The diet-intestinal microbiota dynamics and adaptation in an elevational migration bird, the Himalayan bluetail (Tarsiger rufilatus).

Migratory birds experience changes in their environment and diet during seasonal migrations, thus requiring interactions between diet and gut microbes. Understanding the co-evolution of the host and gut microbiota is critical for elucidating the rapid adaptations of avian gut microbiota. However, dynamics of gut microbial adaptations concerning elevational migratory behavior, which is prevalent but understudied in montane birds remain poorly understood. We focused on the Himalayan bluetail (Tarsiger rufilatus) in the montane forests of Mt. Gongga to understand the diet-gut microbial adaptations of elevational migratory birds. Our findings indicate that elevational migratory movements can rapidly alter gut microbial composition and function within a month. There was a significant interaction between an animal-based diet and gut microbiota across migration stages, underscoring the importance of diet in shaping microbial communities. Furthermore, the gut microbial composition of T. rufilatus may be potentially altered by high-altitude acclimatization. An increase in fatty acid and amino acid metabolism was observed in response to low temperatures and limited resources, resulting in enhanced energy extraction and nutrient utilization. Moreover, microbial communities in distinct gut segments varied in relative abundance and responses to environmental changes. While the bird jejunum exhibited greater susceptibility to food and environmental fluctuations, there was no significant difference in metabolic capacity among gut segments. This study provides initial evidence of rapid diet-gut microbial changes in distinct gut segments of elevational migratory birds and highlights the importance of seasonal sample collection. Our findings provide a deeper understanding of the unique high-altitude adaptation patterns of the gut microbiota for montane elevational migratory birds.

Liver injury in paraquat poisoning: A retrospective cohort study.

BACKGROUND AND AIMS: Liver injury is one of the common complications of paraquat (PQ) poisoning, but whether the degree of liver injury is related to patient prognosis is still controversial. This study aimed to investigate whether liver injury was a risk factor for death in PQ-poisoned patients. METHODS: We conducted a retrospective cohort study of PQ-poisoned patients from the past 10 years (2011-2020) from a large tertiary academic medical centre in China. PQ-poisoned patients were divided into a normal liver function group (n = 580) and a liver injury group (n = 60). Propensity score matching (PSM) analysis was then performed. RESULTS: A total of 640 patients with PQ poisoning were included in this study. To reduce the impact of bias, dose of PQ, urinary PQ concentration and time from poisoning to hospital admission were matched between the two groups. A 3:1 PSM analysis was performed, ultimately including 240 patients. Compared with the normal liver function group, patients in the liver injury group were older, had a higher R value ([ALT/ULN]/[ALP/ULN]) (p < .001) and had a higher mortality rate. Cox regression analysis showed that there was no significant association between alanine aminotransferase, alkaline phosphatase, total bilirubin levels and hazard of death, but age, PQ dose, creatine kinase isoenzyme, creatine kinase, white blood cell count, neutrophil percentage and lymphocyte percentage were associated with mortality in patients with PQ poisoning. CONCLUSIONS: The occurrence of liver injury within 48 h after PQ poisoning was a risk factor for mortality, and such liver injury was likely of a hepatocellular nature. Age, PQ dose, creatine kinase isoenzyme and white blood cell count were positively correlated with mortality, while creatine kinase, percentage of neutrophils and lymphocytes were inversely correlated.

Integration of nonlinear two-photon excited fluorescence and photocatalysis boosts overall water splitting performance.

A nonlinear two-photon excited fluorescence photocatalytic system was constructed for the first time by integrating (ZnO)1-x(GaN)x photocatalyst and a fluorescence solution of phenanthridine derivatives. This work offers a strategy for increasing the photocatalytic solar spectral utilization rate and boosting the expectation for photocatalytic solar-to-hydrogen efficiencies.

Electronic-ionic bi-functional conduction ß-Li3PS4-coated graphene hollow spheres as a highly stable lithium metal anode skeleton.

