Evolutionary analysis of a complete chicken genome.

Microchromosomes are prevalent in nonmammalian vertebrates [P. D. Waters et al., Proc. Natl. Acad. Sci. U.S.A. 118 (2021)], but a few of them are missing in bird genome assemblies. Here, we present a new chicken reference genome containing all autosomes, a Z and a W chromosome, with all gaps closed except for the W. We identified ten small microchromosomes (termed dot chromosomes) with distinct sequence and epigenetic features, among which six were newly assembled. Those dot chromosomes exhibit extremely high GC content and a high level of DNA methylation and are enriched for housekeeping genes. The pericentromeric heterochromatin of dot chromosomes is disproportionately large and continues to expand with the proliferation of satellite DNA and testis-expressed genes. Our analyses revealed that the 41-bp CNM repeat frequently forms higher-order repeats (HORs) at the centromeres of acrocentric chromosomes. The centromere core regions where the kinetochore attaches often encompass telomeric sequence (TTAGGG)n, and in a one of the dot chromosomes, the centromere core recruits an endogenous retrovirus (ERV). We further demonstrate that the W chromosome shares some common features with dot chromosomes, having large arrays of hypermethylated tandem repeats. Finally, using the complete chicken chromosome models, we reconstructed a fine picture of chordate karyotype evolution, revealing frequent chromosomal fusions before and after vertebrate whole-genome duplications. Our sequence and epigenetic characterization of chicken chromosomes shed insights into the understanding of vertebrate genome evolution and chromosome biology.

Transcription factor CsMYB77 negatively regulates fruit ripening and fruit size in citrus.

MYB family transcription factors (TFs) play essential roles in various biological processes, yet their involvement in regulating fruit ripening and fruit size in citrus remains poorly understood. In this study, we have established that the R2R3-MYB TF, CsMYB77, exerts a negative regulatory influence on fruit ripening in both citrus and tomato (Solanum lycopersicum), while also playing a role in modulating fruit size in citrus. The overexpression of CsMYB77 in tomato and Hongkong kumquat (Fortunella hindsii) led to notably delayed fruit ripening phenotypes. Moreover, the fruit size of Hongkong kumquat transgenic lines was largely reduced. Based on DNA affinity purification sequencing and verified interaction assays, SEVEN IN ABSENTIA OF ARABIDOPSIS THALIANA4 (SINAT4) and PIN-FORMED PROTEIN5 (PIN5) were identified as downstream target genes of CsMYB77. CsMYB77 inhibited the expression of SINAT4 to modulate abscisic acid (ABA) signaling, which delayed fruit ripening in transgenic tomato and Hongkong kumquat lines. The expression of PIN5 was activated by CsMYB77, which promoted free indole-3-acetic acid decline and modulated auxin signaling in the fruits of transgenic Hongkong kumquat lines. Taken together, our findings revealed a fruit development and ripening regulation module (MYB77-SINAT4/PIN5-ABA/auxin) in citrus, which enriches the understanding of the molecular regulatory network underlying fruit ripening and size.

Independent Evolution of Sex Chromosomes and Male Pregnancy-Related Genes in Two Seahorse Species.

Unlike birds and mammals, many teleosts have homomorphic sex chromosomes, and changes in the chromosome carrying the sex-determining locus, termed "turnovers", are common. Recent turnovers allow studies of several interesting questions. One question is whether the new sex-determining regions evolve to become completely non-recombining, and if so, how and why. Another is whether (as predicted) evolutionary changes that benefit one sex accumulate in the newly sex-linked region. To study these questions, we analyzed the genome sequences of two seahorse species of the Syngnathidae, a fish group in which many species evolved a unique structure, the male brood pouch. We find that both seahorse species have XY sex chromosome systems, but their sex chromosome pairs are not homologs, implying that at least one turnover event has occurred. The Y-linked regions occupy 63.9% and 95.1% of the entire sex chromosome of the two species and do not exhibit extensive sequence divergence with their X-linked homologs. We find evidence for occasional recombination between the extant sex chromosomes that may account for their homomorphism. We argue that these Y-linked regions did not evolve by recombination suppression after the turnover, but by the ancestral nature of the low crossover rates in these chromosome regions. With such an ancestral crossover landscape, a turnover can instantly create an extensive Y-linked region. Finally, we test for adaptive evolution of male pouch-related genes after they became Y-linked in the seahorse.

