Central-cell-produced attractants control fertilization recovery.

Animal fertilization relies on hundreds of sperm racing toward the egg, whereas, in angiosperms, only two sperm cells are delivered by a pollen tube to the female gametes (egg cell and central cell) for double fertilization. However, unsuccessful fertilization under this one-pollen-tube design can be detrimental to seed production and plant survival. To mitigate this risk, unfertilized-gamete-controlled extra pollen tube entry has been evolved to bring more sperm cells and salvage fertilization. Despite its importance, the underlying molecular mechanism of this phenomenon remains unclear. In this study, we report that, in Arabidopsis, the central cell secretes peptides SALVAGER1 and SALVAGER2 in a directional manner to attract pollen tubes when the synergid-dependent attraction fails or is terminated by pollen tubes carrying infertile sperm cells. Moreover, loss of SALs impairs the fertilization recovery capacity of the ovules. Therefore, this research uncovers a female gamete-attraction system that salvages seed production for reproductive assurance.

Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells.

Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. We carried out high-resolution genetic, epigenetic, and transcriptomic profiling in three major human immune cell types (CD14+ monocytes, CD16+ neutrophils, and naive CD4+ T cells) from up to 197 individuals. We assess, quantitatively, the relative contribution of cis-genetic and epigenetic factors to transcription and evaluate their impact as potential sources of confounding in epigenome-wide association studies. Further, we characterize highly coordinated genetic effects on gene expression, methylation, and histone variation through quantitative trait locus (QTL) mapping and allele-specific (AS) analyses. Finally, we demonstrate colocalization of molecular trait QTLs at 345 unique immune disease loci. This expansive, high-resolution atlas of multi-omics changes yields insights into cell-type-specific correlation between diverse genomic inputs, more generalizable correlations between these inputs, and defines molecular events that may underpin complex disease risk.

Room temperature operation of germanium-silicon single-photon avalanche diode.

The ability to detect single photons has led to the advancement of numerous research fields1-11. Although various types of single-photon detector have been developed12, because of two main factors-that is, (1) the need for operating at cryogenic temperature13,14 and (2) the incompatibility with complementary metal-oxide-semiconductor (CMOS) fabrication processes15,16-so far, to our knowledge, only Si-based single-photon avalanche diode (SPAD)17,18 has gained mainstream success and has been used in consumer electronics. With the growing demand to shift the operation wavelength from near-infrared to short-wavelength infrared (SWIR) for better safety and performance19-21, an alternative solution is required because Si has negligible optical absorption for wavelengths beyond 1 µm. Here we report a CMOS-compatible, high-performing germanium-silicon SPAD operated at room temperature, featuring a noise-equivalent power improvement over the previous Ge-based SPADs22-28 by 2-3.5 orders of magnitude. Key parameters such as dark count rate, single-photon detection probability at 1,310 nm, timing jitter, after-pulsing characteristic time and after-pulsing probability are, respectively, measured as 19 kHz µm-2, 12%, 188 ps, ~90 ns and <1%, with a low breakdown voltage of 10.26 V and a small excess bias of 0.75 V. Three-dimensional point-cloud images are captured with direct time-of-flight technique as proof of concept. This work paves the way towards using single-photon-sensitive SWIR sensors, imagers and photonic integrated circuits in everyday life.

APP substrate ectodomain defines amyloid-ß peptide length by restraining γ-secretase processivity and facilitating product release.

