Acute Disruption Research Articles

Impact of Diphenyl Diselenide on Acute Ethanol-Induced Disruption of Antioxidant Defense and Inflammatory Gene Expression in Rats

Perturbation in antioxidant status which often leads to inflammation of liver cells and alteration in activities of purinergic enzymes are common outcomes of ethanol intoxication, this makes any compound that is able to prevent or repair the redox imbalances induced by alcohol intoxication a potential therapeutic measure. Hence, this study aims to assess the effect of diphenyl diselenide (DPDSe) on oxidative stress indicators, inflammatory genes and activities of purinergic enzymes in ethanol intoxicated male Wistar rats. 10mg/kg DPDSe was administered orally 30 minutes before and after a single dose of 13 ml/kg (28% ethanol solution) was given to the rats. Thereafter, the antioxidant status, activities of purinergic enzymes and expression of redox-sensitive genes in the rats were evaluated. It was observed that ethanol evoked high production of lipid peroxidation with concomitant decrease in thiol level, increased Nucleotidase and NTPDase activities, it also causes the downregulation of Nrf2 and upregulation of (NF-kB), however, pre- and post-treatment with DPDSe caused a reversal effects on the biochemical parameters and molecular parameters evaluated respectively. The reversal of ethanol-induced changes in biochemical parameters, expression of genes linked to inflammation and antioxidant status in the liver of acute ethanol intoxicated rats by DPDSe suggests that it has high prospect as a suitable therapeutic agent for hepatotoxicity linked with acute ethanol intoxication.

Targeted TGF-βR2 Silencing in the Retrotrapezoid Nucleus Mitigates Respiratory Dysfunction and Cognitive Decline in a Mouse Model of Cerebral Amyloid Angiopathy with and without Stroke.

Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid-beta peptides within cerebral blood vessels, leading to neurovascular complications. Ischemic strokes result from acute disruptions in cerebral blood flow, triggering metabolic disturbances and neurodegeneration. Both conditions often co-occur and are associated with respiratory dysfunctions. The retrotrapezoid nucleus (RTN), which is crucial for CO2 sensing and breathing regulation in the brainstem, may play a key role in breathing disorders seen in these conditions. This study aims to investigate the role of Transforming Growth Factor Beta (TGF-β) signaling in the RTN on respiratory and cognitive functions in CAA, both with and without concurrent ischemic stroke.Adult male Tg-SwDI (CAA model) mice and C57BL/6 wild-type controls underwent stereotaxic injections of lentivirus targeting TGF-βR2 in the RTN. Stroke was induced by middle cerebral artery occlusion using a monofilament. Respiratory functions were assessed using whole-body plethysmography, while cognitive functions were evaluated through the Barnes Maze and Novel Object Recognition Test (NORT). Immunohistochemical analysis was conducted to measure TGF-βR2 and GFAP expressions in the RTN.CAA mice exhibited significant respiratory dysfunctions, including reduced respiratory rates and increased apnea frequency, as well as impaired cognitive performance. TGF-βR2 silencing in the RTN improved respiratory functions and cognitive outcomes in CAA mice. In CAA mice with concurrent stroke, TGF-βR2 silencing similarly enhanced respiratory and cognitive functions. Immunohistochemistry confirmed reduced TGF-βR2 and GFAP expressions in the RTN following silencing.Our findings demonstrate that increased TGF-β signaling and gliosis in the RTN contribute to respiratory and cognitive dysfunctions in CAA and CAA with stroke. Targeting TGF-βR2 signaling in the RTN offers a promising therapeutic strategy to mitigate these impairments. This study is the first to report a causal link between brainstem gliosis and both respiratory and cognitive dysfunctions in CAA and stroke models.

Suppression of melanoma by mice lacking MHC-II: Mechanisms and implications for cancer immunotherapy.