Molecular basis underlying default mode network functional abnormalities in postpartum depression with and without anxiety.

Although Postpartum depression (PPD) and PPD with anxiety (PPD-A) have been well characterized as functional disruptions within or between multiple brain systems, however, how to quantitatively delineate brain functional system irregularity and the molecular basis of functional abnormalities in PPD and PPD-A remains unclear. Here, brain sample entropy (SampEn), resting-state functional connectivity (RSFC), transcriptomic and neurotransmitter density data were used to investigate brain functional system irregularity, functional connectivity abnormalities and associated molecular basis for PPD and PPD-A. PPD-A exhibited higher SampEn in medial prefrontal cortex (MPFC) and posterior cingulate cortex (PPC) than healthy postnatal women (HPW) and PPD while PPD showed lower SampEn in PPC compared to HPW and PPD-A. The functional connectivity analysis with MPFC and PPC as seed areas revealed decreased functional couplings between PCC and paracentral lobule and between MPFC and angular gyrus in PPD compared to both PPD-A and HPW. Moreover, abnormal SampEn and functional connectivity were associated with estrogenic level and clinical symptoms load. Importantly, spatial association analyses between functional changes and transcriptome and neurotransmitter density maps revealed that these functional changes were primarily associated with synaptic signaling, neuron projection, neurotransmitter level regulation, amino acid metabolism, cyclic adenosine monophosphate (cAMP) signaling pathways, and neurotransmitters of 5-hydroxytryptamine (5-HT), norepinephrine, glutamate, dopamine and so on. These results reveal abnormal brain entropy and functional connectivities primarily in default mode network (DMN) and link these changes to transcriptome and neurotransmitters to establish the molecular basis for PPD and PPD-A for the first time. Our findings highlight the important role of DMN in neuropathology of PPD and PPD-A.

Efficacy of TNF-α Inhibitors in the Treatment of nr-axSpA: A Systematic Review and Meta-Analysis Based on Randomized Controlled Trials.

INTRODUCTION: A growing number of randomized controlled trials (RCTs) have demonstrated the effectiveness of tumor necrosis factor-α (TNF-α) inhibitors in treating non-radiographic axial spondyloarthritis (nr-axSpA). This study aimed to evaluate the efficacy of TNF-α inhibitors in the treatment of nr-axSpA. METHODS: PubMed, EMBASE, Web of Science, and the Cochrane Library databases were systematically searched for relevant RCTs using specific keywords up to June 2023. The primary outcome was the proportion of patients who achieved Assessment in SpondyloArthritis international Society 40% (ASAS40). Secondary outcomes included ASAS20, Bath Ankylosing Spondylitis Disease Activity Index 50% (BASDAI50), ASAS partial remission, and ASAS5/6. RESULTS: A total of eight RCTs involving 1,376 patients were included. Patients receiving anti-TNF therapy exhibited a higher rate of ASAS40 (pooled RR = 2.36; 95% CI: 1.63-3.42; p < 0.001). In addition, the TNF-α inhibitor group showed higher BASDAI50 rates (pooled RR = 2.06; 95% CI: 1.48-2.89), ASAS20 rates (pooled RR = 1.48; 95% CI: 1.31-1.67), ASAS partial remission rates (pooled RR = 2.33; 95% CI: 1.58-3.43), and ASAS5/6 rates (RR = 3.46; 95% CI: 2.05-5.83) than the placebo group. CONCLUSION: The TNF-α inhibitors were effective in treating nr-axSpA.

A prototype galectin-1 (also known as galecin-2) from large yellow croaker (Larimichthys crocea): Molecular and function study.

