Initial Event Research Articles

The role of glaciations in the evolutionary history of a widely distributed Neotropical open habitat bird

AbstractAimThe Neotropics constitute the most biodiverse region of the world, yet its patterns of diversification and speciation differ among Neotropical areas and are not equally well understood. Particularly, avian evolutionary processes are understudied in the open habitats of temperate South America, where the role of glacial cycles is not clear. We analysed the evolutionary history of a Neotropical widespread bird species as a case study to evaluate its continental‐scale patterns and processes of diversification, with a focus on Patagonia.LocationOpen habitats of the Neotropics.TaxonVanellus chilensis (Aves, Charadriiformes).MethodsWe obtained reduced representation genomic and mitochondrial data from the four subspecies of V. chilensis to perform a phylogenetic/phylogeographical analysis and study the evolutionary history of the species. We complemented these analyses with the study of vocalizations, a reproductive signal in birds.ResultsThe initial diversification event within V. chilensis, approximately 600,000 years ago, split a Patagonian lineage from one containing individuals from the rest of the Neotropics. We found considerable gene flow between these two lineages and a contact zone in northern Patagonia, and showed that genomic admixture extends to northwestern Argentina. Shallower divergence was detected between the two non‐Patagonian subspecies, which are separated by the Amazon River. Vocalizations were significantly different between the two main lineages and were intermediate in their temporal and frequency characteristics in the contact zone.Main ConclusionsPatagonian populations of V. chilensis are clearly differentiated from those of the rest of the Neotropics, possibly as a consequence of Pleistocene glaciations. A secondary contact zone in northern Patagonia with extensive gene flow among lineages appears to be the consequence of post‐glacial, northward expansion of the Patagonian populations. Future analyses focused on the dynamics of the contact zone will allow us to establish whether the species continues to diverge or is homogenizing.

Charge within Nt17 peptides modulates huntingtin aggregation and initial lipid binding events

Toxic aggregation of pathogenic huntingtin protein (htt) is implicated in Huntington's disease and influenced by various factors, including the first seventeen amino acids at the N-terminus (Nt17) and the presence of lipid membranes. Nt17 has a propensity to form an amphipathic α-helix in the presence of binding partners, which promotes α-helix rich oligomer formation and facilitates htt/lipid interactions. Within Nt17 are multiple sites that are subject to post-translational modification, including acetylation and phosphorylation. Acetylation can occur at lysine 6, 9, and/or 15 while phosphorylation can occur at threonine 3, serine 13, and/or serine 16. Such modifications impact aggregation and lipid binding through the alteration of various intra- and intermolecular interactions. When incubated with htt-exon1(46Q), free Nt17 peptides containing point mutations mimicking acetylation or phosphorylation reduced fibril formation and altered oligomer morphologies. Upon exposure to lipid vesicles, changes to peptide/lipid complexation were observed and peptide-containing oligomers demonstrated reduced lipid interactions.

Unraveling the evolutionary dynamics of the TPS gene family in land plants.

Terpenes and terpenoids are key natural compounds for plant defense, development, and composition of plant oil. The synthesis and accumulation of a myriad of volatile terpenoid compounds in these plants may dramatically alter the quality and flavor of the oils, which provide great commercial utilization value for oil-producing plants. Terpene synthases (TPSs) are important enzymes responsible for terpenic diversity. Investigating the differentiation of the TPS gene family could provide valuable theoretical support for the genetic improvement of oil-producing plants. While the origin and function of TPS genes have been extensively studied, the exact origin of the initial gene fusion event - it occurred in plants or microbes - remains uncertain. Furthermore, a comprehensive exploration of the TPS gene differentiation is still pending. Here, phylogenetic analysis revealed that the fusion of the TPS gene likely occurred in the ancestor of land plants, following the acquisition of individual C- and N- terminal domains. Potential mutual transfer of TPS genes was observed among microbes and plants. Gene synteny analysis disclosed a differential divergence pattern between TPS-c and TPS-e/f subfamilies involved in primary metabolism and those (TPS-a/b/d/g/h subfamilies) crucial for secondary metabolites. Biosynthetic gene clusters (BGCs) analysis suggested a correlation between lineage divergence and potential natural selection in structuring terpene diversities. This study provides fresh perspectives on the origin and evolution of the TPS gene family.

