet had relatively small and misaligned domes. CFD analysis identified the rupture point as a flow impingement zone with maximum pressure (Pmax) in five aneurysms (83.3%). Time-averaged wall shear stress (WSS) was locally reduced around this area (1.3±0.7 [Pa]). Hemodynamically unstable areas indicated fragile, thin walls with rupture risk. Microcatheter insertion along the inflow zone, directed towards the caution area, was practiced. The presence of a flow impingement zone with Pmax and low WSS suggests potential aneurysm rupture in CE, particularly with adjunctive techniques. Small aneurysms, especially those with axial misalignment, warrant careful consideration due to the risk of excessive flow impact stress on the aneurysm wall.

Dried blood spot (DBS) testing on confetti is one of the most common methods used to collect and extract DNA from field samples for molecular epidemiology of malaria studies. Here, we investigated whether ethanol or other solutions used to clean scissors are a source of sample contamination. DBS were prepared from 3 drops of blood from two Plasmodium falciparum cultures spotted on confetti, and 3 solutions (water, ethanol and DNase) were used to clean scissors between spots during DNA extraction. For each cleaning solution, two blank confetti were used as negative controls. Samples were analyzed by PCR-based genotyping of merozoite surface proteins 1 & 2 (msp-1 and msp-2), and P. falciparum chloroquine resistance transporter (Pfcrt). A total of 15 samples were analyzed. Based on msp-1 and msp-2 amplification, P. falciparum was detected on blank confetti when scissors were washed with ethanol. Based on Pfcrt amplification, DNA of P. falciparum was detected on blank confetti when scissors were cleaned with ethanol or water. No P. falciparum genes were detected on blank confetti when scissors were cleaned with DNase. Scissors cleaned with DNase prevented cross-contamination between samples during processing of dried blood spots, whereas ethanol (which is commonly used) fails to avert cross-contamination.

In recent years, advancements in brain science and neuroscience have significantly influenced the field of computer science, particularly in the domain of reinforcement learning (RL). Drawing insights from neurobiology and neuropsychology, researchers have leveraged these findings to develop novel mechanisms for understanding intelligent decision-making processes in the brain. Concurrently, the emergence of quantum computing has opened new frontiers in artificial intelligence, leading to the development of quantum machine learning (QML). This study introduces a novel model that integrates Quantum Spiking Neural Networks (QSNN) and Quantum Long Short-Term Memory (QLSTM) architectures, inspired by the complex workings of the human brain. Specifically designed for reinforcement learning tasks in energy-efficient environments, our approach progresses through two distinct stages mirroring sensory and memory systems. In the initial stage, analogous to the brain’s hypothalamus, low-level information is extracted to emulate sensory data processing patterns. Subsequently, resembling the hippocampus, this information is processed at a higher level, capturing and memorizing correlated patterns. We conduct a comparative analysis of our model against existing quantum models such as Quantum Neural Networks and their classical counterparts, elucidating its unique contributions. Through empirical results, we aim to underscore the effectiveness of our approach in optimizing energy consumption in practical scenarios.

Hemangioblasts give rise to endothelial progenitor cells (EPCs), which also express the cell surface markers CD133 and C-kit. They may differentiate into the outgrowth endothelial cells (OECs) that control neovascularization in the developing embryo. Reduced levels of EPC in circulation have been linked to human cardiovascular disorders, according to numerous studies. Furthermore, preeclampsia and senescence have been linked to levels of EPCs produced from cord blood. Uncertainties surround how preeclampsia affects the way EPCs function. It is reasonable to speculate that preeclampsia may have an impact on the function of fetal EPCs during the in utero period; however, given the present literature's suggestion that maternal vasculopathies, including preeclampsia, damage fetal circulation. Additionally, the differentiation potential and general activity of EPCs may serve as an indicator of the health of the fetal vascular system since they promote neovascularization and repair during pregnancy. Thus, the purpose of this review is to compare, through assessment of their quantity, differentiation potency, angiogenic activity, and senescence, the angiogenic function of fetal EPCs obtained from cord blood for normal and pregnancy problems. This will shed light on the relationship between the angiogenic function of fetal EPCs and pregnancy complications, which could have an effect on the management of long-term health issues like metabolic and cardiovascular disorders in offspring with abnormal vasculature development.