Galectin-1 (also known as galecin-2), one member of galectins family, has multiple functions as a pattern recognition receptor (PRR) in innate immune defense system. In the present study, LcGal-1, a prototype galectin, was identified and function investigated in large yellow croaker (Larimichthys crocea). LcGal-1 consists of one carbohydrate recognition domain (CRD), which contains two carbohydrate binding motifs HFNPR and WG-E-R. LcGal-1 had a ubiquitous tissues profile with the highest and lowest expression in spleen and muscle, respectively. Moreover, it was in cytoplasm and nucleus of head-kidney cells in large yellow croaker. RT-qRCR showed that P. plecoglossicida induced LcGal-1 up-regulated expression in liver and gills, and the results were validated by immunohistochemistry analysis. Additionally, the recombinant LcGal-1 (rLcGal-1) showed agglutinate activity on erythrocytes, and the histidine (His) in the HFNPR motif was a key locus to the activity. The agglutination effect of rLcGal-1 on erythrocytes could be inhibited by LPS, α-lactase and d-galactose. The rLcGal-1 was able to bind and agglutinate Gram+ and Gram-bacteria, and damage bacterial membrane as confirmed by PI staining and SEM observation. Transcriptome analysis showed that the overexpressed LcGal-1 in HEK 293T cells could induce 176 DGEs, including 172 boosting genes and 4 falling genes. Collectively, LcGal-1 was a key immune gene involved in the recognition, conjunction, and elimination of pathogens in L. crocea, as well as multiple physiological and pathological regulatory processes.

Least Absolute Shrinkage and Selection Operator-Based Prediction of the Binding Constant of p-Sulfonatocalix[6]/[8]arenes with Alkaloids.

p-Sulfonatocalix[n]arenes (SCnA) have demonstrated great potential for drug encapsulation through host-guest complexation to improve solubility, stability, and bioavailability. In this study, the solubilization effect of SCnA (n = 4, 6, 8) on 95 active compounds derived from traditional Chinese medicine (TCM) was investigated. Based on the significant solubilization effect on alkaloids, SC6A/SC8A and 76 alkaloids were selected as the host and guest, respectively, to determine the binding constant by competitive fluorescence titration. LASSO regression was adopted to investigate the mechanism of the complex of SCnA with alkaloids. The binding constant of alkaloids-SC6A and alkaloids-SC8A was related to the alkaloid alkalinity. Also, the electronegativity, polarization, first ionization potential, hydrogen bond potential, the molecular size, and shape of alkaloids are critical properties to determine alkaloids-SC6A binding constant as well as electronegativity, polarization, hydrophobicity, and the molecular size and shape of alkaloids play an important role for the alkaloids-SC8A binding constant.

Molecular mechanisms underlying human spatial cognitive ability revealed with neurotransmitter and transcriptomic mapping.

Mental rotation, one of the cores of spatial cognitive abilities, is closely associated with spatial processing and general intelligence. Although the brain underpinnings of mental rotation have been reported, the cellular and molecular mechanisms remain unexplored. Here, we used magnetic resonance imaging, a whole-brain spatial distribution atlas of 19 neurotransmitter receptors, transcriptomic data from Allen Human Brain Atlas, and mental rotation performances of 356 healthy individuals to identify the genetic/molecular foundation of mental rotation. We found significant associations of mental rotation performance with gray matter volume and fractional amplitude of low-frequency fluctuations in primary visual cortex, fusiform gyrus, primary sensory-motor cortex, and default mode network. Gray matter volume and fractional amplitude of low-frequency fluctuations in these brain areas also exhibited significant sex differences. Importantly, spatial correlation analyses were conducted between the spatial patterns of gray matter volume or fractional amplitude of low-frequency fluctuations with mental rotation and the spatial distribution patterns of neurotransmitter receptors and transcriptomic data, and identified the related genes and neurotransmitter receptors associated with mental rotation. These identified genes are localized on the X chromosome and are mainly involved in trans-synaptic signaling, transmembrane transport, and hormone response. Our findings provide initial evidence for the neural and molecular mechanisms underlying spatial cognitive ability.

Gut microbial metabolite hyodeoxycholic acid targets the TLR4/MD2 complex to attenuate inflammation and protect against sepsis.