Sequential proteolysis of the amyloid precursor protein (APP) by γ-secretases generates amyloid-ß (Aß) peptides and defines the proportion of short-to-long Aß peptides, which is tightly connected to Alzheimer's disease (AD) pathogenesis. Here, we study the mechanism that controls substrate processing by γ-secretases and Aß peptide length. We found that polar interactions established by the APPC99 ectodomain (ECD), involving but not limited to its juxtamembrane region, restrain both the extent and degree of γ-secretases processive cleavage by destabilizing enzyme-substrate interactions. We show that increasing hydrophobicity, via mutation or ligand binding, at APPC99 -ECD attenuates substrate-driven product release and rescues the effects of Alzheimer's disease-associated pathogenic γ-secretase and APP variants on Aß length. In addition, our study reveals that APPC99 -ECD facilitates the paradoxical production of longer Aßs caused by some γ-secretase inhibitors, which act as high-affinity competitors of the substrate. These findings assign a pivotal role to the substrate ECD in the sequential proteolysis by γ-secretases and suggest it as a sweet spot for the potential design of APP-targeting compounds selectively promoting its processing by these enzymes.

The C-degron pathway eliminates mislocalized proteins and products of deubiquitinating enzymes.

Protein termini are determinants of protein stability. Proteins bearing degradation signals, or degrons, at their amino- or carboxyl-termini are eliminated by the N- or C-degron pathways, respectively. We aimed to elucidate the function of C-degron pathways and to unveil how normal proteomes are exempt from C-degron pathway-mediated destruction. Our data reveal that C-degron pathways remove mislocalized cellular proteins and cleavage products of deubiquitinating enzymes. Furthermore, the C-degron and N-degron pathways cooperate in protein removal. Proteome analysis revealed a shortfall in normal proteins targeted by C-degron pathways, but not of defective proteins, suggesting proteolysis-based immunity as a constraint for protein evolution/selection. Our work highlights the importance of protein termini for protein quality surveillance, and the relationship between the functional proteome and protein degradation pathways.

Surf4 collaborates with derlin-2 and derlin-1 to mediate cyclooxygenase-2 translocation to the cytosol for degradation.

Derlin family members participate in the retrotranslocation of endoplasmic reticulum (ER) lumen proteins to the cytosol for ER-associated degradation (ERAD); however, the proteins facilitating this retrotranslocation remain to be explored. Using CRISPR library screening, we have found that derlin-2 and surfeit locus protein 4 (Surf4) are candidates to facilitate degradation of cyclooxygenase-2 (COX-2, also known as PTGS2). Our results show that derlin-2 acts upstream of derlin-1 and that Surf4 acts downstream of derlin-2 and derlin-1 to facilitate COX-2 degradation. Knockdown of derlin-2 or Surf4 impedes the ubiquitylation of COX-2 and the interaction of COX-2 with caveolin-1 (Cav-1) and p97 (also known as VCP) in the cytosol. Additionally, COX-2 degradation is N-glycosylation dependent. Although derlin-2 facilitates degradation of N-glycosylated COX-2, the interaction between derlin-2 and COX-2 is independent of COX-2 N-glycosylation. Derlin-1, Surf4 and p97 preferentially interact with non-glycosylated COX-2, whereas Cav-1 preferentially interacts with N-glycosylated COX-2, regardless of the N-glycosylation pattern. Collectively, our results reveal that Surf4 collaborates with derlin-2 and derlin-1 to mediate COX-2 translocation from the ER lumen to the cytosol. The derlin-2-derlin-1-Surf4-Cav-1 machinery might represent a unique pathway to accelerate COX-2 degradation in ERAD.

The non-cell-autonomous function of ID1 promotes AML progression via ANGPTL7 from the microenvironment.

The bone marrow microenvironment (BMM) can regulate leukemia stem cells (LSCs) via secreted factors. Increasing evidence suggests that dissecting the mechanisms by which the BMM maintains LSCs may lead to the development of effective therapies for the eradication of leukemia. Inhibitor of DNA binding 1 (ID1), a key transcriptional regulator in LSCs, previously identified by us, controls cytokine production in the BMM, but the role of ID1 in acute myeloid leukemia (AML) BMM remains obscure. Here, we report that ID1 is highly expressed in the BMM of patients with AML, especially in BM mesenchymal stem cells, and that the high expression of ID1 in the AML BMM is induced by BMP6, secreted from AML cells. Knocking out ID1 in mesenchymal cells significantly suppresses the proliferation of cocultured AML cells. Loss of Id1 in the BMM results in impaired AML progression in AML mouse models. Mechanistically, we found that Id1 deficiency significantly reduces SP1 protein levels in mesenchymal cells cocultured with AML cells. Using ID1-interactome analysis, we found that ID1 interacts with RNF4, an E3 ubiquitin ligase, and causes a decrease in SP1 ubiquitination. Disrupting the ID1-RNF4 interaction via truncation in mesenchymal cells significantly reduces SP1 protein levels and delays AML cell proliferation. We identify that the target of Sp1, Angptl7, is the primary differentially expression protein factor in Id1-deficient BM supernatant fluid to regulate AML progression in mice. Our study highlights the critical role of ID1 in the AML BMM and aids the development of therapeutic strategies for AML.