In the brain, astrocytes regulate shape and functions of the synaptic and vascular compartments through a variety of released factors and membrane-bound proteins. An imbalanced astrocyte activity can therefore have drastic negative impacts on brain development, leading to the onset of severe pathologies. Clinical and pre-clinical studies show alterations in astrocyte cell number, morphology, molecular makeup and astrocyte-dependent processes in different affected brain regions in neurodevelopmental (ND) and neuropsychiatric (NP) disorders. Astrocytes proliferate, differentiate and mature during the critical period of early postnatal brain development, a time window of elevated glia-dependent regulation of a proper balance between synapse formation/elimination, which is pivotal in refining synaptic connectivity. Therefore, any intrinsic and/or extrinsic factors altering these processes during the critical period may result in an aberrant synaptic remodelling and onset of mental disorders. The peculiar bridging position of astrocytes between synaptic and vascular compartments further allows them to “compute” the brain state and consequently secrete factors in the bloodstream, which may serve as diagnostic biomarkers of distinct healthy or disease conditions.Here, we collect recent advancements regarding astrogenesis and astrocyte-mediated regulation of neuronal network remodelling during early postnatal critical periods of brain development, focusing on synapse elimination. We then propose alternative hypotheses for an involvement of aberrancies in these processes in the onset of ND and NP disorders. In light of the well-known differential prevalence of certain brain disorders between males and females, we also discuss putative sex-dependent influences on these neurodevelopmental events.From a translational perspective, understanding age- and sex-dependent astrocyte-specific molecular and functional changes may help to identify biomarkers of distinct cellular (dys)functions in health and disease, favouring the development of diagnostic tools or the selection of tailored treatment options for male/female patients.

Until recently, no disease-specific health-related quality of life (HRQoL) instrument existed for pediatric traumatic brain injury (TBI). In this revalidation study, the psychometric properties and the validity of the final German version of the 35-item QOLIBRI-KID/ADO questionnaire were examined in 300 children and adolescents. It is the first self-reported TBI-specific instrument for measuring pediatric HRQoL in individuals aged 8–17 years. The six-factor model fits the data adequately. Internal consistencies were excellent for the total score and satisfactory to excellent for the scale scores. Intraclass correlations indicated good test-retest reliability. Construct validity was supported by overlaps between the QOLBRI-KID/ADO and the PedsQL, which measures generic HRQoL. Discriminant validity indicated that HRQoL was significantly lower in older children and girls, and in those with anxiety, depression, and post-concussion symptoms than in comparison groups, replicating the results of the questionnaire’s first development study. Our results suggest that the QOLIBRI-KID/ADO is a valid and reliable multidimensional instrument for assessing disease-specific HRQoL after pediatric TBI in clinical and research settings, which can additionally be used across the lifespan in combination with the adult version. This may help to improve care, treatment, daily functioning and HRQoL after TBI.

Glucose is a simple sugar molecule. The sugar molecule is chemically symbolised as C6H12O6. This means that the glucose molecule contains 6 carbon atoms (C), 12 hydrogen atoms (H) and 6 oxygen atoms (O). In human blood, the molecule glucose circulates as blood sugar. Normally after eating or drinking, our body breaks down the sugars in food and uses them to obtain energy for our cells. To do this, our pancreas produces insulin. Insulin "pulls" sugar from the blood and puts it into the cells for use. If someone has diabetes, their pancreas can't produce enough insulin. As a result, the level of glucose in the blood rises. This can lead one to many potential complications, including blindness, disease, nerve damage, amputation, stroke, heart attack and damage to blood vessels etc. In this study, a non-invasive method for monitoring blood glucose has been developed and is therefore easily usable. The device developed can measure the glucose level continuously and eliminates the disadvantages of the invasive system. Near-IR sensors (optical sensors) were used to estimate the concentration of glucose in the blood; these sensors have a wavelength of 940 nm. The sensor is placed on the tip of the finger and the output of the optical sensor is then connected to the microcontroller at the analogue input. Another sensor used, but only to provide more medical information was the heartbeat sensor. After processing and regression analysis, the glucose level is predicted, and data is sent via the Bluetooth network to a developed APP. The results of the implemented device were compared with available invasive methods. The study consists of a hardware platform inserted into an armband and then a small black parallelepiped-shaped box in which the optical sensors are inserted. The hardware consists of a microcontroller, a Near-IR optical sensor, a heartbeat sensor and a Bluetooth module.