Sepsis, a critical condition resulting from the systemic inflammatory response to a severe microbial infection, represents a global public health challenge. However, effective treatment or intervention to prevent and combat sepsis is still lacking. Here, we report that hyodeoxycholic acid (HDCA) has excellent anti-inflammatory properties in sepsis. We discovered that the plasma concentration of HDCA was remarkably lower in patients with sepsis and negatively correlated with the severity of the disease. Similar changes in HDCA levels in plasma and cecal content samples were observed in a mouse model of sepsis, and these changes were associated with a reduced abundance of HDCA-producing strains. Interestingly, HDCA administration significantly decreased systemic inflammatory responses, prevented organ injury, and prolonged the survival of septic mice. We demonstrated that HDCA suppressed excessive activation of inflammatory macrophages by competitively blocking lipopolysaccharide binding to the Toll-like receptor 4 (TLR4) and myeloid differentiation factor 2 receptor complex, a unique mechanism that characterizes HDCA as an endogenous inhibitor of inflammatory signaling. Additionally, we verified these findings in TLR4 knockout mice. Our study highlights the potential value of HDCA as a therapeutic molecule for sepsis.

Association between socioeconomic status and post-stroke depression in middle-aged and older adults: results from the China health and retirement longitudinal study.

INTRODUCTION: Post-stroke depression (PSD) is a common neuropsychiatric complication that affects approximately one-third of stroke patients. The treatment and prognosis of this disease are poor. Socioeconomic status (SES) is closely related to health outcomes; however, only a few previous studies have focused on the association between SES and PSD. Given the substantial population of stroke patients in China, it is crucial to examine the potential risk factors associated with PSD. Conducting studies on this population and investigating the influence of economic conditions can provide valuable guiding theoretical insights into PSD prevention and management. METHODS: We used data from the 2018 China Health and Retirement Longitudinal Study and selected appropriate samples for analysis. Depression was estimated using the Center of Epidemiologic Studies Depression Scale-10, a validated tool for assessing depression in the general population. Multiple logistic regression analysis was employed to assess the association between SES and PSD and to evaluate any urban-rural differences. RESULTS: Of the 749 respondents, 370 (49.4%) had depression. Stroke patients with a middle school education demonstrated a greater risk of developing depression than those with a primary school education or below after adjusting for all control variables (odds ratio (OR) = 1.60, 95% confidence interval (CI): 1.03-2.51, P = 0.036). However, stroke patients with a high school education or above had a lower risk of developing depression than those with a primary school education or below (OR = 0.50, 95% CI: 0.28-0.88, P = 0.016). In rural areas, stroke patients with a high school or above education level had lower rates of depression than those with a primary school education or below (OR = 0.44, 95% CI: 0.21-0.91, P = 0.027). This difference was not significant in urban areas. CONCLUSIONS: SES significantly influences the occurrence of PSD, which is reflected by education attainment and annual household expenditures. Education attainment was an independent influence on PSD, with a more pronounced effect in rural versus urban areas. We hope to reduce the prevalence of PSD and enhance the comprehensive management of this disease by modifying the influencing factors. Sex, self-reported health status, activities of daily living, night-time sleep duration, and life satisfaction also influenced the occurrence of PSD.

Effect of cesarean section on the risk of autism spectrum disorders/attention deficit hyperactivity disorder in offspring: a meta-analysis.

PURPOSE: This study was conducted to investigate the relationship between cesarean section (CS) offspring and autism spectrum disorders (ASD)/attention deficit hyperactivity disorder (ADHD). METHODS: Searching of the databases (PubMed, Web of Science, Embase, and Cochrane Library) for studies on the relationship between mode of delivery and ASD/ADHD until August 2022. The primary outcome was the incidence of ASD/ADHD in the offspring. RESULTS: This meta-analysis included 35 studies (12 cohort studies and 23 case-control studies). Statistical results showed a higher risk of ASD (odds ratio (OR) = 1.25, P < 0.001) and ADHD (OR = 1.11, P < 0.001) in CS offspring compared to the VD group. Partial subgroup analysis showed no difference in ASD risk between CS and VD offspring in sibling-matched groups (OR = 0.98, P = 0.625). The risk of ASD was higher in females (OR = 1.66, P = 0.003) than in males (OR = 1.17, P = 0.004) in the CS offspring compared with the VD group. There was no difference in the risk of ASD between CS under regional anesthesia group and VD group (OR = 1.07, P = 0.173). However, the risk of ASD was higher in the CS offspring under general anesthesia than in the VD offspring (OR = 1.62, P < 0.001). CS offspring developed autism (OR = 1.38, P = 0.011) and pervasive developmental disorder-not otherwise specified (OR = 1.46, P = 0.004) had a higher risk than VD offspring, but there was no difference in Asperger syndrome (OR = 1.19, P = 0.115). Offspring born via CS had a higher incidence of ADHD in different subgroup analyses (sibling-matched, type of CS, and study design). CONCLUSIONS: In this meta-analysis, CS was a risk factor for ASD/ADHD in offspring compared with VD.