Immune checkpoint inhibitors interfere with T cell exhaustion but often fail to cure or control cancer long-term in patients. Using a genetic screen in C57BL/6J mice, we discovered a mutation in host H2-Aa that caused strong immune-mediated resistance to mouse melanomas. H2-Aa encodes an MHC class II α chain, and its absence in C57BL/6J mice eliminates all MHC-II expression. H2-Aa deficiency, specifically in dendritic cells (DC), led to a quantitative increase in type 2 conventional DC (cDC2) and a decrease in cDC1. H2-Aa-deficient cDC2, but not cDC1, were essential for melanoma suppression and effectively cross-primed and recruited CD8 T cells into tumors. Lack of T regulatory cells, also observed in H2-Aa deficiency, contributed to melanoma suppression. Acute disruption of H2-Aa was therapeutic in melanoma-bearing mice, particularly when combined with checkpoint inhibition, which had no therapeutic effect by itself. Our findings suggest that inhibiting MHC-II may be an effective immunotherapeutic approach to enhance immune responses to cancer.

IL-33/ST2 signaling in monocyte-derived macrophages maintains blood-brain barrier integrity and restricts infarctions early after ischemic stroke

BackgroundBrain microglia and infiltrating monocyte-derived macrophages are vital in preserving blood vessel integrity after stroke. Understanding mechanisms that induce immune cells to adopt vascular-protective phenotypes may hasten the development of stroke treatments. IL-33 is a potent chemokine released from damaged cells, such as CNS glia after stroke. The activation of IL-33/ST2 signaling has been shown to promote neuronal viability and white matter integrity after ischemic stroke. The impact of IL-33/ST2 on blood-brain barrier (BBB) integrity, however, remains unknown. The current study fills this gap and reveals a critical role of IL-33/ST2 signaling in macrophage-mediated BBB protection after stroke.MethodsTransient middle cerebral artery occlusion (tMCAO) was performed to induce ischemic stroke in wildtype (WT) versus ST2 knockout (KO) male mice. IL-33 was applied intranasally to tMCAO mice with or without dietary PLX5622 to deplete microglia/macrophages. ST2 KO versus WT bone marrow or macrophage cell transplantations were used to test the involvement of ST2+ macrophages in BBB integrity. Macrophages were cocultured in transwells with brain endothelial cells (ECs) after oxygen-glucose deprivation (OGD) to test potential direct effects of IL33-treated macrophages on the BBB in vitro.ResultsThe ST2 receptor was expressed in brain ECs, microglia, and infiltrating macrophages. Global KO of ST2 led to more IgG extravasation and loss of ZO-1 in cerebral microvessels 3 days post-tMCAO. Intranasal IL-33 administration reduced BBB leakage and infarct severity in microglia/macrophage competent mice, but not in microglia/macrophage depleted mice. Worse BBB injury was observed after tMCAO in chimeric WT mice reconstituted with ST2 KO bone marrow, and in WT mice whose monocytes were replaced by ST2 KO monocytes. Macrophages treated with IL-33 reduced in vitro barrier leakage and maintained tight junction integrity after OGD. In contrast, IL-33 exerted minimal direct effects on the endothelial barrier in the absence of macrophages. IL-33-treated macrophages demonstrated transcriptional upregulation of an array of protective factors, suggesting a shift towards favorable phenotypes.ConclusionOur results demonstrate that early-stage IL-33/ST2 signaling in infiltrating macrophages reduces the extent of acute BBB disruption after stroke. Intranasal IL-33 administration may represent a new strategy to reduce BBB leakage and infarct severity.

Compromised endothelial Wnt/β-catenin signaling mediates the blood-brain barrier disruption and leads to neuroinflammation in endotoxemia.