Although Li metal is considered the most potential anode for Li based batteries, the repeatedly large volume variation and low Coulombic efficiency (CE) are still serious challenges for commercial application. Herein, the interconnect closed hollow graphene spheres with electronic-ionic bi-functional conduction network containing Li4.4Sn nanoparticles loaded internally and ß-Li3PS4 solid electrolyte layer coated externally (ß-LPS/SG/Li4.4Sn) is proposed to achieve uniform and dense Li deposition. Density functional theory (DFT) calculation and experimental results show that Li4.4Sn owns larger Li binding energy and lower nucleation overpotential than spherical graphene (SG), thus being able to guide Li traversing and depositing inside the hollow spheres. The Tafel curves, Li+ diffusion activation energy and experimental results reveal that the ß-Li3PS4 coating layer significantly improves the ionic conductivity of the negative skeleton, covers the defect sites on the SG surface, provides continuous ion transmission channels and accelerates Li+ migration rate. The synergy of both can inhibit the formation of dendritic Li and reduce side reaction between freshly deposited lithium and the organic electrolyte. It's found that Li is preferentially deposited within the SG, evenly deposited on the spherical shell surface until it's completely filled to obtain a dense lithium layer without tip effect. As a result, the ß-LPS/SG/Li4.4Sn anode exhibits a long life of up to 2800 h, an extremely low overpotential (∼13 mV) and a high CE of 99.8 % after 470 cycles. The LiFePO4-based full cell runs stably with a high capacity retention of 86.93 % after 800 cycles at 1C. It is considered that the novel structure design of Li anode skeleton with electron-ionic bi-functional conduction is a promising direction to construct long-term stable lithium metal anodes.

Non-O blood types are associated with a greater risk of large artery atherosclerosis stroke and dysregulation of cholesterol metabolism: an observational study.

BACKGROUND: Previous research on ABO blood types and stroke has been controversial, predominantly suggesting heightened risk of stroke in non-O blood types. Nonetheless, investigations into the correlation and underlying mechanisms between ABO blood groups and stroke subtypes, especially within Chinese cohorts, remain limited. METHODS: The ABO blood types of 9,542 ischaemic stroke (IS) patients were inferred using two ABO gene loci (c.261G > del; c.802G > A). The healthy population was derived from the 1000 Genomes Project. Patients were classified by the causative classification system (CCS). Volcano plot and gene ontology (GO) analysis were employed to explore protein differential expression among blood types. Additionally, HT29 and SW480 cell lines with downregulated ABO expression were generated to evaluate its impact on cholesterol uptake and efflux. RESULTS: A greater proportion of stroke patients had non-O blood types (70.46%) than did healthy individuals (61.54%). Notable differences in blood type distributions were observed among stroke subtypes, with non-O blood type patients mainly classified as having large artery atherosclerosis (LAA). Clinical baseline characteristics, such as the low-density lipoprotein cholesterol level, activated partial thromboplastin time and thrombin time, varied significantly among blood types. A volcano plot revealed 17 upregulated and 42 downregulated proteins in the O blood type. GO term analysis indicated that downregulated proteins were primarily associated with lipid metabolism pathways. In vitro experiments revealed that reducing ABO gene expression decreased cholesterol uptake and increased cholesterol efflux. CONCLUSIONS: This study revealed that the non-O blood type increased the risk of LAA stroke through cholesterol metabolism.

Identification of endoplasmic reticulum stress genes in human stroke based on bioinformatics and machine learning.