Caffeic acid attenuates tissue damage and inflammatory response in Klebsiella pneumonia by modulating AhR-Src-STAT3-IL-10 signaling pathway.

CA is a plant derivative with antibacterial and antiviral pharmacological effects, however, the therapeutic effect of CA on Klebsiella pneumonia and its mechanism study is still unclear. A rat KP model was established in vitro, a pneumonia cell model was established in vivo, the histopathological changes in the lungs were observed by HE staining after CA treatment, the expression of relevant inflammatory factors was detected by ELISA, the changes in the expression of proteins related to the AhR-Src-STAT3-IL-10 signaling pathway were detected by Western blot and immunofluorescence in the lungs, and the interactions between the proteins were verified by COIP relationship. The results showed that CA was able to attenuate the injury and inflammatory response of lung tissues, and molecular docking showed that there were binding sites between CA and AhR, and COIP demonstrated that AhR interacted with both STAT3 and Ser. In addition, CA was able to up-regulate the expression levels of pathway-related proteins of AhR, IL-10, p-Src, and p-STAT3, and AhR knockdown was able to reduce LPS-induced inflammatory responses and up-regulate pathway-related proteins, whereas CA treatment of AhR-knockdown-treated A549 cells did not show any statistically significant difference compared with the AhR knockdown group, demonstrating that CA exerts its pharmacological effects. These findings elucidated the mechanism of CA in the treatment of KP and demonstrated that CA is a potential therapeutic agent for KP.

Pre-hospital symptom clusters and symptom network analysis in decompensated cirrhotic patients: A cross-sectional study.

AIMS: To generate pre-hospital symptom networks, explore core, bridge and sentinel symptoms, identify pre-hospital symptom clusters and analyse relationship between influencing factors and symptom clusters in decompensated cirrhosis patients. DESIGN: A cross-sectional study design using the Strengthening the Reporting of Observational Studies in Epidemiology checklist. METHODS: Demographical, physiological, psychological and sociological characteristics and the pre-hospital symptoms of 292 decompensated cirrhotic patients were collected from October 2021 to March 2023 in China. Frequencies, percentages, means, standard deviations, independent samples t-tests, one-way analysis of variance, exploratory factor analysis, multiple stepwise regression analysis and network analysis were used for data analysis. RESULTS: 'I don't look like myself' and itching were core and bridge symptoms, while bloating and lack of energy were sentinel symptoms in decompensated cirrhotic patients. Monthly family income, anxiety, depression, social support and disease duration influenced the neuropsychological symptom cluster, with worrying as the strongest predictor symptom. Influential factors for cirrhosis-specific symptom cluster included Child-Pugh class, monthly family income, disease duration, anxiety and depression, with itching being the strongest predictor symptom. Monthly family income, disease duration and depression were influential factors for gastrointestinal symptom cluster, with loss of appetite as the strongest predictor symptom. CONCLUSIONS: Neuropsychological, cirrhosis-specific and gastrointestinal symptom clusters were formed in decompensated cirrhotic patients. Through network analysis, direct connections between symptoms, symptom clusters and their influencing factors were revealed, thereby offering clinicians a foundation for effectively managing patients' pre-hospital symptoms. IMPACT: Decompensated cirrhosis patients commonly have multiple symptoms, while the management of pre-hospital symptoms is often suboptimal. This study identified neuropsychological, cirrhosis-specific, gastrointestinal symptom clusters and recognized core, bridge and sentinel symptoms in these patients. It also revealed the most prominent symptoms within each cluster. This provides insight into the hierarchy of symptoms, improving symptom management in decompensated cirrhosis. PATIENT AND PUBLIC INVOLVEMENT: There was no patient or public involvement.

Microbial inoculants using spent mushroom substrates as carriers improve soil multifunctionality and plant growth by changing soil microbial community structure.