The blood-brain barrier (BBB) is a critical interface that maintains the central nervous system homeostasis by controlling the exchange of substances between the blood and the brain. Disruption of the BBB plays a vital role in the development of neuroinflammation and neurological dysfunction in sepsis, but the mechanisms by which the BBB becomes disrupted during sepsis are not well understood. Here, we induced endotoxemia, a major type of sepsis, in mice by intraperitoneal injection of lipopolysaccharide (LPS). LPS acutely increased BBB permeability, activated microglia, and heightened inflammatory responses in brain endothelium and parenchyma. Concurrently, LPS or proinflammatory cytokines activated the NF-κB pathway, inhibiting Wnt/β-catenin signaling in brain endothelial cells in vitro and in vivo. Cell culture study revealed that NF-κB p65 directly interacted with β-catenin to suppress Wnt/β-catenin signaling. Pharmacological NF-κB pathway inhibition restored brain endothelial Wnt/β-catenin signaling activity and mitigated BBB disruption and neuroinflammation in septic mice. Furthermore, genetic or pharmacological activation of brain endothelial Wnt/β-catenin signaling substantially alleviated LPS-induced BBB leakage and neuroinflammation, while endothelial conditional ablation of the Wnt7a/7b co-receptor Gpr124 exacerbated the BBB leakage caused by LPS. Mechanistically, Wnt/β-catenin signaling activation rectified the reduced expression levels of tight junction protein ZO-1 and transcytosis suppressor Mfsd2a in brain endothelial cells of mice with endotoxemia, inhibiting both paracellular and transcellular permeability of the BBB. Our findings demonstrate that endotoxemia-associated systemic inflammation decreases endothelial Wnt/β-catenin signaling through activating NF-κB pathway, resulting in acute BBB disruption and neuroinflammation. Targeting the endothelial Wnt/β-catenin signaling may offer a promising therapeutic strategy for preserving BBB integrity and treating neurological dysfunction in sepsis.

Regulatory Peptide Pro-Gly-Pro Accelerates Neuroregeneration of Primary Neuroglial Culture after Mechanical Injury in Scratch Test

The scratch test is used as an experimental in vitro model of mechanical damage to primary neuronal cultures to study the mechanisms of cell death in damaged areas. The involvement of NMDA receptors in processes leading to delayed neuronal death, due to calcium dysregulation and synchronous mitochondrial depolarization, has been previously demonstrated. In this study, we explored the neuroregenerative potential of Pro-Gly-Pro (PGP)—an endogenous regulatory peptide with neuroprotective and anti-inflammatory properties and a mild chemoattractant effect. Mechanical injury to the primary neuroglial culture in the form of a scratch caused acute disruption of calcium homeostasis and mitochondrial functions. This was accompanied by neuronal death alongside changes in the profile of neuronal markers (BDNF, NSE and GFAP). In another series of experiments, under subtoxic doses of glutamate (Glu, 33 μM), delayed changes in [Ca2+]i and ΔΨm, i.e., several days after scratch application, were more pronounced in cells in damaged neuroglial cultures. The percentage of cells that restored the initial level of [Ca2+]i (p < 0.05) and the rate of recovery of ΔΨm (p < 0.01) were decreased compared with undamaged cells. Prophylactic application of PGP (100 μM, once) prevented the increase in [Ca2+]i and the sharp drop in mitochondrial potential [ΔΨm] at the time of scratching. Treatment with PGP (30 μM, three or six days) reduced the delayed Glu-induced disturbances in calcium homeostasis and cell death. In the post-glutamate period, the surviving neurons more effectively restored the initial levels of [Ca2+]i (p < 0.001) and Ψm (p < 0.0001). PGP also increased intracellular levels of BDNF and reduced extracellular NSE. In the context of the peptide’s therapeutic effect, the recovery of the damaged neuronal network occurred faster due to reduced astrogliosis and increased migration of neurons to the scratch area. Thus, the peptide PGP has a neuroprotective effect, increasing the survival of neuroglial cells after mechanical trauma in vitro by reducing cellular calcium overload and preventing mitochondrial dysfunction. Additionally, the tripeptide limits the post-traumatic consequences of mechanical damage: it reduces astrogliosis and promotes neuronal regeneration.

Very High Early Failure Rate Following Primary Repair of Acute Extensor Mechanism Disruption After Total Knee Arthroplasty