Fibroblast growth factor 2

Fibroblast Growth Factor 2 (FGF2), also known as basic fibroblast growth factor, is a potent stimulator of growth and differentiation in multiple tissues. Its discovery traces back over 50 years ago when it was first isolated from bovine pituitary extracts due to its ability to stimulate fibroblast proliferation. Subsequent studies investigating the genomic structure of FGF2 identified multiple protein isoforms, categorized as the low molecular weight and high molecular weight FGF2. These isoforms arise from alternative translation initiation events and exhibit unique molecular and cellular functions. In this concise review, we aim to provide an overview of what is currently known about the structure, expression, and functions of the FGF2 isoforms within the contexts of development, homeostasis, and disease.

SAT146 Recurrent Hypoglycemia Following Asparaginase Therapy For Childhood Cancer: Institutional Experience

Abstract Disclosure: M. Tantoush: None. Background: Asparaginase (ASP) is a cornerstone pediatric leukemia and lymphoma therapy. Hyperglycemia following ASP is described, but hypoglycemia is infrequently identified as a complication. Following hypoglycemic events in children receiving ASP therapy, evaluation of associations and outcomes was undertaken. Aim: Evaluate and describe the risk factors, prevalence, duration, severity, recurrence and outcomes of children developing ASP-induced hypoglycemia. Method: Retrospective cohort study using electronic medical records to identify all patients who received ASP (PEGylated or non-PEGylated), and had diagnosis of hypoglycemia between 6/1/2017 and 6/30/22 at Texas Children's Hospital. We defined ASP-induced hypoglycemia as blood glucose (BG) <70 mg/dl 2-8 weeks from ASP administration, without alternative causes. If hypoglycemia evaluation was completed, hyperinsulinism was defined by: BG < 50 mg/dL; insulin > 2 mIU/mL; β-hydroxybutyrate < 1.8 mmol/L; free fatty acids < 1.7 mmol/L; or a post-glucagon BG > 30 mg/dL. Demographic and clinically relevant data were collected. Descriptive analysis was completed. Univariate regression models using Stata16 were analyzed. A p-value <0.05 was statistically significant. Results: Patients receiving ASP totaled 722, with 56 (7.6%) having ASP-induced hypoglycemia. Cancer diagnosis included acute lymphoblastic leukemia (n=50), lymphoblastic lymphoma (n=5) or acute myeloid leukemia (n=1). Median age was 4.4 years (IQR: 2.6 - 8.1), with 46% Hispanic and 59% male. Median BMI z-score was +0.4 (IQR: -0.3 - 1.2). Initial hypoglycemia event was during Induction therapy in 86% (n=48), with median time from ASP to hypoglycemia diagnosis 11 days (IQR: 6-15). Median lowest BG was 51 mg/dL (IQR: 43-57) with median duration 11 days (IQR: 7-19). Treatment included dietary change (52%, n=29), cornstarch (29%, n=16), and continuous feedings (13%, n=7). Continuous BG monitoring was utilized in 9 (16%). A critical sample was obtained in 18 (32%) with all evaluations consistent with hyperinsulinism. Recurrent hypoglycemia with subsequent ASP doses occurred in 42 (74%), with a median duration 14 days (IQR: 8-21; max: 56 days). Overall cancer survival following ASP-induced hypoglycemia was 80% (85% if excluding relapse disease), with 3 years’ median follow up. Severity of hypoglycemia (lowest BG, number of events, or length of events) was not associated with age, sex, ethnicity, or BMI z-score in univariate analysis. Conclusion: ASP-induced hypoglycemia is relatively common, often recurs with subsequent dosing, and may become severe requiring intensive therapy. Prospective screening of patients receiving ASP may be appropriate to prevent and manage events. Patients completed chemotherapy without change in survival at 3 years’ follow-up. Further studies to elucidate prognostic factors of ASP-induced hypoglycemia are needed. Presentation: Saturday, June 17, 2023

Extra- and intranuclear heat perception and triggering mechanisms in plants.