Superantigen-fused T cell engagers for tumor antigen-mediated robust T cell activation and tumor cell killing.

Inadequate T cell activation has severely limited the success of T cell engager (TCE) therapy, especially in solid tumors. Enhancing T cell activity while maintaining the tumor specificity of TCEs is the key to improving their clinical efficacy. However, currently, there needs to be more effective strategies in clinical practice. Here, we design novel superantigen-fused TCEs that display robust tumor antigen-mediated T cell activation effects. These innovative drugs are not only armed with the powerful T cell activation ability of superantigens but also retain the dependence of TCEs on tumor antigens, realizing the ingenious combination of the advantages of two existing drugs. Superantigen-fused TCEs have been preliminarily proven to have good (>30-fold more potent) and specific (>25-fold more potent) antitumor activity in vitro and in vivo. Surprisingly, they can also induce the activation of T cell chemotaxis signals, which may promote T cell infiltration and further provide an additional guarantee for improving TCE efficacy in solid tumors. Overall, this proof-of-concept provides a potential strategy for improving the clinical efficacy of TCEs.

Oxygen-Binding Sites of Enriched Gold Nanoclusters for Capturing Mitochondrial Reverse Electrons.

Reverse electron transfer (RET), an abnormal backward flow of electrons from complexes III/IV to II/I of mitochondria, causes the overproduction of a reduced-type CoQ to boost downstream production of mitochondrial superoxide anions that leads to ischemia-reperfusion injury (IRI) to organs. Herein, we studied low-coordinated gold nanoclusters (AuNCs) with abundant oxygen-binding sites to form an electron-demanding trapper that allowed rapid capture of electrons to compensate for the CoQ/CoQH2 imbalance during RET. The AuNCs were composed of only eight gold atoms that formed a Cs-symmetrical configuration with all gold atoms exposed on the edge site. The geometry and atomic configuration enhance oxygen intercalation to attain a d-band electron deficiency in frontier orbitals, forming an unusually high oxidation state for rapid mitochondrial reverse electron capture under a transient imbalance of CoQ/CoQH2 redox cycles. Using hepatic IRI cells/animals, we corroborated that the CoQ-like AuNCs prevent inflammation and liver damage from IRI via recovery of the mitochondrial function.

HBeeID: a molecular tool that identifies honey bee subspecies from different geographic populations.

BACKGROUND: Honey bees are the principal commercial pollinators. Along with other arthropods, they are increasingly under threat from anthropogenic factors such as the incursion of invasive honey bee subspecies, pathogens and parasites. Better tools are needed to identify bee subspecies. Genomic data for economic and ecologically important organisms is increasing, but in its basic form its practical application to address ecological problems is limited. RESULTS: We introduce HBeeID a means to identify honey bees. The tool utilizes a knowledge-based network and diagnostic SNPs identified by discriminant analysis of principle components and hierarchical agglomerative clustering. Tests of HBeeID showed that it identifies African, Americas-Africanized, Asian, and European honey bees with a high degree of certainty even when samples lack the full 272 SNPs of HBeeID. Its prediction capacity decreases with highly admixed samples. CONCLUSION: HBeeID is a high-resolution genomic, SNP based tool, that can be used to identify honey bees and screen species that are invasive. Its flexible design allows for future improvements via sample data additions from other localities.