After ischemic stroke (IS), secondary injury is intimately linked to endoplasmic reticulum (ER) stress and body-brain crosstalk. Nonetheless, the underlying mechanism systemic immune disorder mediated ER stress in human IS remains unknown. In this study, 32 candidate ER stress-related genes (ERSRGs) were identified by overlapping MSigDB ER stress pathway genes and DEGs. Three Key ERSRGs (ATF6, DDIT3 and ERP29) were identified using LASSO, random forest, and SVM-RFE. IS patients with different ERSRGs profile were clustered into two groups using consensus clustering and the difference between 2 group was further explored by GSVA. Through immune cell infiltration deconvolution analysis, and middle cerebral artery occlusion (MCAO) mouse scRNA analysis, we found that the expression of 3 key ERSRGs were closely related with peripheral macrophage cell ER stress in IS and this was further confirmed by RT-qPCR experiment. These ERS genes might be helpful to further accurately regulate the central nervous system and systemic immune response through ER stress and have potential application value in clinical practice in IS.

Transcriptome analysis identifies an ASD-Like phenotype in oligodendrocytes and microglia from C58/J amygdala that is dependent on sex and sociability.

BACKGROUND: Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with higher incidence in males and is characterized by atypical verbal/nonverbal communication, restricted interests that can be accompanied by repetitive behavior, and disturbances in social behavior. This study investigated brain mechanisms that contribute to sociability deficits and sex differences in an ASD animal model. METHODS: Sociability was measured in C58/J and C57BL/6J mice using the 3-chamber social choice test. Bulk RNA-Seq and snRNA-Seq identified transcriptional changes in C58/J and C57BL/6J amygdala within which DMRseq was used to measure differentially methylated regions in amygdala. RESULTS: C58/J mice displayed divergent social strata in the 3-chamber test. Transcriptional and pathway signatures revealed immune-related biological processes differ between C58/J and C57BL/6J amygdala. Hypermethylated and hypomethylated genes were identified in C58/J versus C57BL/6J amygdala. snRNA-Seq data in C58/J amygdala identified differential transcriptional signatures within oligodendrocytes and microglia characterized by increased ASD risk gene expression and predicted impaired myelination that was dependent on sex and sociability. RNA velocity, gene regulatory network, and cell communication analysis showed diminished oligodendrocyte/microglia differentiation. Findings were verified using Bulk RNA-Seq and demonstrated oxytocin's beneficial effects on myelin gene expression. LIMITATIONS: Our findings are significant. However, limitations can be noted. The cellular mechanisms linking reduced oligodendrocyte differentiation and reduced myelination to an ASD phenotype in C58/J mice need further investigation. Additional snRNA-Seq and spatial studies would determine if effects in oligodendrocytes/microglia are unique to amygdala or if this occurs in other brain regions. Oxytocin's effects need further examination to understand its' potential as an ASD therapeutic. CONCLUSIONS: Our work demonstrates the C58/J mouse model's utility in evaluating the influence of sex and sociability on the transcriptome in concomitant brain regions involved in ASD. Our single-nucleus transcriptome analysis elucidates potential pathological roles of oligodendrocytes and microglia in ASD. This investigation provides details regarding regulatory features disrupted in these cell types, including transcriptional gene dysregulation, aberrant cell differentiation, altered gene regulatory networks, and changes to key pathways that promote microglia/oligodendrocyte differentiation. Our studies provide insight into interactions between genetic risk and epigenetic processes associated with divergent affiliative behavior and lack of positive sociability.

Transcriptional determinism and stochasticity contribute to the complexity of autism-associated SHANK family genes.

Precision of transcription is critical because transcriptional dysregulation is disease causing. Traditional methods of transcriptional profiling are inadequate to elucidate the full spectrum of the transcriptome, particularly for longer and less abundant mRNAs. SHANK3 is one of the most common autism causative genes. Twenty-four Shank3-mutant animal lines have been developed for autism modeling. However, their preclinical validity has been questioned due to incomplete Shank3 transcript structure. We apply an integrative approach combining cDNA-capture and long-read sequencing to profile the SHANK3 transcriptome in humans and mice. We unexpectedly discover an extremely complex SHANK3 transcriptome. Specific SHANK3 transcripts are altered in Shank3-mutant mice and postmortem brain tissues from individuals with autism spectrum disorder. The enhanced SHANK3 transcriptome significantly improves the detection rate for potential deleterious variants from genomics studies of neuropsychiatric disorders. Our findings suggest that both deterministic and stochastic transcription of the genome is associated with SHANK family genes.