BackgroundExtensor mechanism disruption is a devastating complication following total knee arthroplasty (TKA). Despite its morbidity, there is no consensus regarding the optimal treatment strategy. We aimed to determine the survivorship, clinical outcomes, and improvement in patient-reported outcome measures after primary repair of acute extensor mechanism disruptions following primary or revision TKA. MethodsA retrospective review identified 41 acute extensor mechanism disruptions (33 primary TKAs and eight revision TKAs) from 2015 to 2021. The study group was 56% women, the mean body mass index was 33, the mean age was 66 years, and the mean follow-up was 3 years. Extensor mechanism disruption occurred at the patellar tendon (n = 17), quadriceps tendon (n = 15), and patella (n = 9) at a mean of 10 months following TKA. Surgical management was primary repair (n = 30) or primary repair with augmentation (allograft or autograft) (n = 11). Kaplan-Meier analysis estimated survivorship. ResultsThe 2-year survivorship free from all-cause reoperation was 72 and 23% following primary and revision TKA, respectively (P = 0.013). The 2-year survivorship free from all-cause reoperation was 66% for primary repair versus 61% for primary repair with augmentation (P = 0.95). There were 17 (41%) patients who underwent reoperation, most commonly for rerupture (n = 4) in two primary repairs and two primary repairs with augmentation (P = 0.288). Revision TKA (P = 0.049) and increased time from disruption to repair (P = 0.039) were risk factors for reoperation. Neither did the mean extensor lag significantly improve nor did patients see improvement in their patient-reported outcome measures. ConclusionsAfter primary and revision TKA, acute extensor mechanism disruption treated with primary repair with or without augmentation had very poor early survivorship free from all-cause reoperation. Patients should be counseled appropriately, and alternative surgical techniques should be considered.

Dynamic response of the intestinal microbiome to Eimeria maxima-induced coccidiosis in chickens.

We have observed for the first time the dynamic response of the intestinal microbiota to Eimeria maxima infection, synchronized with its life cycle. Minimal changes occur in both the ileal and cecal microbiota during early infection, while significant alterations coincide with acute infection and disruption of the intestinal mucosal lining. As animals recover from coccidiosis, the intestinal microbiota largely returns to normal. E. maxima-induced intestinal inflammation likely creates an environment conducive to the growth of aerotolerant anaerobes such as Lactobacillus, as well as facultative anaerobes such as Escherichia, Enterococcus, and Staphylococcus, while suppressing the growth of obligate anaerobes such as short-chain fatty acid-producing bacteria. These findings expand our understanding of the temporal dynamics of the microbiota structure during Eimeria infection and offer insights into the pathogenesis of coccidiosis, supporting the rationale for microbiome-based strategies in the control and prevention of this condition.

Neurodegenerative Disorders in the Context of Vascular Changes after Traumatic Brain Injury

Traumatic brain injury (TBI) results from external biomechanical forces that cause structural and physiological disturbances in the brain, leading to neuronal, axonal, and vascular damage. TBIs are predominantly mild (65%), with moderate (10%) and severe (25%) cases also prevalent. TBI significantly impacts health, increasing the risk of neurodegenerative diseases such as dementia, post injury. The initial phase of TBI involves acute disruption of the blood–brain barrier (BBB) due to vascular shear stress, leading to ischemic damage and amyloid-beta accumulation. Among the acute cerebrovascular changes after trauma are early progressive hemorrhage, micro bleeding, coagulopathy, neurovascular unit (NVU) uncoupling, changes in the BBB, changes in cerebral blood flow (CBF), and cerebral edema. The secondary phase is characterized by metabolic dysregulation and inflammation, mediated by oxidative stress and reactive oxygen species (ROS), which contribute to further neurodegeneration. The cerebrovascular changes and neuroinflammation include excitotoxicity from elevated extracellular glutamate levels, coagulopathy, NVU, immune responses, and chronic vascular changes after TBI result in neurodegeneration. Severe TBI often leads to dysfunction in organs outside the brain, which can significantly impact patient care and outcomes. The vascular component of systemic inflammation after TBI includes immune dysregulation, hemodynamic dysfunction, coagulopathy, respiratory failure, and acute kidney injury. There are differences in how men and women acquire traumatic brain injuries, how their brains respond to these injuries at the cellular and molecular levels, and in their brain repair and recovery processes. Also, the patterns of cerebrovascular dysfunction and stroke vulnerability after TBI are different in males and females based on animal studies.

Acute sleep disruption reduces fear memories in male and female mice.