The escalating impact of global warming on crop yield and quality poses a significant threat to future food supplies. Breeding heat-resistant crop varieties holds promise, but necessitates a deeper understanding of the molecular mechanisms underlying plant heat tolerance. Recent studies have shed light on the initial events of heat perception in plants. In this review, we provide a comprehensive summary of the recent progress made in unraveling the mechanisms of heat perception and response in plants. Calcium ion (Ca2+), hydrogen peroxide (H2O2), and nitric oxide (NO) have emerged as key participants in heat perception. Furthermore, we discuss the potential roles of the NAC transcription factor NTL3, thermo-tolerance 3.1 (TT3.1), and Target of temperature 3 (TOT3) as thermosensors associated with the plasma membrane. Additionally, we explore the involvement of cytoplasmic HISTONE DEACETYLASE 9 (HDA9), mRNA encoding the phytochrome-interacting factor 7 (PIF7), and chloroplasts in mediating heat perception. This review also highlights the role of intranuclear transcriptional condensates formed by phytochrome B (phyB), EARLY FLOWERING 3 (ELF3), and guanylate-binding protein (GBP)-like GTPase 3 (GBPL3) in heat perception. Finally, we raise the unresolved questions in the field of heat perception that require further investigation in the future.

The rs2228145 Variant of the Interleukin-6 Receptor (IL-6R) Gene Impacts on In Vitro Cellular Responses to SARS-CoV-2 VOC B1.1.7 Recombinant Spike Protein

Given the variability in inflammatory responses to SARS-CoV-2 infection observed within human populations, we aimed to develop an in vitro model system (based on monocyte-macrophages, a key relevant cell type) that could yield insights regarding the impact of rs2228145, a clinically relevant polymorphism within the coding region of a key inflammatory gene in the body’s response to SARS-CoV-2 infection: the interleukin-6 receptor (IL-6R) gene. Three monocyte-macrophage cell-lines (U937, THP-1, MM6) were shown to exhibit AA, AC and CC rs2228145 genotypes, respectively, and to exhibit an MM6 > THP-1 > U937 pattern regarding basal levels of soluble IL-6R (sIL-6R) release. Similar MM6 > THP-1 > U937 patterns were seen regarding the extents to which (i) circulating levels of the IL-6/sIL-6R ‘active complex’ increased and (ii) phosphorylation of the downstream transcription-factor STAT3 occurred, following treatment with SARS-CoV-2 spike protein (SP). Moreover, a blocking antibody for the ACE-2 entry receptor for SARS-CoV-2 suppressed effects (i) and (ii), suggesting that interaction between SP and ACE-2 is the initial event that triggers IL-6/IL-6R signalling in our system. Production of IL-8 occurred to greater extents in A549 lung epithelial cells treated with tissue-culture supernatants from SP-treated MM6 cultures than SP-treated THP-1 or U937 cultures. Our data indicate that the rs2228145 genotype significantly impacts upon SP-associated IL-6/sIL-6R signalling in vitro, suggesting that it may influence in vivo risk of developing severe COVID-19 and/or long-COVID symptoms following infection by SARS-CoV-2. Thus, the rs2228145 genotype may have potential as a biomarker that differentiates between patients at risk of developing severe and/or prolonged symptoms following infection by SARS-CoV-2 and those who are at less risk.

Factors influencing autumn-winter movements of midcontinent Mallards and consequences for harvest and habitat management.