Improving the ferroelectric properties of Lu doped Hf0.5Zr0.5O2thin films by capping a CeOxlayer.

Lu doped Hf0.5Zr0.5O2(HZO) ferroelectric films were prepared on Pt/TiN/SiO2/Si substrate by chemical solution deposition method, and an interfacial engineering strategy for improving the ferroelectric property was explored by capping the Lu doped HZO films with a cerium oxide layer. Compared with the Lu doped HZO film without the CeOxcoating layer, the Lu doped HZO film with the CeOxcoating layer has a larger remanent polarization (2Pr= 34.72µC cm-2) and presents weaker wake-up behavior, which result from the higher orthogonal phase ratio and the lower oxygen vacancy of the CeOxcoated Lu doped HZO film. In addition, the CeOxcoating can remarkably improve the fatigue resistance and retention performance of the Lu doped HZO films. It is hoped that the results can provide an effective approach for the realization of high-performance and highly reliable hafnium oxide based ferroelectric thin films.

Iodine-doped carbon nanotubes boosting the adsorption effect and conversion kinetics of lithium-sulfur batteries.

Compared with lithium-ion batteries (LIBs), lithium-sulfur batteries (LSBs), based on electrochemical reactions involving multi-step 16-electron transformations provide higher specific capacity (1672 mAh g-1) and specific energy (2600 Wh kg-1), exhibiting great potential in the field of energy storage. However, the inherent insulation of sulfur, slow electrochemical reaction kinetics and detrimental shuttle-effect of lithium polysulfides (LiPSs) restrict the development of LSBs in practical applications. Herein, the iodine-doped carbon nanotubes (I-CNTs) is firstly reported as sulfur host material to the enhance the adsorption-conversion kinetics of LSBs. Iodine doping can significantly improve the polarity of I-CNTs. Iodine atoms with lone pair electrons (Lewis base) in iodine-doped CNTs can interact with lithium cations (Lewis acidic) in LiPSs, thereby anchoring polysulfides and suppressing subsequent shuttling behavior. Moreover, the charge transfer between iodine species (electron acceptor) and CNTs (electron donor) decreases the gap band and subsequently improves the conductivity of I-CNTs. The enhanced adsorption effect and conductivity are beneficial for accelerating reaction kinetics and enhancing electrocatalytic activity. The in-situ Raman spectroscopy, quasi in-situ electrochemical impedance spectroscopy (EIS) and Li2S potentiostatic deposition current-time (i-t) curves were conducted to verify mechanism of complex sulfur reduction reaction (SRR). Owing to above advantages, the I-CNTs@S composite cathode exhibits an ultrahigh initial capacity of 1326 mAh g-1 as well as outstanding cyclicability and rate performance. Our research results provide inspirations for the design of multifunctional host material for sulfur/carbon composite cathodes in LSBs.

A Superparamagnetic Composite Hydrogel Scaffold as In Vivo Dynamic Monitorable Theranostic Platform for Osteoarthritis Regeneration.