Sleep problems are a prominent feature of mental health conditions including post-traumatic stress disorder (PTSD). Despite its potential importance, the role of sleep in the development of and/or recovery from trauma-related illnesses is not understood. Interestingly, there are reports that sleep disruption immediately after a traumatic experience can reduce fear memories, an effect that could be utilized therapeutically in humans. While the mechanisms of this effect are not completely understood, one possible explanation for these findings is that immediate sleep disruption interferes with consolidation of fear memories, rendering them weaker and more sensitive to intervention. Here, we allowed fear-conditioned mice to sleep immediately after fear conditioning during a time frame (18 h) that includes and extends beyond periods typically associated with memory consolidation before subjecting them to 6-h of sleep disruption. Mice exposed to this delayed regimen showed dramatic reductions in fear during tests conducted immediately after sleep disruption, as well as 24 h later. This sleep disruption regimen also increased levels of mRNA encoding brain-derived neurotrophic factor (BDNF), a molecule implicated in neuroplasticity, in the basolateral amygdala (BLA), a brain area implicated in fear and its extinction. These findings raise the possibility that the effects of our delayed sleep disruption regimen are not due to disruption of memory consolidation, but instead are caused by BDNF-mediated neuroadaptations within the BLA that actively suppress expression of fear. Treatments that safely reduce expression of fear memories would have considerable therapeutic potential in the treatment of conditions triggered by trauma.

Hospital Nurse Staffing Legislation: Mixed Approaches In Some States, While Others Have No Requirements.

Legislative agendas aimed at regulating nurse staffing in US hospitals have intensified after acute workforce disruptions triggered by COVID-19. Emerging evidence consistently demonstrates the benefits of higher nurse staffing levels, although uncertainty remains regarding whether and which legislative approaches can achieve this outcome. The purpose of this study was to provide a comprehensive updated review of hospital nurse staffing requirements across all fifty states. As of January 2024, seven states had laws pertaining to staffing ratios for at least one hospital unit, including California and Oregon, which had ratios pertaining to multiple units. Eight states required nurse staffing committees, of which six specified a percentage of committee members who must be registered nurses. Eleven states required nurse staffing plans. Five states had pending legislation, and one state, Idaho, had passed legislation banning minimum nurse staffing requirements. The variety of state regulations provides an opportunity for comparative evaluations of efficacy and feasibility to inform new legislation on the horizon.

An Analysis of STEMI Cases in the Postgraduate Hospital in Khost, Afghanistan

Myocardial infarction, specifically ST elevation myocardial infarction (STEMI), involves the development of localized ischemic necrosis in the heart muscle due to an acute disruption of coronary blood flow. It clinically presents as burning, pressing, or squeezing chest pain that radiates to the left arm, collarbone, scapula, or jaw, along with symptoms such as shortness of breath, a feeling of fear, and cold sweat. Immediate hospitalization in a cardiac intensive care unit is crucial for patients with a developed myocardial infarction, as delays in treatment can be fatal. This study is a descriptive case series conducted in the year 1397 of the Islamic calendar. Out of 1602 inpatients admitted to Khost Postgraduate Hospital during this period, 50 patients were diagnosed with STEMI. The primary objectives of this research were to determine the frequency and pattern of STEMI cases at Khost Postgraduate Hospital during the year 1396 of the Islamic calendar.

Morphological characteristics of the stromal-parenchymatous component of the liver of fetal and newborn developed under the conditions of maternal hypertension disease

Background. Extragenital pathology of the mother can cause various changes in the body of the newborn, which in the future are the cause of violations in physical and mental development, and also causes an increase in somatic and infectious diseases in such children. Therefore, timely diagnosis of liver diseases in newborns and young children remains an urgent problem today. Purpose – the article is devoted to the study of the morphological features of the stromal-parenchymal component of the liver of fetuses and newborns that developed under conditions of maternal hypertension. Materials and Methods. Research was conducted on liver preparations of fetuses and newborns who died at the age of 37 weeks of gestation – the 1st day of postnatal life. All the studied material was divided into two groups. The control group (group K) included fetuses and newborns from healthy mothers (18 cases) who died due to acute disruption of umbilical-placental circulation and birth trauma. The comparison group (group C) consisted of 36 fetuses and newborns from mothers with stage II hypertension. The obtained micropreparations were stained with hematoxylin and eosin, picrofuchsin according to the van Gizon method, and according to the Mallory method. The parenchymal, stromal, and vascular components were calculated as a percentage, and then the stromal-parenchymal ratio was calculated. Results. The results we obtained during the conducted research indicated that the influence of chronic intrauterine hypoxia, which developed against the background of stage II hypertensive disease in the mother, leads to the development of destructive-dystrophic changes in the liver tissue of fetuses and newborns. Chronic intrauterine hypoxia with maternal arterial hypertension leads to parenchymal losses and has a pronounced stimulating effect on the stromal component of the liver, and this can lead to a significant decrease in the functional activity of the liver under the influence of certain triggers and increases the risk of developing liver failure and liver cirrhosis in the future. Conclusions. During our research, it was established that chronic intrauterine hypoxia, which develops against the background of stage II hypertensive disease in the mother, leads to the development of significant destructive-dystrophic changes in the liver tissue of fetuses and newborns. There is a decrease in the volume of the parenchyma due to the volume of hepatocytes and an increase in the volume of the stroma with vessels due to the volume of the portal tracts (11.2 ± 2.2% compared to the control – 3.4 ± 0.3%), the volume of the central veins (12.9 ± 1.3% compared to the control – 9.4 ± 0.4%), the volume of sinusoids (13.3 ± 1.1% compared to the control – 11.3 ± 0.8%). It was established that the morphological changes described by us in the liver of fetuses and newborns in the subsequent ontogenesis may become a prerequisite for the development of hepatobiliary system pathology in such children.