Annual phenology and distributions of migratory wildlife have been noticeably influenced by climate change, leading to concerns about sustainable populations. Recent studies exploring conditions influencing autumn migration departure have provided conflicting insights regarding factors influencing the movements of Mallards (Anas platyrhynchos), a popular game species. We determined factors affecting timing and magnitude of long-distance movements of 97 juvenile Mallards during autumn-winter across the midcontinent of North America marked with implanted transmitters in North and South Dakota, 2018-2019. Factors influencing variation in movement timing, along with direction and magnitudes, depended on type of movement (i.e., regional [25-310 km], initial migration, or subsequent migration movements [>310 km]). Photoperiod influenced probability of initiating all movements, although the effect was most influential for regional movements. Minimum temperature most influenced initial migration events (probability of movement increased 29% for each 1°C decrease); favorable winds also increased likelihood of initial migration events. Probability of subsequent migration events increased 80% for each 1 cm increase in depth of snow. Subsequent migration movements also were 2.0 times more likely to occur on weekend days, indicating disturbance from humans may influence movements. Migration distances increased 166 km for each 1°C reduction in minimum temperature. We also observed markedly different autumn-winter distributions of marked birds between years. Median locations during autumn-winter 2018-2019 were ~250 km farther north and ~300 km farther west during mid-December-January compared to the same time in 2019-2020. Concurrently, harvest rates for marked females and males were 10% and 26% during autumn-winter 2018-2019 and 26% and 31% during autumn-winter 2019-2020. Climate-related changes may result in increasingly variable autumn-winter distributions, with implications for wildlife recreationalists, conservation planners, and harvest managers.

The adverse consequences of not using sunscreens.

The adverse effects of solar ultraviolet radiation (UVR) on normal skin are well established, especially in those with poorly melanized skin. Clinically, these effects may be classified as acute, such as erythema or chronic such as keratinocyte and melanocyte skin cancers. Apart from skin type genetics, clinical responses to solar UVR are dependent on geophysical (e.g., solar intensity) and behavioural factors. The latter are especially important because they may result in 'solar overload' with unwanted clinical consequences and ever greater burdens to healthcare systems. Correctly used, sunscreens can mitigate the acute and chronic effects of solar UVR exposure. Laboratory studies also show that sunscreens can inhibit the initial molecular and cellular events that are responsible for clinical outcomes. Despite public health campaigns, global trends continue to show increasing incidence of all types of skin cancer. Large-scale epidemiological studies have shown the benefits of sunscreen use in preventing skin cancer, though it is likely that sunscreen use has not been optimal in such studies. It is evident that without substantial changes in sun-seeking behaviour, sunscreen use is a very important part of the defence against the acute and chronic effects of solar exposure. Ideally, sunscreens should be able to provide the level of protection that reduces the risk of skin cancer in susceptible skin types to that observed in heavily melanized skin.

Immunologic Implications for Stroke Recovery: Unveiling the Role of the Immune System in Pathogenesis, Neurorepair, and Rehabilitation.

Stroke is a debilitating neurologic condition characterized by an interruption or complete blockage of blood flow to certain areas of the brain. While the primary injury occurs at the time of the initial ischemic event or hemorrhage, secondary injury mechanisms contribute to neuroinflammation, disruption of the blood-brain barrier (BBB), excitotoxicity, and cerebral edema in the days and hours after stroke. Of these secondary mechanisms of injury, significant dysregulation of various immune populations within the body plays a crucial role in exacerbating brain damage after stroke. Pathological activity of glial cells, infiltrating leukocytes, and the adaptive immune system promote neuroinflammation, BBB damage, and neuronal death. Chronic immune activation can additionally encourage the development of neurologic deficits, immunosuppression, and dysregulation of the gut microbiome. As such, immunotherapy has emerged as a promising strategy for the clinical management of stroke in a highly patient-specific manner. These strategies include regulatory T cells (Tregs), cell adhesion molecules, cytokines, and monoclonal antibodies. However, the use of immunotherapy for stroke remains largely in the early stages, highlighting the need for continued research efforts before widespread clinical use.