The combined use of lasmiditan and triptan is unexplored in medical literature. This study aimed to investigate whether the intake of lasmiditan following triptan improves migraine pain. Following triptan intake, if headache relief was less than 50% at 1 hour, patients took 50 mg lasmiditan within 2 hours of migraine onset. Patients recorded headache intensity and adverse events(AEs) caused by lasmiditan at 1, 2, and 4 hours after intake of additional 50 mg of lasmiditan. A significant reduction in pain scale was observed post 50 mg lasmiditan intake (p &lt; 0.001, t-test). Pain relief was reported for 32 migraine attacks (80%) at 1 hour after additional lasmiditan intake. Although AEs were observed in 63% of the patients who took an additional lasmiditan, most were mild and resolved 1 hour after lasmiditan intake. Our study revealed the significant headache reliefs provided by an additional lasmiditan for patients who did not achieve satisfactory results following initial triptan intake for treating migraine. The AEs associated with this treatment strategy were mild and lasted for a short term. This study suggested that the combination of triptan and lasmiditan is promising for the treatment of migraine and should be studied in a randomized placebo-controlled trial.

Clinical and laboratory diagnostics are particularly important in monitoring the internal homeostasis of the body in high-yielding animals, especially in dairy cows, whose metabolism is under constant pressure to obtain high parameters of milk production and reproduction. Knowledge of laboratory test results and relationships based on significant correlations between various milk and blood parameters may be very useful in veterinary diagnostics and helpful in cattle practice in order to protect animal health and the quality of milk production. The aim of the study was to analyze the correlation between selected hematological biomarkers such as white blood corpuscles (WBC), red blood corpuscles (RBC), hemoglobin concentration (HGB), hematocrit (HCT), platelets (PLT), erythrocyte mean corpuscular volume (MCV), mean corpuscular hemoglobin content (MHC), mean corpuscular hemoglobin concentration (MCHC) and selected quantitative-qualitative parameters of cow’s milk such as current milk production, somatic cells count (SCC), colony of bacteria forming units (CFU), milk fat (MF), milk protein (MP), milk lactose (ML), milk solids (S), solids non-fat in milk (SNF), daily milk production. Samples were collected three times at daily intervals from 11 clinically healthy late-lactation dairy cows obtaining 33 sets of test results. This repeated study of cows allowed for obtaining a homogeneous group in order to determine statistical correlations between selected blood and milk parameters. Many significant correlations were found between the examined parameters. In cows, significant positive correlations were recorded between milk production and HGB, HCT, MCV or MHC. Significant negative correlations were also found between SCC and HGB, SCC and HCT, SNF and MCV, SNF and MHC, and between MF and RBC.

Health-Related Quality of Life (HRQoL) encompasses the comprehensive evaluation of an indi-vidual's health and well-being across multiple dimensions. Mindfulness, recognized as a scientifi-cally supported strategy for anxiety management, plays a role in enhancing both physical and mental health. The Gut-Brain Axis (GBA) serves as the bidirectional communication link between the gastrointestinal system and the central nervous system. This study aims to explore the associa-tion between Mindfulness and factors influencing the GBA in both healthy individuals and those with Inflammatory Bowel Diseases (IBD). A cross-sectional investigation involved 338 adults, in-cluding 50 IBD patients, utilizing validated Greek scales for Mindfulness (MAAS-15), Mediterra-nean Diet (14-MEDAS), and HRQoL (EQ-5D-5L). The questionnaire gathered demographic, an-thropometric, and lifestyle data. Among healthy participants, EQ-5D-5L showed a moderate cor-relation with the MAAS-15 scale (r=0.389, p

Fever control is essential in patients with severe traumatic brain injury (TBI). The efficacy of therapeutic hypothermia (TH) in severe TBI has been investigated over the last few decades; however, in contrast to experimental studies showing benefits, no evidence of efficacy has been demonstrated in clinical practice. In this review, the mechanisms and history of hypothermia were briefly outlined, while the results of major randomized controlled trials (RCTs) and meta-analyses investigating TH for adult TBI are introduced and discussed. The retrieved meta-analyses showed conflicting results, with a limited number of studies indicating benefits of TH. Some studies have shown benefits of long-term TH compared with short-term TH. Although TH is effective at lowering elevated intracranial pressure (ICP), reduced ICP does not lead to favorable outcomes. Low-quality RCTs overestimated the benefits of TH, while high-quality RCTs showed no difference or worse outcomes with TH. RCTs assessing standardized TH quality demonstrated the benefits of TH. As TBI has heterogeneous and complicated pathologies, applying a uniform treatment may not be ideal. A meta-analysis of young patients who underwent early cooling and hematoma removal showed better TH results. TH should not be abandoned, and its optimal should be advocated on an individual basis.