Optimization of Mother-to-Child Hepatitis B Virus Prevention Program: Integration of Maternal Screening and Infant Post-Vaccination Serologic Testing.

BACKGROUND: Evaluation of the impact of a hepatitis B virus (HBV) prevention program that incorporates maternal antiviral prophylaxis on mother-to-child transmission (MTCT) is limited using real-world data. METHODS: We analyzed data on maternal HBV screening, neonatal immunization, and post-vaccination serologic testing (PVST) for hepatitis B surface antigen (HBsAg) among at-risk infants born to HBV carrier mothers from the National Immunization Information System during 2008-2022. Through linkage with the National Health Insurance Database, information on maternal antiviral therapy was obtained. Multivariate logistic regression was performed to explore MTCT risk in relation to infant-mother characteristics and prevention strategies. RESULTS: In total, 2 460 218 deliveries with maternal HBV status were screened. Between 2008 and 2022, the annual HBsAg and hepatitis B e antigen (HBeAg) seropositivity rates among native pregnant women decreased from 12.2% to 2.6% and from 2.7% to 0.4%, respectively (P for both trends < .0001). Among the 22 859 at-risk infants who underwent PVST, the MTCT rates differed between infants born to HBsAg-positive/HBeAg-negative and HBeAg-positive mothers (0.75% and 6.33%, respectively; P < .001). MTCT risk increased with maternal HBeAg positivity (odds ratio [OR], 9.29; 95% confidence interval [CI], 6.79-12.73) and decreased with maternal antiviral prophylaxis (OR, 0.28; 95% CI, .16-.49). For infants with maternal HBeAg positivity, MTCT risk was associated with mothers born in the immunization era (OR, 1.40; 95% CI, 1.17-1.67). CONCLUSIONS: MTCT was related to maternal HBeAg positivity and effectively prevented by maternal prophylaxis in the immunized population. At-risk infants born to maternal vaccinated cohorts might possibly pose further risk.

Thyroid hormone receptor-beta agonist HSK31679 alleviates MASLD by modulating gut microbial sphingolipids.

BACKGROUND & AIMS: As the first approved medication for metabolic dysfunction-associated steatohepatitis (MASH), the thyroid hormone receptor-ß (THR-ß) agonist MGL-3196 (resmetirom) has garnered much attention as a liver-directed, bioactive oral drug. However, studies on MGL-3196 have also identified remarkable heterogeneity of individual clinical efficacy and its interference with gut microbiota in host hepatoenteral circulation remains to be elucidated. METHODS: We compared MASH attenuation by MGL-3196 and its derivative drug HSK31679 between germ-free (GF) and specific-pathogen free (SPF) mice to evaluate the role of gut microbiota. Then cross-omics analyses of microbial metagenome, metabolome and single-cell RNA-sequencing were applied to a randomized, double-blind, placebo-controlled multiple ascending dose cohort receiving HSK31679 treatment (n = 32) or placebo (n = 8), to comprehensively investigate the altered gut microbiota metabolism and circulating immune signatures. RESULTS: HSK31679 outperformed MGL-3196 in ameliorating MASH diet-induced steatohepatitis of SPF mice but not GF mice. In the multiple ascending dose cohort of HSK31679, the relative abundance of B. thetaiotaomicron was significantly enriched, impairing glucosylceramide synthase (GCS)-catalyzed monoglucosylation of microbial Cer(d18:1/16:0) and Cer(d18:1/24:1). In contrast to the non-inferior effect of MGL-3196 and HSK31679 on MASH resolution in GFBTΔGCS mice, HSK31679 led to superior benefit on steatohepatitis in GFBTWT mice, due to its steric hindrance of R123 and Y401 of gut microbial GCS. For participants with high fecal GCS activity, the administration of 160 mg HSK31679 induced a shift in peripheral compartments towards an immunosuppressive niche, characterized by decreased CD8α+ dendritic cells and MINCLE+ macrophages. CONCLUSIONS: This study provided novel insights into the gut microbiota that are key to the efficacy of HSK31679 treatment, revealing microbial GCS as a potential predictive biomarker in MASH, as well as a new target for further microbiota-based treatment strategies for MASH. IMPACT AND IMPLICATIONS: Remarkable heterogeneity in individual clinical efficacy of thyroid hormone receptor-ß agonists and their interferences with the microbiome in host hepatoenteral circulation are poorly understood. In our current germ-free mouse models and a randomized, double-blind, multiple-dose cohort study, we identified microbial glucosylceramide synthase as a key mechanistic node in the resolution of metabolic dysfunction-associated steatohepatitis. Microbial glucosylceramide synthase activity could be a predictive biomarker of response to HSK31679 treatment or a new target for microbiota-based therapeutics in metabolic dysfunction-associated steatohepatitis.