Peat is typically used as a carrier for microbial inoculants; however, due to its non-renewable nature alternatives need to be identified as reliable and renewable carriers for mineral-solubilizing inoculants. In pot experiments, solid microbial inoculants were comprised of peat (P), biochar (BC), and spent mushroom substrates (SMS) using Medicago sativa L. as experimental materials, and the purpose of this study is to assess the effect of solid microbial inoculants on soil multifunctionality and plant growth. The results revealed that the SMS microbial inoculant had the greatest positive impact on plant biomass and significantly stimulated soil multifunctionality which is typically managed or assessed based on various soil functions or processes that are crucial for sustaining productivity, in contrast to the peat microbial inoculant, particularly at a supply level of 100 g/pot. There was no significant correlation between soil multifunctionality and bacterial/fungal microbial diversity. However, according to the co-occurrence network of bacteria and fungi, soil multifunctionality was intimately correlated with the biodiversity of the main ecological clusters (modules) of bacteria and fungi, rather than to the entire soil microbial community structure. The keystone species of module hubs and connectors play critical roles in maintaining the stability of ecological clusters of microbial co-occurrence networks and linkages between ecological clusters. Soil pH is a major predictor of changes in plant biomass, and leads to changes therein by affecting the major ecological clusters of bacterial and fungal co-occurrence networks. These results suggested that SMS may serve as a good alternative to peat as a carrier of mineral-solubilizing microorganisms to maintain soil multifunctionality and promote plant growth.

[Association of metal/metalloids exposure with abnormal liver function among occupational population in a mining area of Hunan Province:a prospective study].

OBJECTIVE: To investigate the association of metals/metalloids exposure with risk of liver disfunction among occupational population in Hunan Province, and to explore the potential dose-response relationship. METHODS: In 2017, a mining area in Hunan Province was chosen as the research site, and eligible workers were recruited as study subjects. General demographic characteristics, levels of 23 metals/metalloids in plasma and urine, and liver function index(total bilirubin(TBIL), alanine amino transferase(ALT), globulin(GLB) and γ-glutamyl transferase(GGT)) were obtained by questionnaire, physical examination and laboratory tests. Participants were followed up in 2018, 2019 and 2020 respectively. Cox proportional risk model was used to evaluate the relationship between metal/metalloids exposure and risk of liver disfunction, and dose-response relationship curves were plotted by using the restricted cubic spline function. RESULTS: A total of 891 employees were recruited in the study, 576(65.0%)were aged ≤45 years, 832(93.4%) were male and 530(59.5%) worked as smelters. After adjusting various factors such as age, gender, BMI, type of work, education, smoking, alcohol consumption, diet, stress, medical history, exercise and tea consumption, positive correlations were found between plasma tungsten(HR=4.90, 95%CI 1.17-20.48) and urinary barium(HR=1.07, 95%CI 1.02-1.12) levels with abnormally elevated TBIL levels. Additionally, a significant association was observed between plasma thallium and the risk of elevated ALT levels(HR=11.15, 95%CI 1.97-63.29). CONCLUSION: Plasma tungsten and thallium, along with barium found in urine, are risk factors for the development of abnormally elevated liver function indices in occupational groups.

Novel tripeptide RKH derived from Akkermansia muciniphila protects against lethal sepsis.

OBJECTIVE: The pathogenesis of sepsis is complex, and the sepsis-induced systemic proinflammatory phase is one of the key drivers of organ failure and consequent mortality. Akkermansia muciniphila (AKK) is recognised as a functional probiotic strain that exerts beneficial effects on the progression of many diseases; however, whether AKK participates in sepsis pathogenesis is still unclear. Here, we evaluated the potential contribution of AKK to lethal sepsis development. DESIGN: Relative abundance of gut microbial AKK in septic patients was evaluated. Cecal ligation and puncture (CLP) surgery and lipopolysaccharide (LPS) injection were employed to establish sepsis in mice. Non-targeted and targeted metabolomics analysis were used for metabolites analysis. RESULTS: We first found that the relative abundance of gut microbial AKK in septic patients was significantly reduced compared with that in non-septic controls. Live AKK supplementation, as well as supplementation with its culture supernatant, remarkably reduced sepsis-induced mortality in sepsis models. Metabolomics analysis and germ-free mouse validation experiments revealed that live AKK was able to generate a novel tripeptide Arg-Lys-His (RKH). RKH exerted protective effects against sepsis-induced death and organ damage. Furthermore, RKH markedly reduced sepsis-induced inflammatory cell activation and proinflammatory factor overproduction. A mechanistic study revealed that RKH could directly bind to Toll-like receptor 4 (TLR4) and block TLR4 signal transduction in immune cells. Finally, we validated the preventive effects of RKH against sepsis-induced systemic inflammation and organ damage in a piglet model. CONCLUSION: We revealed that a novel tripeptide, RKH, derived from live AKK, may act as a novel endogenous antagonist for TLR4. RKH may serve as a novel potential therapeutic approach to combat lethal sepsis after successfully translating its efficacy into clinical practice.