Type I/type III IFN and related factors regulate JEV infection and BBB endothelial integrity

BackgroundJapanese encephalitis virus (JEV) remains a predominant cause of Japanese encephalitis (JE) globally. Its infection is usually accompanied by disrupted blood‒brain barrier (BBB) integrity and central nervous system (CNS) inflammation in a poorly understood pathogenesis. Productive JEV infection in brain microvascular endothelial cells (BMECs) is considered the initial event of the virus in penetrating the BBB. Type I/III IFN and related factors have been described as negative regulators in CNS inflammation, whereas their role in JE remains ambiguous.MethodsRNA-sequencing profiling (RNA-seq), real-time quantitative PCR, enzyme-linked immunosorbent assay, and Western blotting analysis were performed to analyze the gene and protein expression changes between mock- and JEV-infected hBMECs. Bioinformatic tools were used to cluster altered signaling pathway members during JEV infection. The shRNA-mediated immune factor-knockdown hBMECs and the in vitro transwell BBB model were utilized to explore the interrelation between immune factors, as well as between immune factors and BBB endothelial integrity.ResultsRNA-Seq data of JEV-infected hBMECs identified 417, 1256, and 2748 differentially expressed genes (DEGs) at 12, 36, and 72 h post-infection (hpi), respectively. The altered genes clustered into distinct pathways in gene ontology (GO) terms and KEGG pathway enrichment analysis, including host antiviral immune defense and endothelial cell leakage. Further investigation revealed that pattern-recognition receptors (PRRs, including TLR3, RIG-I, and MDA5) sensed JEV and initiated IRF/IFN signaling. IFNs triggered the expression of interferon-induced proteins with tetratricopeptide repeats (IFITs) via the JAK/STAT pathway. Distinct PRRs exert different functions in barrier homeostasis, while treatment with IFN (IFN-β and IFN-λ1) in hBMECs stabilizes the endothelial barrier by alleviating exogenous destruction. Despite the complex interrelationship, IFITs are considered nonessential in the IFN-mediated maintenance of hBMEC barrier integrity.ConclusionsThis research provided the first comprehensive description of the molecular mechanisms of host‒pathogen interplay in hBMECs responding to JEV invasion, in which type I/III IFN and related factors strongly correlated with regulating the hBMEC barrier and restricting JEV infection. This might help with developing an attractive therapeutic strategy in JE.

Advances in Cardiac Workup for Transient Ischemic Attack: Improving Diagnostic Yield and Reducing Recurrent Stroke Risk.

Transient ischemic attack (TIA) is a warning sign for an impending stroke, with a 10-20% chance of a stroke occurring within 90 days of the initial event. Current clinical practice for cardiac workup in TIA includes cardiac enzymes, with 12-lead electrocardiogram, transthoracic echocardiography, and 24-hour Holter monitoring. However, the diagnostic yield of these investigations is variable, and there is a need for better diagnostic approaches to increase the detection of cardiac abnormalities in a cost-effective way. This review article examines the latest research on emerging diagnostic tools and strategies and discusses the potential benefits and challenges of using these advanced diagnostic approaches in clinical practice. Novel biomarkers, imaging techniques, and prolonged rhythm monitoring devices have shown great promise in enhancing the diagnostic yield of cardiac workup in TIA patients. Echocardiography, Transcranial Doppler ultrasound, cardiac MRI, and cardiac CT are among the promising diagnostic tools being studied. We conclude the article with a suggested diagnostic algorithm for cardiac workup in TIA. Further research is necessary to enhance their usefulness and to outline future directions for research and clinical practice in this field.

RNA Post-transcriptional Modifications of an Early-Stage Large-Subunit Ribosomal Intermediate.