Identification of COQ2 as a regulator of proliferation and lipid peroxidation through genome-scale CRISPR-Cas9 screening in myeloma cells.

Multiple myeloma (MM) is the second most common malignant haematological disease with a poor prognosis. The limit therapeutic progress has been made in MM patients with cancer relapse, necessitating deeper research into the molecular mechanisms underlying its occurrence and development. A genome-wide CRISPR-Cas9 loss-of-function screening was utilized to identify potential therapeutic targets in our research. We revealed that COQ2 plays a crucial role in regulating MM cell proliferation and lipid peroxidation (LPO). Knockout of COQ2 inhibited cell proliferation, induced cell cycle arrest and reduced tumour growth in vivo. Mechanistically, COQ2 promoted the activation of the MEK/ERK cascade, which in turn stabilized and activated MYC protein. Moreover, we found that COQ2-deficient MM cells increased sensitivity to the LPO activator, RSL3. Using an inhibitor targeting COQ2 by 4-CBA enhanced the sensitivity to RSL3 in primary CD138+ myeloma cells and in a xenograft mouse model. Nevertheless, co-treatment of 4-CBA and RSL3 induced cell death in bortezomib-resistant MM cells. Together, our findings suggest that COQ2 promotes cell proliferation and tumour growth through the activation of the MEK/ERK/MYC axis and targeting COQ2 could enhance the sensitivity to ferroptosis in MM cells, which may be a promising therapeutic strategy for the treatment of MM patients.

Efficient Electrochemical Microsensor for the Simultaneous Measurement of Hydrogen Peroxide and Ascorbic Acid in Living Brains.

Hydrogen peroxide (H2O2) and ascorbic acid (AA), acting as two significant indicative species, correlate with the oxidative stress status in living brains, which have historically been considered to be involved mainly in neurodegenerative disorders such as Alzheimer's disease, Huntington's disease, and Parkinson's disease (PD). The development of efficient biosensors for the simultaneous measurement of their levels in living brains is vital to understand their roles played in the brain and their interactive relationship in the progress of these diseases. Herein, a robust ratiometric electrochemical microsensor was rationally designed to realize the determination of H2O2 and AA simultaneously. Therefore, a specific probe was designed and synthesized with both recognition units responsible for reacting with H2O2 to produce a detectable signal on the microsensor and linkage units helping the probe modify onto the carbon substrate. A topping ingredient, single-walled carbon nanotubes (SWCNTs) was added on the surface of the electrode, with the purpose of not only facilitating the oxidation of AA but also absorbing methylene blue (MB), prompting to read out the inner reference signal. This proposed electrochemical microsensor exhibited a robust ability to real-time track H2O2 and AA in linear ranges of 0.5-900 and 10-1000 µM with high selectivity and accuracy, respectively. Eventually, the efficient electrochemical microsensor was successfully applied to the simultaneous measurement of H2O2 and AA in the rat brain, followed by microinjection, and in the PD mouse brain.