This article provides exact analytical formulae for various kinds of rainbow step barrier options. These are highly flexible and sophisticated multi-asset barrier options based on the following principle : the option life is divided into several time intervals on which different barriers are monitored w.r.t. different underlying assets. From a mathematical point of view, new formulae are provided for the first passage time of a multidimensional geometric Brownian motion to a boundary defined as a step function. The article shows how to implement the obtained valuation formulae in a simple and very efficient manner. Numerical results highlight a strong sensitivity of rainbow step barrier options to the correlations between the underlying assets.

Advanced glycation end products (AGEs) play a significant role in the aging processes, further regarding as a hallmark of aging. Despite the importance, a lack of monitoring tools has hampered the study of relationship between AGEs and aging. Here, we firstly report a novel AGEs-selective probe, AGO. AGO presented its ability to detect AGEs more sensitively than a conventional approach of measuring autofluorescence from AGEs. In addition, we confirmed that AGO can detect AGEs depending on kinetics, reflecting by a preference to ribose-derived AGEs. Finally, AGO revealed its competence to visualize glycation products in glycation mimicking model, made by collagen framework. We believe that this study will enrich molecular toolboxes to understand physiological processes of AGEs during aging processes.

The increasing prevalence of Metabolic Syndrome (MetS), a serious condition associated with elevated risks of cardiovascular diseases, stroke, and type 2 diabetes, underscores the urgent need for effective diagnostic tools. This research carefully examines the effectiveness of 16 diverse machine learning (ML) models in predicting MetS, a multifaceted health condition linked to increased risks of heart disease and other serious health complications. Utilizing a comprehensive, unpublished dataset of imbalanced blood test results, spanning from 2017 to 2022, from the Laboratory Information System of the General Hospital of Amfissa, Greece, our study embarks on a novel approach to enhance MetS diagnosis. By harnessing the power of advanced ML techniques, we aim to predict MetS with greater accuracy using non-invasive blood test data, thereby reducing the reliance on more invasive diagnostic methods. Central to our methodology is the application of the Borda count method, an innovative technique employed to refine the dataset. This process prioritizes the most relevant variables, as determined by the performance of the leading ML models, ensuring a more focused and effective analysis. Our selection of models, encompassing a wide array of ML techniques, allows for a comprehensive comparison of their individual predictive capabilities in identifying MetS. This study not only illuminates the unique strengths of each ML model in predicting MetS but also reveals the expansive potential of these methods in the broader landscape of health diagnostics. The insights gleaned from our analysis are pivotal in shaping more efficient strategies for the management and prevention of Metabolic Syndrome, thereby addressing a significant concern in public health.

Rabies remains a significant global threat, yet accurate estimations of its impact are hindered by the lack of confirmatory diagnoses. Postmortem confirmation of rabies traditionally involves invasive brain tissue testing, a process met with resistance from deceased patients' families, impeding consent. This paper presents and evaluates an innovative yet unpublished transnasal approach for postmortem brain tissue collection, offering a minimally invasive, easier, faster, and safer method. This method preserves the cadaver's integrity, potentially easing family reluctance towards autopsies. The limited testing of both human and animal rabies in Ghana highlights the challenges in diagnosing this fatal disease. Scarce diagnostic resources and the complexity of obtaining brain tissue samples exacerbate the issue. Cultural and religious beliefs surrounding autopsies contribute to familial hesitation, viewing these procedures as disruptive and disfiguring, further complicating consent. The transnasal technique involves approaching the brain tissue through the nostrils and cribriform plate without any superficial manipulation of the patient's head and face, thereby preserving aesthetics and natural features of the person. Technological advancements and seamless One Health collaboration among governmental, non-governmental, and research entities locally and globally culminated in Ghana's first confirmed rabies diagnosis using this method of brain tissue collection. This success emphasizes the efficiency and feasibility of transnasal brain collection approach and the invaluable role of the One Health approach and collaborative efforts in overcoming diagnostic challenges in rabies control.