Protein production by ribosomes is fundamental to life, and proper assembly of the ribosome is required for protein production. The RNA, which is post-transcriptionally modified, provides the platform for ribosome assembly. Thus, a complete understanding of ribosome assembly requires the determination of the RNA post-transcriptional modifications in all of the ribosome assembly intermediates and on each pathway. There are 26 RNA post-transcriptional modifications in 23S RNA of the mature Escherichia coli (E. coli) large ribosomal subunit. The levels of these modifications have been investigated extensively only for a small number of large subunit intermediates and under a limited number of cellular and environmental conditions. In this study, we determined the level of incorporations of 2-methyl adenosine, 3-methyl pseudouridine, 5-hydroxycytosine, and seven pseudouridines in an early-stage E. coli large-subunit assembly intermediate with a sedimentation coefficient of 27S. The 27S intermediate is one of three large subunit intermediates accumulated in E. coli cells lacking the DEAD-box RNA helicase DbpA and expressing the helicase inactive R331A DbpA construct. The majority of the investigated modifications are incorporated into the 27S large subunit intermediate to similar levels to those in the mature 50S large subunit, indicating that these early modifications or the enzymes that incorporate them play important roles in the initial events of large subunit ribosome assembly.

Research on Initiating Events Analysis of Small Helium-Xenon Gas Cooled Nuclear Reactor

Initiating event analysis is an essential prerequisite of conducting probabilistic safety assessment for nuclear reactors, which plays an important role in improving the core design, identifying fault, and guiding operation. In order to determine the initiating event list of SIMONS (Small Innovative helium-xenon cooled Mobile Nuclear power System), preliminary researches on the initial event of SIMONS were carried out using the MLD (Main Logic Diagram) analysis method and referring to the initial event list and initial event analysis theory of other nuclear reactors such as HTGR (High Temperature Gas-cooled Reactor), MSR (Molten Salt Reactor), and PWR (Pressurized water reactor). With employing these methods, a total of 31 initial events are identified for SIMONS based on its latest conceptual design. These initial events are then divided into six groups according to the accident types, which are core heat removal increase, core heat removal decrease, abnormal reactivity and power distribution, pipeline crevasse and equipment leakage, anticipated transients without scram, and disasters (internal and external). The obtained results can provide a theoretical basis for the further safety analysis of SIMONS.

Improvement of methods for analyzing the technical condition of electromechanical equipment of nuclear power plants

The article analyzes the problem of diagnostics of NPP electric drive valves. Failure of this type of equipment can become the initial event for design or beyond design accident. Therefore, during the period of preventive maintenance at NPPs diagnostics of up to 2000 units of valves is carried out mainly by registration and analysis of the motor current signal during opening and closing. However, the applied statistical and frequency analysis methods do not always provide the necessary quality of diagnostics. The article points out the disadvantage of the applied methods – insensitivity to the dynamics of electromechanical equipment in terms of nonlinear manifestations of defects. As a tool for analyzing these manifestations the phase-plane method is proposed and its theoretical basis is outlined. The diagnostic signal is described as a vector diagram of a harmonic series subjected to amplitude and phase modulation. The most characteristic forms of phase trajectories - cardioids, nephroids, epicycloids – are shown. The main advantages of the phase-plane method over traditional frequency methods – sensitivity, possibility to identify the type of modulation, phase shift, dynamic and chaotic manifestations – are demonstrated by examples of processing diagnostic signals of NPP equipment. An important advantage of signal representation in the form of phase portrait is the visualization of dynamic features of the signal. The result of the work is a new method that allows to extract additional information about the object state by analyzing the non-stationary component of the initial data. It is proposed to introduce the phase-plane method into the practice of processing diagnostic signals of electric drive valves and other electromechanical equipment operated at NPPs.

Learning Language, Un/Learning Empathy in Medical School.