Osteoarthritis (OA) is a prevalent disease, characterized by subchondral fractures in its initial stages, which has no precise and specific treatment now. Here, a novel multifunctional scaffold is synthesized by photopolymerizing glycidyl methacrylate-modified hyaluronic acid (GMHA) as the matrix in the presence of hollow porous magnetic microspheres based on hydroxyapatite. In vivo subchondral bone repairing results demonstrate that the scaffold's meticulous design has most suitable properties for subchondral bone repair. The porous structure of inorganic particles within the scaffold facilitates efficient transport of loaded exogenous vascular endothelial growth factor (VEGF). The Fe3O4 nanoparticles assembled in microspheres promote the osteogenic differentiation of bone marrow mesenchymal stem cells and accelerate the new bone generation. These features enable the scaffold to exhibit favorable subchondral bone repair properties and attain high cartilage repair scores. The therapy results prove that the subchondral bone support considerably influences the upper cartilage repair process. Furthermore, magnetic resonance imaging monitoring demonstrates that Fe3O4 nanoparticles, which are gradually replaced by new bone during osteochondral defect repair, allow a noninvasive and radiation-free assessment to track the newborn bone during the OA repair process. The composite hydrogel scaffold (CHS) provides a versatile platform for biomedical applications in OA treatment.

KDM4C represses liver fibrosis by regulating H3K9me3 methylation of ALKBH5 and m6A methylation of snail1 mRNA.

OBJECTIVE: We aimed to disclose the molecular mechanism of snail1 in liver fibrosis. METHODS: Carbon tetrachloride (CCl4) was used to induce a liver fibrosis model in mice whereby serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were evaluated, and liver pathological alternations were assessed. Rat hepatic stellate cells (HSC-T6) were irritated with transforming growth factor (TGF)-ß1, followed by assessment of cell viability and migration. The levels of snail1, ALKBH5, and lysine specific demethylase 4C (KDM4C) were quantified by immunohistochemistry, western blot, or reverse transcription-quantitative polymerase chain reaction, in addition to α-smooth muscle actin (SMA), anti-collagen type I α1 (COL1A1), vimentin, and E-cadherin. Photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation and RNA stability were evaluated to determine the relationship between ALKBH5 and snail1. Changes in KDM4C-bound ALKBH5 promoter and enrichment of histone H3 lysine 9 trimethylation (H3K9me3) at the ALKBH5 promoter were determined using chromatin immunoprecipitation. RESULTS: In fibrosis mice, snail1 was upregulated while ALKBH5 and KDM4C were downregulated. KDM4C overexpression reduced serum ALT and AST levels, liver injury, and α-SMA, COL1A1 and VIMENTIN expressions but increased E-cadherin expression. However, the aforementioned trends were reversed by concurrent overexpression of snail1. In HSC-T6 cells exposed to TGF-ß1, ALKBH5 overexpression weakened cell viability and migration, downregulated α-SMA, COL1A1 and VIMENTIN, upregulated E-CADHERIN, and decreased m6A modification of snail1 and its mRNA stability. KDM4C increased ALKBH5 expression by lowering H3K9me3 level, but inhibited HSC-T6 cell activation by regulating the ALKBH5/snail1 axis. CONCLUSION: KDM4C decreases H3K9me3 methylation to upregulate ALKBH5 and subsequently inhibits snail1, ultimately impeding liver fibrosis.

Cryo-electron tomography reveals the packaging pattern of RuBisCOs in Synechococcus ß-carboxysome.

Carboxysomes are large self-assembled microcompartments that serve as the central machinery of a CO2-concentrating mechanism (CCM). Biogenesis of carboxysome requires the fine organization of thousands of individual proteins; however, the packaging pattern of internal RuBisCOs remains largely unknown. Here we purified the intact ß-carboxysomes from Synechococcus elongatus PCC 7942 and identified the protein components by mass spectrometry. Cryo-electron tomography combined with subtomogram averaging revealed the general organization pattern of internal RuBisCOs, in which the adjacent RuBisCOs are mainly arranged in three distinct manners: head-to-head, head-to-side, and side-by-side. The RuBisCOs in the outermost layer are regularly aligned along the shell, the majority of which directly interact with the shell. Moreover, statistical analysis enabled us to propose an ideal packaging model of RuBisCOs in the ß-carboxysome. These results provide new insights into the biogenesis of ß-carboxysomes and also advance our understanding of the efficient carbon fixation functionality of carboxysomes.

Root nitrogen reallocation: what makes it matter?