The purpose of this study is to investigate the influence of heat stress on some biochemical parameters in the blood of dairy cows raised in Bulgaria. The study was conducted on a dairy farm with a capacity of 500 cows, Holstein breed, raised in free-group housing in individual resting boxes. The research was carried out over three seasons: spring, summer, and autumn, with a total of 90 blood samples collected from the cows raised on the farm - 30 blood samples for each season, including cows from the 30th to the 60th day of lactation. Temperature and humidity data were obtained from the nearest meteorological station to the farm. Based on this data, the minimum, average, and maximum values of the temperature-humidity index were calculated. The analysis of variance revealed that the month of the study significantly influenced the following blood parameters: glucose, urea, total protein, cortisol, prolactin, and Ca (P < 0.001). Analysis of the data expressed by LS mean values clearly shows that during the hot months, dairy cows experience a deficit of energy from carbohydrate sources, which they compensate for from other non-carbohydrate sources. Confirmation of this is seen in the blood glucose values, which during the summer are 1.50 mmol/l, approximately twice as low as the values measured during spring and autumn. Regarding urea concentration, a final product of protein metabolism, the values recorded during the summer are 5.3 mmol/l, 1.5 times higher compared to other study periods. As a result of the metabolic load on the liver, the values of hepatic enzymes (ASAT and ALAT) decrease during the summer months, respectively to 93.92 and 17.68 U/L. Cortisol levels in the blood during the summer were registered at 50.92 nmol/l, indicating that cows are under stress. Values for prolactin are of interest, with the highest values being recorded in spring - 1.09 mlU/I. During the summer and autumn studies, the values are 0.99 and 0.89 mlU/I, respectively. A similar trend of decreasing values from spring to autumn season is observed in total blood protein, namely 89.93; 81.99, and 74.36 g/l.

Keywords: gut microbiota; small intestinal bacteria overgrowth; SIBO; diet, dysbiosis; microbial ecology.

Marmosets from the Callithrix genus (six species) are anthropoids distributed in many Brazilian biomes, but anthropogenic pressure is a risk for hybridization and virtually the extinction of some species. Despite this, only a few data are available on reproductive ecology, which is a gap in understanding the physiological modulation of the socio-sexual behavior of free-ranging marmosets. In this study, we characterized fecal concentrations of progesterone, estrogens, and glucocorticoids of six breeding and non-breeding females from two groups of free-ranging C. penicillata, which is the species with the largest geographical distribution and most important in hybridization studies. The fecal progesterone was significantly higher in females who gave birth than non-breeding females, which was linked to reproductive status. The levels of fecal estrogens and glucocorticoids did not differ between breeding and non-breeding females. The data are according to the few studies on steroid values of free-ranging and captive marmosets. This study shows the concentrations of progesterone and glucocorticoids in free-ranging C. penicillata for the first time. Overall, the high levels of progesterone associated with pregnancy in free-ranging C. penicillata as well as levels of estrogens and glucocorticoids close to those reported for other species, suggest a conserved pattern of hormonal secretion between Callithrix species that have been studied in captivity.

In this study, we evaluated the antibacterial effect against Staphylococcus aureus and Salmonella Typhimurium in fried fish paste using floating electrode-dielectric barrier discharge (FE-DBD) plasma (1.1 kV, 43 kHz, N2 1.5 m/s, 1-60 min). In addition, quality evaluation (pH, VBN) of fried fish paste was conducted after FE-DBD plasma treatment. When FE-DBD plasma was treated for 1, 5, 10, 20, 30 and 60 min, S. aureus decreased by 0.16-1.13 log10 CFU/g, and S. Typhimurium decreased 0.25-1.13 log10 CFU/g. Both decreased &gt; log10 CFU/g at 60 min. The D-value was 58.92 and R2 was 0.97 for S. aureus using first-order kinetics, and the D-value was 43.60 and R2 was 0.97 for S. Typhimurium using the Weibull model. There was no significant difference in pH after FE-DBD plasma treatment (p &gt; 0.05). However, volatile basic nitrogen (VBN) significantly decreased as the treatment time increased (p &lt; 0.05), and it was the lowest at 60 min to 3.46. Therefore, FE-DBD plasma treatment could be considered as a technology for preserving the quality of processed foods.

The reasons for the circular sense of human color perception generated by two sorts of color opponent neurons and three cone types are not well understood. Here we use geometrical analysis to examine the hypothesis that opponency, the recursive nature of color perception, and trichromacy arise as the most efficient ways of distinguishing spectrally different points on a plane using a minimum of color classes and receptor types.