This article considers the ways in which empathy for patients and related solidarity with communities may be trained out of medical students during medical school. The article focuses especially on the pre-clinical years of medical school, those that begin with orientation and initiation events such as the White Coat Ceremony. The ethnographic data for the article come from field notes and recordings from my own medical training as well as hundreds of hours of observant participation and interviews with medical students over the past several years. Exploring the framework of language socialization, I argue that learning the verbal, textual and bodily language of medical practice contributes to the increasing experience of separation between physicians and patients. Further considering the ethnographic data, I argue that we also learn a form of empathy limited to performance that short circuits clinical care and the possibility for solidarity for health equity. The article concludes with implications for medical education and the medical social sciences and humanities.

O.6.2-2 Building momentum: lessons learned in the promotion of physical activity in primary healthcare settings

Abstract Purpose Physical activity plays a vital role in promoting and maintaining good physical and mental health, but too many individuals are not meeting recommendations. Policies that support physical activity prescription (PAP) within primary healthcare (PHC) settings are a key tenet of a comprehensive, systems-wide approach to increase physical activity and help prevent and manage many non-communicable diseases, including cancers. The fourth Building Momentum report sets out the emerging evidence for the benefits of promoting physical activity in PHC, and explains why designing and enacting such policies is good for individual health and economies. This is the first known report of its kind, offering a global policy perspective on developments and progress, as well as guidance on foundational policy processes and components. Description Physical activity is a WCRF International policy priority, directly related to our cancer prevention recommendations and MOVING framework and policy database. Research, writing and publication were managed by WCRF International. The current state of evidence and policies were evaluated through a literature review, and interviews conducted with subject-matter experts selected for their knowledge and experience. The report was evaluated through two rounds of review, including by interviewees, physical activity experts, and individuals from the WCRF Network, Policy Advisory Group, and the WHO. The report will be disseminated through an initial online launch event that will showcase the main findings, country reflections and guidance. Further dissemination will be through WCRF International’s health professional and policy networks, social media, and potentially conferences like HEPA. Conclusions The fourth Building Momentum report provides guidance on how to establish successful policies for PAP in PHC. It addresses key issues and potential barriers to adoption, as well as identifying foundational policy processes, including: using the evidence, building shared policy objectives, the importance of local contexts and equity underpinning all policy elements. It also identifies components for designing effective policies, including: PHC professional training, health systems capacity, incentivizing structures, the importance of communication and collaboration, and creating supportive patient environments. Engaging with these findings, as well as examples of national programmes, will enable governments and health systems to enact well-designed policy on physical activity promotion in PHC.

Neuroanatomical zones of human traumatic brain injury reveal significant differences in protein profile and protein oxidation: Implications for secondary injury events.

Traumatic brain injury (TBI) causes significant neurological deficits and long-term degenerative changes. Primary injury in TBI entails distinct neuroanatomical zones, i.e., contusion (Ct) and pericontusion (PC). Their dynamic expansion could contribute to unpredictable neurological deterioration in patients. Molecular characterization of these zones compared with away from contusion (AC) zone is invaluable for TBI management. Using proteomics-based approach, we were able to distinguish Ct, PC and AC zones in human TBI brains. Ct was associated with structural changes (blood-brain barrier (BBB) disruption, neuroinflammation, axonal injury, demyelination and ferroptosis), while PC was associated with initial events of secondary injury (glutamate excitotoxicity, glial activation, accumulation of cytoskeleton proteins, oxidative stress, endocytosis) and AC displayed mitochondrial dysfunction that could contribute to secondary injury events and trigger long-term degenerative changes. Phosphoproteome analysis in these zones revealed that certain differentially phosphorylated proteins synergistically contribute to the injury events along with the differentially expressed proteins. Non-synaptic mitochondria (ns-mito) was associated with relatively more differentially expressed proteins (DEPs) compared to synaptosomes (Syn), while the latter displayed increased protein oxidation including tryptophan (Trp) oxidation. Proteomic analysis of immunocaptured complex I (CI) from Syn revealed increased Trp oxidation in Ct > PC > AC (vs. control). Oxidized W272 in the ND1 subunit of CI, revealed local conformational changes in ND1 and the neighboring subunits, as indicated by molecular dynamics simulation (MDS). Taken together, neuroanatomical zones in TBI show distinct protein profile and protein oxidation representing different primary and secondary injury events with potential implications for TBI pathology and neurological status of the patients.