Root nitrogen (N) reallocation involves remobilization of root N-storage pools to support shoot growth. Representing a critical yet underexplored facet of plant function, we developed innovative frameworks to elucidate its connections with key ecosystem components. First, root N reallocation increases with plant species richness and N-acquisition strategies, driven by competitive stimulation of plant N demand and synergies in N uptake. Second, competitive root traits and mycorrhizal symbioses, which enhance N foraging and uptake, exhibit trade-offs with root N reallocation. Furthermore, root N reallocation is attenuated by N-supply attributes such as increasing litter quality, soil fungi-to-bacteria ratios, and microbial recruitment in the hyphosphere/rhizosphere. These frameworks provide new insights and research avenues for understanding the ecological roles of root N reallocation.

Genotype-phenotype Correlations of Ocular Posterior Segment Abnormalities in Marfan Syndrome.

Purpose: Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 ( (FBN1). In addition to typical phenotypes such as ectopia lentis (EL) and aortic dilation, patients with MFS are prone to ocular posterior segment abnormalities, including retinal detachment (RD), maculopathy, and posterior staphyloma (PS). This study aims to investigate the correlations between FBN1 genotype and posterior segment abnormalities within a Chinese cohort of MFS. Design: Retrospective study. Participants: One hundred twenty-one eyes of 121 patients with confirmed FBN1 mutations between January 2015 and May 2023 were included. Methods: Comprehensive ophthalmic examination findings were reviewed, and the incidence of RD, atrophic, tractional, and neovascular maculopathy (ATN classification system), and PS was analyzed between different genotype groups. Only the more severely affected eye from each patient was included. Main Outcome Measures: Clinical features and risk factors. Results: Of 121 patients, 60 eyes (49.59%) exhibited posterior segment abnormalities, including RD (4, 3.31%), maculopathy (47, 38.84%), and PS (54, 44.63%). The mean age was 11.53 ± 11.66 years, with 79.34% of patients <20 years old. The location and region of mutations were found to be associated with the incidence of maculopathy (P = 0.013, P = 0.033) and PS (P = 0.043, P = 0.036). Mutations in the middle region had a lower incidence of maculopathy and PS (P = 0.028 and P = 0.006, respectively) than those in C-terminal region. Mutations in the transforming growth factor-ß (TGF-ß) regulating sequence exhibited a higher incidence of maculopathy and PS (P = 0.020, P = 0.040). Importantly, the location and region of mutations were also associated with the incidence of atrophic maculopathy (P = 0.013 and P = 0.033, respectively). Mutations in the middle region had a significantly lower probability of atrophic maculopathy (P = 0.006), while mutations in the TGF-ß regulating region had a higher incidence of atrophic maculopathy (P = 0.020). Conclusions: Maculopathy and PS were associated with the location and region of FBN1 mutations. Patients with mutations in the TGF-ß regulating region faced an increased risk of developing retinopathy. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Tenecteplase for Ischemic Stroke at 4.5 to 24 Hours without Thrombectomy.