WGCNA and transcriptome profiling reveal hub genes for key development stage seed size/oil content between wild and cultivated soybean.

BACKGROUND: Soybean is one of the most important oil crops in the world. The domestication of wild soybean has resulted in significant changes in the seed oil content and seed size of cultivated soybeans. To better understand the molecular mechanisms of seed formation and oil content accumulation, WDD01514 (E1), ZYD00463 (E2), and two extreme progenies (E23 and E171) derived from RILs were used for weighted gene coexpression network analysis (WGCNA) combined with transcriptome analysis. RESULTS: In this study, both seed weight and oil content in E1 and E171 were significantly higher than those in E2 and E23, and 20 DAF and 30 DAF may be key stages of soybean seed oil content accumulation and weight increase. Pathways such as "Photosynthesis", "Carbon metabolism", and "Fatty acid metabolism", were involved in oil content accumulation and grain formation between wild and cultivated soybeans at 20 and 30 DAF according to RNA-seq analysis. A total of 121 oil content accumulation and 189 seed formation candidate genes were screened from differentially expressed genes. WGCNA identified six modules related to seed oil content and seed weight, and 76 candidate genes were screened from modules and network. Among them, 16 genes were used for qRT-PCR and tissue specific expression pattern analysis, and their expression-levels in 33-wild and 23-cultivated soybean varieties were subjected to correlation analysis; some key genes were verified as likely to be involved in oil content accumulation and grain formation. CONCLUSIONS: Overall, these results contribute to an understanding of seed lipid metabolism and seed size during seed development, and identify potential functional genes for improving soybean yield and seed oil quantity.

METTL14 is decreased and regulates m6 A modification of α-synuclein in Parkinson's disease.

N6-methyladenosine (m6A), an emerging modification of messenger RNA, has been implicated in many biological processes. However, its role in Parkinson's disease (PD) remains largely unknown. Here, we investigated the role of m6A modification and its underlying mechanism in PD. First, 86 individuals with PD and 86 healthy controls were recruited from a pilot multicenter cohort. Levels of m6A and its modulators in peripheral blood mononuclear cells of patients with PD and controls were measured using an m6A RNA methylation quantification kit and quantitative real-time PCR. The underlying mechanism of m6A modification in PD was investigated in vitro through RNA immunoprecipitation assay, RNA stability assay, gene silencing or overexpression, western blot, and confocal immunoassay. The results show that mRNA levels of m6A, METTL3, METTL14, and YTHDF2 in patients with PD were significantly lower than in healthy controls, and METTL14 was the main factor involved in abnormal m6A modification. Area under the curve (AUC) analysis suggests METTL14 may provide excellent diagnostic capability for PD, especially when combined with plasma α-synuclein (α-syn). Spearman correlation analysis identified that METTL14 was moderately negatively correlated with plasma α-syn and the motor function of PD. Mechanistic experiments demonstrated that Mettl14 targets and regulates the expression of the α-syn gene using its methylation function. Overexpression of Mettl14 dramatically increased m6 A modification of α-syn mRNA and weakened its stability. Further results suggest that α-syn mRNA was modified by Mettl14 binding of an m6 A motif in the coding region of α-syn mRNA, while the reading protein Ythdf2 was involved in recognizing m6 A-modified α-syn mRNA. Taken together, our results reveal the potential of METTL14 as a novel diagnostic biomarker for PD and identify modification of pathogenic α-syn protein by METTL14 via an m6 A-YTHDF2-dependent mechanism.