Unraveling Leukocyte Profile Shifts and Platelet Dynamics Following Leukoreduced Packed Red Cell Transfusions in Very Low Birth Weight Preterm Neonates.

Background Packed red blood cell (PRBC) transfusions are routine in neonatal care and the most common blood product administered to sick neonates. However, their impact on leukocyte and platelet profiles in very low birth weight (VLBW) preterm infants remains largely unexplored.This study examines leukocyte profile shifts and platelet dynamics following leukoreduced PRBC transfusions in VLBW preterm infants, offering insights to improve neonatal care and reduce unnecessary interventions. Methods The study utilized a retrospective cohort design within a single center, focusing on VLBW preterm infants who received PRBC transfusions at a level 3 NICU between January 2014 and June 2019. Data collection encompassed white blood cell (WBC) and platelet count measurements taken 24 hours before and up to 72 hours after PRBC transfusion. Neonates lacking complete blood count (CBC) data within the 72-hour post-transfusion window were excluded. A subgroup analysis distinguished the outcome between the initial PRBC transfusion and subsequent ones. The statistical significance of pre- and post-transfusion laboratory data was determined using the Wilcoxon signed ranks test and paired T-test. Results A cohort of 108 VLBW preterm infants who underwent a total of 402 PRBC transfusions was included in the analysis. The subjects exhibited a mean gestational age of 27.2 ± 2.5 weeks and a mean birth weight of 913 ± 264 grams. Analysis of pre- and post-transfusion data revealed no significant differences in total white blood cell count (WBC), absolute neutrophil count (ANC), absolute monocyte count (AMC), absolute eosinophil count, and absolute lymphocyte count. Notably, the platelet count was significantly decreased in the post-transfusion group (p < 0.001). In a subset analysis limited to the first-time transfusions among the 108 infants, a statistically significant increase was observed in total WBC, AMC, and ANC following transfusion. Conclusions The findings of this study highlight that PRBC transfusions can prompt an increase in neutrophils, monocytes, and eosinophils, coupled with a decline in platelet counts, all within a 72-hour window post-transfusion. Notably, these changes were predominantly discernible after the initial transfusion, with subsequent transfusions demonstrating consistency, except for the observed platelet count reduction. Recognizing these patterns could prove instrumental in averting undue investigations for suspected sepsis, particularly following the initial transfusion event. However, further in-depth investigations are necessary to uncover the underlying factors responsible for the shifts in leukocyte and platelet profiles triggered by PRBC transfusions.

SARS-CoV-2 variants of concern elicit divergent early immune responses in hACE2 transgenic mice.

Knowledge about early immunity to SARS-CoV-2 variants of concern mainly comes from the analysis of human blood. Such data provide limited information about host responses at the site of infection and largely miss the initial events. To gain insights into compartmentalization and the early dynamics of host responses to different SARS-CoV-2 variants, we utilized human angiotensin converting enzyme 2 (hACE2) transgenic mice and tracked immune changes during the first days after infection by RNAseq, multiplex assays, and flow cytometry. Viral challenge infection led to divergent viral loads in the lungs, distinct inflammatory patterns, and innate immune cell accumulation in response to ancestral SARS-CoV-2, Beta (B.1.351) and Delta (B.1.617.2) variant of concern (VOC). Compared to other SARS-CoV-2 variants, infection with Beta (B.1.351) VOC spread promptly to the lungs, leading to increased inflammatory responses. SARS-CoV-2-specific antibodies and T cells developed within the first 7 days postinfection and were required to reduce viral spread and replication. Our studies show that VOCs differentially trigger transcriptional profiles and inflammation. This information contributes to the basic understanding of immune responses immediately postexposure to SARS-CoV-2 and is relevant for developing pan-VOC interventions including prophylactic vaccines.