BACKGROUND: Tenecteplase is an effective thrombolytic agent for eligible patients with stroke who are treated within 4.5 hours after the onset of stroke. However, data regarding the effectiveness of tenecteplase beyond 4.5 hours are limited. METHODS: In a trial conducted in China, we randomly assigned patients with large-vessel occlusion of the middle cerebral artery or internal carotid artery who had salvageable brain tissue as identified on perfusion imaging and who did not have access to endovascular thrombectomy to receive tenecteplase (at a dose of 0.25 mg per kilogram of body weight; maximum dose, 25 mg) or standard medical treatment within 4.5 to 24 hours after the time that the patient was last known to be well (including after stroke on awakening and unwitnessed stroke). The primary outcome was the absence of disability, which was defined as a score of 0 or 1 on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability), at day 90. The key safety outcomes were symptomatic intracranial hemorrhage and death. RESULTS: A total of 516 patients were enrolled; 264 were randomly assigned to receive tenecteplase and 252 to receive standard medical treatment. Less than 2% of the patients (4 in the tenecteplase group and 5 in the standard-treatment group) underwent rescue endovascular thrombectomy. Treatment with tenecteplase resulted in a higher percentage of patients with a modified Rankin scale score of 0 or 1 at 90 days than standard medical treatment (33.0% vs. 24.2%; relative rate, 1.37; 95% confidence interval, 1.04 to 1.81; P = 0.03). Mortality at 90 days was 13.3% with tenecteplase and 13.1% with standard medical treatment, and the incidence of symptomatic intracranial hemorrhage within 36 hours after treatment was 3.0% and 0.8%, respectively. CONCLUSIONS: In this trial involving Chinese patients with ischemic stroke due to large-vessel occlusion, most of whom did not undergo endovascular thrombectomy, treatment with tenecteplase administered within 4.5 to 24 hours after stroke onset resulted in less disability and similar survival as compared with standard medical treatment, and the incidence of symptomatic intracranial hemorrhage appeared to be higher. (Funded by the National Natural Science Foundation of China and others; TRACE-III ClinicalTrials.gov number, NCT05141305.).

Unique challenges required reassessment and alterations to critical reagents to rescue a neutralizing antibody assay.

Aim: To redevelop a neutralizing antibody (NAb) assay to be much more drug tolerant, have a large dynamic range and have high inhibition when using high levels of positive control (PC). Materials & methods: Early assay data suggested that typical biotin labeling of the capture reagent (Drug 1, produced in a human cell line) was blocking it from binding with the PC or the detection target, and that the detection target was out competing the PC. Methodical biotin labeling experiments were performed at several challenge ratios and an Fc linker was added to the detection target. Results & conclusion: A larger dynamic range, high inhibition and higher drug tolerance were achieved by adding an acid dissociation step to the assay, performing atypical biotin labeling of Drug 1 and switching to a detection target that contained an Fc linker to increase steric hinderance and decrease its binding affinity to Drug 1.

Many of the drugs available today are produced by a living organism and these are called biologics. Biologics are larger than chemical drugs and the human body can detect them as foreign and create antibodies against them. This is called immunogenicity. When the antibodies created against the biologic blocks the drug's ability to work correctly, they are called neutralizing antibodies (NAbs). Testing for NAbs is one of the requirements of regulatory agencies for biologics. Here we describe challenges encountered developing an assay to test for NAbs against a biologic.

Data-Driven Analysis Reveals Cortical Infarction Patterns Correlated With Inflammation and Prognosis: A Retrospective, Multicenter Cohort Study.

BACKGROUND: We aim to identify the distinct lesion patterns and regions associated with functional outcome and inflammation in patients with acute ischemic stroke, and investigate whether the association between lesion patterns and functional outcome was mediated by inflammation. METHODS AND RESULTS: We performed nonnegative matrix factorization to derived low-dimensional lesion patterns (atoms), and Bayesian linear regression models were applied to explore the associations of lesion patterns with inflammatory factors including high-sensitivity C-reactive protein and interleukin-6, as well as functional outcome (defined as modified Rankin Scale score at 3 months). The difference distribution mean and 95% highest probability density interval (HPDI) were calculated. Mediation analysis was used to examine the mediating effects of inflammation on the relationships between lesion patterns and functional outcome. Seven lesion patterns were derived from 5914 patients with acute ischemic stroke. Lesion patterns distributed in the cortical regions were associated with inflammatory response, including atom 1 (interleukin-6: mean, 0.113 [95% HPDI, 0.073-0.162]; high-sensitivity C-reactive protein: mean, 0.082 [95% HPDI, 0.038-0.123]) and atom 4 (interleukin-6: mean, 0.113 [95% HPDI, 0.071-0.167]; high-sensitivity C-reactive protein: mean, 0.108 [95% HPDI, 0.058-0.165]). These lesion patterns were also significantly associated with functional outcome (atom 1: mean, 1.958 [95% HPDI, 1.538-2.383]; atom 4: mean, 2.245 [95% HPDI, 1.773-2.741]). Mediation analysis suggested that interleukin-6 explained 15.34% and 7.47% in the association of atom 1 and atom 4 with functional outcome, respectively. CONCLUSIONS: Certain lesion patterns that are associated with both inflammation and functional outcome of acute ischemic stroke, especially cortical infarction, may play a role in functional outcome through modulating inflammatory reactions.