A severe consequence of SARS-CoV-2 infection that manifests as systemic inflammation and multi-organ involvement is called Multisystem Inflammatory Syndrome in Children (MIS-C). This review examines the possible relationship between gut barrier integrity, the microbiome, dysregulation of interleukin-6 (IL-6) signaling, and MIS-C. Clinical and biochemical features of MIS-C are similar to those of other hyperinflammatory syndromes, suggesting a dysregulated immune response. One possible explanation for the systemic inflammation seen in MIS-C patients is SARS-CoV-2-induced dysregulation of the IL-6 signaling pathway. In addition, new data suggest a reciprocal link between gut barrier integrity and IL-6. SARS-CoV-2 exhibits bacteriophage-like behavior, highlighting the role of bacteria as a reservoir for the virus and emphasizing the importance of understanding the bacteriophagic mechanism of the virus in fecal-oral transmission. Increased translocation of viral products and bacterial toxins may result from disrupting the intestinal barrier and cause systemic inflammation. On the other hand, systemic inflammation can weaken the integrity of the intestinal barrier, which feeds back into the loop of immunological dysregulation. In the context of MIS-C, understanding the interaction between SARS-CoV-2 infection, IL-6, and gut barrier integrity may shed light on the etiology of the disease and guide treatment options.

Time estimation was investigated in 24 healthy adults, 12 women and 12 men, before and after an exhaustive exercise. We compared the capability of estimating time intervals in the range from 1 to 5 s using tasks requiring mental count and tasks that did not allow the mental count. Time estimation and blood lactate levels were evaluated before and at the end of the exercise. We found that the perception of time intervals between 1 and 5 s was affected at the end of the exercise. The observed effects, associated with a significant increase in blood lactate levels, were different in the two types of time estimation used in the present study. In experimental conditions in which participants had to evaluate duration of the time interval by mental counting, at the end of exercise a significant reduction in the overestimation of time made at rest was observed. On the other hand, when participants had to assess the difference in duration between two events without the possibility to mentally count, at the end of the exercise a significant deterioration in performance was observed. In both cases, no gender differences were seen.

In this study, the problem of overcoming the infinite energy barrier separating the bradyonic and tachyonic realms is investigated. Making use of the Majorana equation for particles with arbitrary spin and the Heisenberg uncertainty principle, it is proved that, under certain conditions of spatial confinement, quantum fluctuations allow particles with very small mass and velocity close to the speed of light to pass in the tachyonic realm, avoiding the problem of the infinite barrier (bradyon–tachyon tunnelling). This theoretical approach allows an avoidance of the difficulties encountered in quantum field theory when it is extended to particles with imaginary rest mass.

Endometriosis is a prevalent chronic inflammatory disease characterized by a considerable delay between initial symptoms and diagnosis through surgery. The pressing need for a timely, non-invasive diagnostic solution underscores the focus of current research efforts. This study examines the diagnostic potential of the menstrual blood lipidome. The lipid profile of 39 samples (23 women with endometriosis and 16 patient of control group) was acquired using reverse-phase high-performance liquid chromatography-mass spectrometry with LipidMatch processing and identification. Profiles were normalized based on total ion counts. Significant differences in lipids were determined using the Mann-Whitney test. Lipids for the diagnostic model, based on logistic regression, were selected using a combination of variance importance projection filters and Akaike information criteria. Levels of ceramides, sphingomyelins, cardiolipins, triacylglycerols, acyl- and alkenyl-phosphatidylethanolamines, and alkenyl-phosphatidylcholines increased, while acyl- and alkyl-phosphatidylcholines decreased in cases of endometriosis. PE P-16:0/18:1 and CL 16:0_18:0_22:5_22:6 serve as marker lipids in the diagnostic model, exhibiting a sensitivity of 81% and specificity of 85%. The diagnostic approach based on dried spots of menstrual blood holds promise as an alternative to traditional non-invasive methods for endometriosis screening.