Dual-Site Chemosensor for Visualizing •OH-GSH Redox and Tracking Ferroptosis-Inducing Pathways In Vivo.

Oxidative stress, characterized by an imbalance between oxidative and antioxidant processes, results in excessive accumulation of intracellular reactive oxygen species. Among these responses, the regulation of intracellular hydroxyl radicals (•OH) and glutathione (GSH) is vital for physiological processes. Real-time in situ monitoring these two opposing bioactive species and their redox interactions is essential for understanding physiological balance and imbalance. In this study, we developed a dual-site fluorescence chemosensor OG-3, which can independently image both exogenous and endogenous •OH and GSH in separate channels both within cells and in vivo, eliminating issues of spatiotemporal inhomogeneous distribution and cross-interference. With its imaging capabilities of monitoring •OH-GSH redox, OG-3 elucidated two different pathways for ferroptosis induction: (i) inhibition of system xc- to block cystine uptake (extrinsic pathway) and (ii) GPX4 inactivation, leading to the loss of antioxidant defense (intrinsic pathway). Moreover, we assessed the antiferroptotic function and effects of ferroptosis inhibitors by monitoring •OH and GSH fluctuations during ferroptosis. This method provides a reliable platform for identifying potential ferroptosis inhibitors, contributing to our understanding of relevant metabolic and physiological mechanisms. It shows potential for elucidating the regulation of ferroptosis mechanisms and investigating further strategies for therapeutic applications.

A novel model for predicting prognosis and response to immunotherapy in nasopharyngeal carcinoma patients.

Blood-based biomarkers of immune checkpoint inhibitors (ICIs) response in patients with nasopharyngeal carcinoma (NPC) are lacking, so it is necessary to identify biomarkers to select NPC patients who will benefit most or least from ICIs. The absolute values of lymphocyte subpopulations, biochemical indexes, and blood routine tests were determined before ICIs-based treatments in the training cohort (n = 130). Then, the least absolute shrinkage and selection operator (Lasso) Cox regression analysis was developed to construct a prediction model. The performances of the prediction model were compared to TNM stage, treatment, and Epstein-Barr virus (EBV) DNA using the concordance index (C-index). Progression-free survival (PFS) was estimated by Kaplan-Meier (K-M) survival curve. Other 63 patients were used for validation cohort. The novel model composed of histologic subtypes, CD19+ B cells, natural killer (NK) cells, regulatory T cells, red blood cells (RBC), AST/ALT ratio (SLR), apolipoprotein B (Apo B), and lactic dehydrogenase (LDH). The C-index of this model was 0.784 in the training cohort and 0.735 in the validation cohort. K-M survival curve showed patients with high-risk scores had shorter PFS compared to the low-risk groups. For predicting immune therapy responses, the receiver operating characteristic (ROC), decision curve analysis (DCA), net reclassifcation improvement index (NRI) and integrated discrimination improvement index (IDI) of this model showed better predictive ability compared to EBV DNA. In this study, we constructed a novel model for prognostic prediction and immunotherapeutic response prediction in NPC patients, which may provide clinical assistance in selecting those patients who are likely to gain long-lasting clinical benefits to anti-PD-1 therapy.

Analyzing genetic diversity in luffa and developing a Fusarium wilt-susceptible linked SNP marker through a single plant genome-wide association (sp-GWAS) study.