Dynamic mRNA network profiles in macrophages challenged with lipopolysaccharide.

OBJECTIVES: To elucidate the transcriptome of macrophages in an inflammation model induced by lipopolysaccharide (LPS), providing insight into the molecular basis of inflammation. METHODS: We utilized RNA sequencing (RNA-seq) to analyze dynamic changes in gene expression in RAW264.7 macrophages treated with LPS at multiple time points. Differentially expressed genes (DEGs) were identified using the edgeR package. Short Time-series Expression Miner (STEM) and KEGG pathway enrichment analyses were conducted to determine temporal expression patterns during inflammation. RESULTS: We identified 2,512 DEGs, with initial inflammatory responses occurring in two distinct phases at 1 h and 3 h. Venn diagram analysis revealed 78 consistently dysregulated genes throughout the inflammatory process. A key module of 18 dysregulated genes was identified, including Irg1, which may exert an inhibitory effect on inflammation. Further, a second metabolic shift in activated macrophages was observed at the late middle stage (12 h). Multi-omics analysis highlighted the ribosome's potential regulatory role in the inflammatory response. CONCLUSIONS: This study provides a detailed view of the molecular mechanisms underlying inflammation in macrophages and reveals a dynamic genetic landscape crucial for further research. Our findings underscore the complex interaction between gene expression, metabolic shifts, and ribosomal functions in response to LPS-induced inflammation.

Association of triglyceride glucose index with stroke: from two large cohort studies and mendelian randomization analysis.

INTRODUCTION: The triglyceride glucose index (TyG) is associated with cardiovascular diseases; however, its association with stroke remains unclear. This study aimed to elucidate this relationship by examining two extensive cohort studies using two-sample Mendelian randomization (MR). METHODS: Using data from the 1999-2018 National Health and Nutrition Examination Survey (NHANES) and the Medical Information Mart for Intensive Care (MIMIC)-IV, the correlation between TyG (continuous and quartile) and stroke was examined using multivariate Cox regression models and sensitivity analyses. Two-sample MR was employed to establish causality between TyG and stroke using the inverse variance weighting method. Genome-wide association study catalog queries were performed for single nucleotide polymorphism-mapped genes, and the STRING platform used to assess protein interactions. Functional annotation and enrichment analyses were also conducted. RESULTS: From the NHANES and MIMIC-IV cohorts, we included 740 and 589 participants with stroke, respectively. After adjusting for covariates, TyG was linearly associated with the risk of stroke death (NHANES: hazard ratio [HR] 0.64, 95% confidence interval [CI]: 0.41-0.99, P=0.047; Q3 vs. Q1, HR 0.62, 95%CI: 0.40-0.96, P=0.033; MIMIC-IV: HR 0.46, 95%CI: 0.27-0.80, P=0.006; Q3 vs. Q1, HR 0.32, 95%CI: 0.12-0.86; Q4 vs. Q1, HR 0.30, 95%CI: 0.10-0.89, P=0.030, P for trend=0.017). Two-sample MR analysis showed genetic prediction supported a causal association between a higher TyG and a reduced risk of stroke (odds ratio 0.711, 95%CI: 0.641-0.788, P=7.64e-11). CONCLUSIONS: TyG was causally associated with a reduced risk of stroke. TyG is a critical factor for stroke risk management.