In this study, a commercial sodium butyrate protected by a new buffer salt solution (NSB) was tested to determine whether it can be used as an antibiotic alternative in broiler production. 192 1-day-old broilers were randomly allocated to three dietary treatments: soybean meal diet (CON), antibiotic diet (ANT, basal diet + 100 mg/kg aureomycin), and NSB (basal diet + 800 mg/kg NSB). The growth performance, serum anti-inflammatory cytokines, intestinal morphology, gut barrier function, antioxidative parameters, SCFAs content, and cecal microbiota were analyzed. The result showed that NSB significantly improved ADFI, ADG (p < 0.01), and decreased FCR (p < 0.01). Serum anti-inflammatory cytokine IL-10 was up-regulated (p < 0.01), and pro-inflammatory TNF-α was down-regulated (p < 0.05) by NSB supplementation. H&E results showed that VH and VH: CD ratio significantly increased (p < 0.05) in the jejunum and ileum in the NSB group. Furthermore, ZO-1 (p < 0.01), claudin-1 (p < 0.01), and occludin (p < 0.05) in the jejunum and claudin-1 (p < 0.01) and mucin-2 (p < 0.05) in the ileum significantly up-regulated in the NSB group, respectively. Additionally, SOD (p < 0.05) and T-AOC/MDA ratio (p < 0.01) in the jejunum and SOD in the ileum were significantly increased (p < 0.05) in the NSB group. The MDA level also significantly increased (p < 0.01) in the ANT group in the jejunum. Propionic acid (p < 0.05) and butyric acid (p < 0.01) content significantly increased in the NSB group in the jejunum and ileum segments. The 16S rRNA sequencing results showed no significant difference (p > 0.05) in alpha and beta diversity among the groups. LEFSe analysis also indicated that Peptostreptococcaceae, Colidextribacter, Firmicutes, Oscillospira, and Erysipelatoclostridiaceae, which promote SCFA production (p < 0.05), were identified as dominant taxon-enriched bacterial genera in the NSB group. The Spearman correlation analysis revealed that Colidextribacter with ADFI, ADG, VH, claudin-1 (p < 0.05), and unclassified_f__Peptostreptococcaceae with ADFI, IL-10, and ZO-1 were positively correlated (p < 0.05). Furthermore, ADFI and ADG with IL-10, claudin-1, SOD, T-AOC, and butyric acid (p < 0.05), and similarly, ADG with VH (p < 0.05) showed a positive correlation. In conclusion, NSB enhanced the growth performance by improving jejunum and ileum morphology, serum anti-inflammatory cytokines, regulating intestinal barrier function and antioxidant capacity, SCFAs content, and cecum microbiota, showing its potential use as an alternative to antibiotics in poultry nutrition.

Brain is the most complex organ in the human body and it is divided into two hemispheres - left and right hemispheres. Left hemisphere is responsible for control of right side of our body whereas right hemisphere is responsible for control of left side of our body. Brain image segmentation from different neuroimaging modalities is one of the important parts in clinical diagnostic tools. Neuroimaging based digital imagery generally contain noise, inhomogeneity, aliasing artifacts, and orientational deviations. Therefore, accurate segmentation of brain images is a very difficult task. However, the development of accurate segmentation of brain images is very important and crucial for a correct diagnosis of any brain related diseases. One of the fundamental segmentation tasks is to identify and segment inter-hemispheric fissure/mid-sagittal plane, which separate the two hemispheres of the brain. Moreover, the symmetric/asymmetric analyses of left and right hemispheres of brain structures are important for radiologists to analyze diseases such as Alzheimer's, Autism, Schizophrenia, Lesions and Epilepsy. Therefore, in this paper we have analyzed the existing computational techniques used to find brain symmetric/asymmetric analysis in various neuroimaging techniques (MRI/CT/PET/SPECT), which are utilized for detecting various brain related disorders.

The gut microbiota (GM) communicates with the brain via biochemical signaling constituting the gut-brain axis, which significantly regulates the body's physiological processes. The GM dysbiosis can impact the digestive system and the functioning of the central nervous system (CNS) linked to the onset of neurodegenerative diseases. In this review, the scientific data compiled from diverse sources primarily emphasizes the neuropathological characteristics linked to the accumulation of modified insoluble proteins (such as β-Amyloid peptides and hyperphosphorylated tau proteins) in Alzheimer’s Disease (AD) and the potential impact of gut microbiota (GM) on AD susceptibility or resilience. The specific GM profile of human beings may serve as an essential tool for preventing or progressing neurodegenerative diseases like AD. This review focuses mainly on the effect of gut microfauna on the gut-brain axis in the onset and progression of AD. The GM produces various bioactive molecules that may serve as proinflammatory or anti-inflammatory signaling, contributing directly or indirectly to the repression or progression of neurodegenerative disorders by modulating the response of the brain axis. Human studies must focus on further understanding the gut-brain axis and venture to clarify microbiota-based therapeutic strategies for AD.