BACKGROUND: Luffa (Luffa spp.) is an economically important crop of the Cucurbitaceae family, commonly known as sponge gourd or vegetable gourd. It is an annual cross-pollinated crop primarily found in the subtropical and tropical regions of Asia, Australia, Africa, and the Americas. Luffa serves not only as a vegetable but also exhibits medicinal properties, including anti-inflammatory, antidiabetic, and anticancer effects. Moreover, the fiber derived from luffa finds extensive applications in various fields such as biotechnology and construction. However, luffa Fusarium wilt poses a severe threat to its production, and existing control methods have proven ineffective in terms of cost-effectiveness and environmental considerations. Therefore, there is an urgent need to develop luffa varieties resistant to Fusarium wilt. Single-plant GWAS (sp-GWAS) has been demonstrated as a promising tool for the rapid and efficient identification of quantitative trait loci (QTLs) associated with target traits, as well as closely linked molecular markers. RESULTS: In this study, a collection of 97 individuals from 73 luffa accessions including two major luffa species underwent single-plant GWAS to investigate luffa Fusarium wilt resistance. Utilizing the double digest restriction site associated DNA (ddRAD) method, a total of 8,919 high-quality single nucleotide polymorphisms (SNPs) were identified. The analysis revealed the potential for Fusarium wilt resistance in accessions from both luffa species. There are 6 QTLs identified from 3 traits, including the area under the disease progress curve (AUDPC), a putative disease-resistant QTL, was identified on the second chromosome of luffa. Within the region of linkage disequilibrium, a candidate gene homologous to LOC111009722, which encodes peroxidase 40 and is associated with disease resistance in Cucumis melo, was identified. Furthermore, to validate the applicability of the marker associated with resistance from sp-GWAS, an additional set of 21 individual luffa plants were tested, exhibiting 93.75% accuracy in detecting susceptible of luffa species L. aegyptiaca Mill. CONCLUSION: In summary, these findings give a hint of genome position that may contribute to luffa wild resistance to Fusarium and can be utilized in the future luffa wilt resistant breeding programs aimed at developing wilt-resistant varieties by using the susceptible-linked SNP marker.

A functional variant rs912304 for late-onset T1D risk contributes to islet dysfunction by regulating proinflammatory cytokine-responsive gene STXBP6 expression.

BACKGROUND: Our previous genome­wide association studies (GWAS) have suggested rs912304 in 14q12 as a suggestive risk variant for type 1 diabetes (T1D). However, the association between this risk region and T1D subgroups and related clinical risk features, the underlying causal functional variant(s), putative candidate gene(s), and related mechanisms are yet to be elucidated. METHODS: We assessed the association between variant rs912304 and T1D, as well as islet autoimmunity and islet function, stratified by the diagnosed age of 12. We used epigenome bioinformatics analyses, dual luciferase reporter assays, and expression quantitative trait loci (eQTL) analyses to prioritize the most likely functional variant and potential causal gene. We also performed functional experiments to evaluate the role of the causal gene on islet function and its related mechanisms. RESULTS: We identified rs912304 as a risk variant for T1D subgroups with diagnosed age ≥ 12 but not < 12. This variant is associated with residual islet function but not islet-specific autoantibody positivity in T1D individuals. Bioinformatics analysis indicated that rs912304 is a functional variant exhibiting spatial overlaps with enhancer active histone marks (H3K27ac and H3K4me1) and open chromatin status (ATAC-seq) in the human pancreas and islet tissues. Luciferase reporter gene assays and eQTL analyses demonstrated that the biallelic sites of rs912304 had differential allele-specific enhancer activity in beta cell lines and regulated STXBP6 expression, which was defined as the most putative causal gene based on Open Targets Genetics, GTEx v8 and Tiger database. Moreover, Stxbp6 was upregulated by T1D-related proinflammatory cytokines but not high glucose/fat. Notably, Stxbp6 over-expressed INS-1E cells exhibited decreasing insulin secretion and increasing cell apoptosis through Glut1 and Gadd45ß, respectively. CONCLUSIONS: This study expanded the genomic landscape regarding late-onset T1D risk and supported islet function mechanistically connected to T1D pathogenesis.

Temporal trends in population attributable fractions of modifiable risk factors for dementia: a time-series study of the English Longitudinal Study of Ageing (2004-2019).