Sleep Disruption Precedes Forebrain Synaptic Tau Burden and Contributes to Cognitive Decline in a Sex-Dependent Manner in the P301S Tau Transgenic Mouse Model.

Sleep disruption and impaired synaptic processes are common features in neurodegenerative diseases, including Alzheimer's disease (AD). Hyperphosphorylated Tau is known to accumulate at neuronal synapses in AD, contributing to synapse dysfunction. However, it remains unclear how sleep disruption and synapse pathology interact to contribute to cognitive decline. Here, we examined sex-specific onset and consequences of sleep loss in AD/tauopathy model PS19 mice. Using a piezoelectric home-cage monitoring system, we showed PS19 mice exhibited early-onset and progressive hyperarousal, a selective dark-phase sleep disruption, apparent at 3 months in females and 6 months in males. Using the Morris water maze test, we report that chronic sleep disruption (CSD) accelerated the onset of decline of hippocampal spatial memory in PS19 males only. Hyperarousal occurs well in advance of robust forebrain synaptic Tau burden that becomes apparent at 6-9 months. To determine whether a causal link exists between sleep disruption and synaptic Tau hyperphosphorylation, we examined the correlation between sleep behavior and synaptic Tau, or exposed mice to acute or chronic sleep disruption at 6 months. While we confirm that sleep disruption is a driver of Tau hyperphosphorylation in neurons of the locus ceruleus, we were unable to show any causal link between sleep loss and Tau burden in forebrain synapses. Despite the finding that hyperarousal appears earlier in females, female cognition was resilient to the effects of sleep disruption. We conclude sleep disruption interacts with the synaptic Tau burden to accelerate the onset of cognitive decline with greater vulnerability in males.

Subanesthetic Ketamine Suppresses Locus Coeruleus-Mediated Alertness Effects: A 7T fMRI Study.

The NMDA antagonist S-ketamine is gaining increasing use as a rapid-acting antidepressant, although its exact mechanisms of action are still unknown. In this study, we investigated ketamine in respect to its properties toward central noradrenergic mechanisms and how they influence alertness behavior. We investigated the influence of S-ketamine on the locus coeruleus (LC) brain network in a placebo-controlled, cross-over, 7T functional, pharmacological MRI study in 35 healthy male participants (25.1 ± 4.2 years) in conjunction with the attention network task to measure LC-related alertness behavioral changes. We could show that acute disruption of the LC alertness network to the thalamus by ketamine is related to a behavioral alertness reduction. The results shed new light on the neural correlates of ketamine beyond the glutamatergic system and underpin a new concept of how it may unfold its antidepressant effects.

Targeted TGF-βR2 Knockdown in the Retrotrapezoid Nucleus Mitigates Respiratory Dysfunction and Cognitive Decline in a Mouse Model of Cerebral Amyloid Angiopathy with and without Stroke.

Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid-beta peptides within cerebral blood vessels, leading to neurovascular complications. Ischemic strokes result from acute disruptions in cerebral blood flow, triggering metabolic disturbances and neurodegeneration. Both conditions often co-occur and are associated with respiratory dysfunctions. The retrotrapezoid nucleus (RTN), which is crucial for CO2 sensing and breathing regulation in the brainstem, may play a key role in breathing disorders seen in these conditions. This study aims to investigate the role of Transforming Growth Factor Beta (TGF-β) signaling in the RTN on respiratory and cognitive functions in CAA, both with and without concurrent ischemic stroke. Adult male Tg-SwDI (CAA model) mice and C57BL/6 wild-type controls underwent stereotaxic injections of lentivirus targeting TGF-β2R2 in the RTN. Stroke was induced by middle cerebral artery occlusion using a monofilament. Respiratory functions were assessed using whole-body plethysmography, while cognitive functions were evaluated through the Barnes Maze and Novel Object Recognition Test (NORT). Immunohistochemical analysis was conducted to measure TGF-βR2 and GFAP expressions in the RTN. CAA mice exhibited significant respiratory dysfunctions, including reduced respiratory rates and increased apnea frequency, as well as impaired cognitive performance. TGF-βR2 knockdown in the RTN improved respiratory functions and cognitive outcomes in CAA mice. In CAA mice with concurrent stroke, TGF-βR2 knockdown similarly enhanced respiratory and cognitive functions. Immunohistochemistry confirmed reduced TGF-βR2 and GFAP expressions in the RTN following knockdown. Our findings demonstrate that increased TGF-β signaling and gliosis in the RTN contribute to respiratory and cognitive dysfunctions in CAA and CAA with stroke. Targeting TGF-βR2 signaling in the RTN offers a promising therapeutic strategy to mitigate these impairments. This study is the first to report a causal link between brainstem gliosis and both respiratory and cognitive dysfunctions in CAA and stroke models.

Linking Basement Membrane and Slit Diaphragm in Drosophila Nephrocytes.

The glomerular basement membrane and the slit diaphragm are essential parts of the filtration barrier. How these layers collaborate remains unclear. The podocyte-like nephrocytes in Drosophila harbor both a slit diaphragm and a basement membrane, serving as a model to address this critical question. Basement membrane components and matrix receptors were silenced using RNAi in nephrocytes. Slit diaphragms were analyzed by immunofluorescence followed by automated quantification. Tracer endocytosis was applied for functional readouts. Immunofluorescence indicated a significant reduction of slit diaphragm density upon loss of laminin and collagen IV components. This was accompanied by reduced expression of fly nephrin and shallower membrane invaginations. Tracer studies revealed that the basement membrane defines properties of the nephrocyte filtration barrier. Acute enzymatic disruption of the basement membrane via collagenase rapidly caused slit diaphragm mislocalization and disintegration, which was independent of cell death. Loss of matrix-interacting receptors, particularly integrins mys and mew, phenocopied basement membrane disruption. Integrins and nephrin co-localized at the slit diaphragm in nephrocytes in a mutually dependent manner, interacting genetically. Human integrin α3 interacted physically with nephrin. The glomerular basement membrane model in Drosophila nephrocytes reveals that matrix receptor-mediated cues ensure correct positioning of the slit diaphragm and the overall filtration barrier architecture.

Socio-Economic Impacts of Endemic and Epidemic Diseases on Livestock Production Systems in Tanzania

Purpose: The aim of the study was to examine socio-economic impacts of endemic and epidemic diseases on livestock production systems in Tanzania. Methodology: This study adopted a desk methodology. A desk study research design is commonly known as secondary data collection. This is basically collecting data from existing resources preferably because of its low cost advantage as compared to a field research. Our current study looked into already published studies and reports as the data was easily accessed through online journals and libraries. Findings: The study revealed that endemic diseases such as brucellosis, foot-and-mouth disease (FMD), and contagious caprine pleuropneumonia (CCPP) pose ongoing challenges to livestock health, productivity, and household livelihoods. Epidemic diseases like avian influenza and peste des petits ruminants (PPR) can cause sudden outbreaks, leading to acute disruptions in production and trade. These disease outbreaks result in various socio-economic consequences, including decreased livestock productivity, loss of income for farmers, increased veterinary and containment costs, and disruptions in domestic and international trade. Additionally, diseases can exacerbate poverty and food insecurity among rural communities reliant on livestock for sustenance and income generation. Unique Contribution to Theory, Practice and Policy: Economic theory of disease control & social-ecological systems theory may be used to anchor future studies on socio-economic impacts of endemic and epidemic diseases on livestock production systems in Tanzania. Building technical capacity at the grassroots level empowers communities to implement effective disease management strategies and adopt biosecurity measures. Establishing community-based disease surveillance systems that empower local communities to monitor and report disease outbreaks in livestock populations. Providing financial support and risk-sharing mechanisms mitigate economic losses and encourage proactive disease management practices. Establish data-sharing mechanisms and surveillance networks that facilitate real-time exchange of information on disease outbreaks, epidemiological trends, and economic impacts.