High Myopia Normative Database of Peripapillary Retinal Nerve Fiber Layer Thickness to Detect Myopic Glaucoma in a Chinese Population.

PURPOSE: To develop and validate the performance of a high myopia (HM)-specific normative database of peripapillary retinal nerve fiber layer (pRNFL) thickness in differentiating HM from highly myopic glaucoma (HMG). DESIGN: Cross-sectional multicenter study. PARTICIPANTS: A total of 1367 Chinese participants (2325 eyes) with nonpathologic HM or HMG were included from 4 centers. After quality control, 1108 eyes from 694 participants with HM were included in the normative database; 459 eyes from 408 participants (323 eyes with HM and 136 eyes with HMG) and 322 eyes from 197 participants (131 eyes with HM and 191 eyes with HMG) were included in the internal and external validation sets, respectively. Only HMG eyes with an intraocular pressure > 21 mmHg were included. METHODS: The pRNFL thickness was measured with swept-source (SS) OCT. Four strategies of pRNFL-specified values were examined, including global and quadrantic pRNFL thickness below the lowest fifth or the lowest first percentile of the normative database. MAIN OUTCOMES MEASURES: The accuracy, sensitivity, and specificity of the HM-specific normative database for detecting HMG. RESULTS: Setting the fifth percentile of the global pRNFL thickness as the threshold, using the HM-specific normative database, we achieved an accuracy of 0.93 (95% confidence interval [CI], 0.90-0.95) and 0.85 (95% CI, 0.81-0.89), and, using the first percentile as the threshold, we acheived an accuracy of 0.85 (95% CI, 0.81-0.88) and 0.70 (95% CI, 0.65-0.75) in detecting HMG in the internal and external validation sets, respectively. The fifth percentile of the global pRNFL thickness achieved high sensitivities of 0.75 (95% CI, 0.67-0.82) and 0.75 (95% CI, 0.68-0.81) and specificities of 1.00 (95% CI, 0.99-1.00) and 1.00 (95% CI, 0.97-1.00) in the internal and external validation datasets, respectively. Compared with the built-in database of the OCT device, the HM-specific normative database showed a higher sensitivity and specificity than the corresponding pRNFL thickness below the fifth or first percentile (P < 0.001 for all). CONCLUSIONS: The HM-specific normative database is more capable of detecting HMG eyes than the SS OCT built-in database, which may be an effective tool for differential diagnosis between HMG and HM. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Thickness-dependent loss-induced failure of an ideal ENZ-enhanced optical response in planar ultrathin transparent conducting oxide films.

Ultrathin planar transparent conducting oxide (TCO) films are commonly used to enhance the optical response of epsilon-near-zero (ENZ) devices; however, our results suggest that thickness-dependent loss renders them ineffective. Here, we investigated the thickness-dependent loss of indium tin oxide (ITO) films and their effect on the ENZ-enhanced optical responses of ITO and ITO/SiO2 multilayer stacks. The experimental and computational results show that the optical loss of ITO films increases from 0.47 to 0.70 as the thickness decreases from 235 to 52 nm, which results in a reduction of 60% and 45% in the maximum field enhancement factor of a 52-nm monolayer ITO and 4-layer ITO/SiO2 multilayer stack, respectively. The experimental results show that the ENZ-enhanced nonlinear absorption coefficient of the 52-nm single-layer ITO film is -1.6 × 103 cm GW-1, which is 81% lower than that of the 235-nm ITO film (-8.6 × 103 cm GW-1), indicating that the thickness-dependent loss makes the ultrathin TCO films unable to obtain greater nonlinear responses. In addition, the increased loss reduces the cascading Berreman transmission valley intensity of the 4-layer ITO/SiO2 multilayer stack, resulting in a 42% reduction in the ENZ-enhanced nonlinear absorption coefficient compared to the 235-nm ITO film and a faster hot electron relaxation time. Our results suggest that the thickness and loss trade-off is an intrinsic property of TCO films and that the low-loss ultrathin TCO films are the key to the robust design and fabrication of novel ENZ devices based on flat ultrathin TCO films.