BACKGROUND: Interest in modifiable risk factors (MRFs) for dementia is high, given the personal, social, and economic impact of the disorder, especially in ageing societies such as the United Kingdom. Exploring the population attributable fraction (PAF) of dementia attributable to MRFs and how this may have changed over time remains unclear. Unravelling the temporal dynamics of MRFs is crucial for informing the development of evidence-based and effective public health policies. This investigation examined the temporal trajectories of MRFs for dementia in England. METHODS: We used data from the English Longitudinal Study of Ageing, a panel study over eight waves collected between 2004 and 2019 (76,904 interviews in total). We calculated the PAFs for twelve MRFs (including six early- to mid-life factors and six late-life factors), as recommended by the Lancet Commission, and the individual weighted PAFs (IW-PAFs) for each risk factor. Temporal trends were analysed to understand the changes in the overall PAF and IW-PAF over the study period. Subgroup analyses were conducted by sex and socioeconomic status (SES). RESULTS: The overall PAF for dementia MRFs changed from 46.73% in 2004/2005 to 36.79% in 2018/2019, though this trend was not statistically significant. During 2004-2019, hypertension, with an average IW-PAF of 8.21%, was the primary modifiable determinant of dementia, followed by obesity (6.16%), social isolation (5.61%), hearing loss (4.81%), depression (4.72%), low education (4.63%), physical inactivity (3.26%), diabetes mellitus (2.49%), smoking (2.0%), excessive alcohol consumption (1.16%), air pollution (0.42%), and traumatic brain injury (TBI) (0.26%). During 2004-2019, only IW-PAFs of low education, social isolation, and smoking showed significant decreasing trends, while IW-PAFs of other factors either did not change significantly or increased (including TBI, diabetes mellitus, and air pollution). Upon sex-specific disaggregation, a higher overall PAF for MRFs was found among women, predominantly associated with later-life risk factors, most notably social isolation, depression, and physical inactivity. Additionally, hearing loss, classified as an early- to mid-life factor, played a supplementary role in the identified sex disparity. A comparable discrepancy was evident upon PAF evaluation by SES, with lower income groups experiencing a higher dementia risk, largely tied to later-life factors such as social isolation, physical inactivity, depression, and smoking. Early- to mid-life factors, in particular, low education and obesity, were also observed to contribute to the SES-associated divergence in dementia risk. Temporal PAF and IW-PAF trends, stratified by sex and SES, revealed that MRF PAF gaps across sex or SES categories have persisted or increased. CONCLUSIONS: In England, there was little change over time in the proportion of dementia attributable to known modifiable risk factors. The observed trends underscore the continuing relevance of these risk factors and the need for targeted public health strategies to address them.

Correlating Thickness and Phase of Single Co(OH)2 Micro-Platelets to the Intrinsic Activity of Oxygen Evolution Electrocatalysis.

Morphology, crystal phase, and its transformation are important structures that frequently determine electrocatalytic activity, but the correlations of intrinsic activity with them are not completely understood. Herein, using Co(OH)2 micro-platelets with well-defined structures (phase, thickness, area, and volume) as model electrocatalysts of oxygen evolution reaction, multiple in situ microscopy is combined to correlate the electrocatalytic activity with morphology, phase, and its transformation. Single-entity morphology and electrochemistry characterized by atomic force microscopy and scanning electrochemical cell microscopy reveal a thickness-dependent turnover frequency (TOF) of α-Co(OH)2. The TOF (≈9.5 s-1) of α-Co(OH)2 with ≈14 nm thickness is ≈95-fold higher than that (≈0.1 s-1) with ≈80 nm. Moreover, this thickness-dependent activity has a critical thickness of ≈30 nm, above which no thickness-dependence is observed. Contrarily, ß-Co(OH)2 reveals a lower TOF (≈0.1 s-1) having no significant correlation with thickness. Combining single-entity electrochemistry with in situ Raman microspectroscopy, this thickness-dependent activity is explained by more reversible Co3+/Co2+ kinetics and larger ratio of active Co sites of thinner α-Co(OH)2, accompanied with faster phase transformation and more extensive surface restructuration. The findings highlight the interactions among thickness, ratio of active sites, kinetics of active sites, and phase transformation, and offer new insights into structure-activity relationships at single-entity level.