The water extracts from the oil cakes of Prinsepia utilis repair the epidermal barrier via up-regulating Corneocyte Envelope-proteins, lipid synthases, and tight junction proteins

Ethnopharmacological relevancePrinsepia utilis Royle, native to the Himalayan region, has a long history of use in traditional medicine for its heat-clearing, detoxification, anti-inflammatory, and analgesic properties. Oils extracted from P. utilis seeds are also used in cooking and cosmetics. With the increasing market demand, this extraction process generates substantial industrial biowastes. Recent studies have found many health benefits with using aqueous extracts of these biowastes, which are also rich in polysaccharides. However, there is limited research related to the reparative effects of the water extracts of P. utilis oil cakes (WEPUOC) on disruptions of the skin barrier function. Aim of the studyThis study aimed to evaluate the reparative efficacy of WEPUOC in both acute and chronic epidermal permeability barrier disruptions. Furthermore, the study sought to explore the underlying mechanisms involved in repairing the epidermal permeability barrier. Materials and methodsMouse models with induced epidermal disruptions, employing tape-stripping (TS) and acetone wiping (AC) methods, were used. The subsequent application of WEPUOC (100 mg/mL) was evaluated through various assessments, with a focus on the upregulation of mRNA and protein expression of Corneocyte Envelope (CE) related proteins, lipid synthase-associated proteins, and tight junction proteins. ResultsThe polysaccharide was the major phytochemicals of WEPUOC and its content was determined as 32.2% by the anthranone-sulfuric acid colorimetric method. WEPUOC significantly reduced transepidermal water loss (TEWL) and improved the damaged epidermal barrier in the model group. Mechanistically, these effects were associated with heightened expression levels of key proteins such as FLG (filaggrin), INV (involucrin), LOR (loricrin), SPT, FASN, HMGCR, Claudins-1, Claudins-5, and ZO-1. ConclusionsWEPUOC, obtained from the oil cakes of P. utilis, is rich in polysaccharides and exhibits pronounced efficacy in repairing disrupted epidermal barriers through increased expression of critical proteins involved in barrier integrity. Our findings underscore the potential of P. utilis wastes in developing natural cosmetic prototypes for the treatment of diseases characterized by damaged skin barriers, including atopic dermatitis and psoriasis.

Bioactive Properties of Venoms Isolated from Whiptail Stingrays and the Search for Molecular Mechanisms and Targets.

The venom-containing barb attached to their 'whip-like' tail provides stingrays a defensive mechanism for evading predators such as sharks. From human encounters, dermal stingray envenomation is characterized by intense pain often followed by tissue necrosis occurring over several days to weeks. The bioactive components in stingray venoms (SRVs) and their molecular targets and mechanisms that mediate these complex responses are not well understood. Given the utility of venom-derived proteins from other venomous species for biomedical and pharmaceutical applications, we set out to characterize the bioactivity of SRV extracts from three local species that belong to the Dasyatoidea 'whiptail' superfamily. Multiple cell-based assays were used to quantify and compare the in vitro effects of these SRVs on different cell lines. All three SRVs demonstrated concentration-dependent growth-inhibitory effects on three different human cell lines tested. In contrast, a mouse fibrosarcoma cell line was markedly resistant to all three SRVs, indicating the molecular target(s) for mediating the SRV effects are not expressed on these cells. The multifunctional SRV responses were characterized by an acute disruption of cell adhesion leading to apoptosis. These findings aim to guide future investigations of individual SRV proteins and their molecular targets for potential use in biomedical applications.