Null and missense mutations of ERI1 cause a recessive phenotypic dichotomy in humans.

ERI1 is a 3'-to-5' exoribonuclease involved in RNA metabolic pathways including 5.8S rRNA processing and turnover of histone mRNAs. Its biological and medical significance remain unclear. Here, we uncover a phenotypic dichotomy associated with bi-allelic ERI1 variants by reporting eight affected individuals from seven unrelated families. A severe spondyloepimetaphyseal dysplasia (SEMD) was identified in five affected individuals with missense variants but not in those with bi-allelic null variants, who showed mild intellectual disability and digital anomalies. The ERI1 missense variants cause a loss of the exoribonuclease activity, leading to defective trimming of the 5.8S rRNA 3' end and a decreased degradation of replication-dependent histone mRNAs. Affected-individual-derived induced pluripotent stem cells (iPSCs) showed impaired in vitro chondrogenesis with downregulation of genes regulating skeletal patterning. Our study establishes an entity previously unreported in OMIM and provides a model showing a more severe effect of missense alleles than null alleles within recessive genotypes, suggesting a key role of ERI1-mediated RNA metabolism in human skeletal patterning and chondrogenesis.

m6ACali: machine learning-powered calibration for accurate m6A detection in MeRIP-Seq.

We present m6ACali, a novel machine-learning framework aimed at enhancing the accuracy of N6-methyladenosine (m6A) epitranscriptome profiling by reducing the impact of non-specific antibody enrichment in MeRIP-Seq. The calibration model serves as a genomic feature-based classifier that refines the identification of m6A sites, distinguishing those genuinely present from those that can be detected in in-vitro transcribed (IVT) control experiments. We find that m6ACali effectively identifies non-specific binding peaks reported by exomePeak2 and MACS2 in novel MeRIP-Seq datasets without the need for paired IVT controls. The model interpretation revealed that off-target antibody binding sites commonly occur at short exons and short mRNAs, originating from high read coverage regions that share the motif sequence with true m6A sites. We also reveal that the ML strategy can efficiently adjust differentially methylated peaks and other antibody-dependent, base-resolution m6A detection techniques. As a result, m6ACali offers a promising method for the universal enhancement of m6A profiles generated by MeRIP-Seq experiments, elevating the benchmark for omics-level m6A data integration.

m6A-Atlas v2.0: updated resources for unraveling the N6-methyladenosine (m6A) epitranscriptome among multiple species.

N 6-Methyladenosine (m6A) is one of the most abundant internal chemical modifications on eukaryote mRNA and is involved in numerous essential molecular functions and biological processes. To facilitate the study of this important post-transcriptional modification, we present here m6A-Atlas v2.0, an updated version of m6A-Atlas. It was expanded to include a total of 797 091 reliable m6A sites from 13 high-resolution technologies and two single-cell m6A profiles. Additionally, three methods (exomePeaks2, MACS2 and TRESS) were used to identify >16 million m6A enrichment peaks from 2712 MeRIP-seq experiments covering 651 conditions in 42 species. Quality control results of MeRIP-seq samples were also provided to help users to select reliable peaks. We also estimated the condition-specific quantitative m6A profiles (i.e. differential methylation) under 172 experimental conditions for 19 species. Further, to provide insights into potential functional circuitry, the m6A epitranscriptomics were annotated with various genomic features, interactions with RNA-binding proteins and microRNA, potentially linked splicing events and single nucleotide polymorphisms. The collected m6A sites and their functional annotations can be freely queried and downloaded via a user-friendly graphical interface at: http://rnamd.org/m6a.

DirectRMDB: a database of post-transcriptional RNA modifications unveiled from direct RNA sequencing technology.

With advanced technologies to map RNA modifications, our understanding of them has been revolutionized, and they are seen to be far more widespread and important than previously thought. Current next-generation sequencing (NGS)-based modification profiling methods are blind to RNA modifications and thus require selective chemical treatment or antibody immunoprecipitation methods for particular modification types. They also face the problem of short read length, isoform ambiguities, biases and artifacts. Direct RNA sequencing (DRS) technologies, commercialized by Oxford Nanopore Technologies (ONT), enable the direct interrogation of any given modification present in individual transcripts and promise to address the limitations of previous NGS-based methods. Here, we present the first ONT-based database of quantitative RNA modification profiles, DirectRMDB, which includes 16 types of modification and a total of 904,712 modification sites in 25 species identified from 39 independent studies. In addition to standard functions adopted by existing databases, such as gene annotations and post-transcriptional association analysis, we provide a fresh view of RNA modifications, which enables exploration of the epitranscriptome in an isoform-specific manner. The DirectRMDB database is freely available at: http://www.rnamd.org/directRMDB/.

RMDisease V2.0: an updated database of genetic variants that affect RNA modifications with disease and trait implication.

Recent advances in epitranscriptomics have unveiled functional associations between RNA modifications (RMs) and multiple human diseases, but distinguishing the functional or disease-related single nucleotide variants (SNVs) from the majority of 'silent' variants remains a major challenge. We previously developed the RMDisease database for unveiling the association between genetic variants and RMs concerning human disease pathogenesis. In this work, we present RMDisease v2.0, an updated database with expanded coverage. Using deep learning models and from 873 819 experimentally validated RM sites, we identified a total of 1 366 252 RM-associated variants that may affect (add or remove an RM site) 16 different types of RNA modifications (m6A, m5C, m1A, m5U, Ψ, m6Am, m7G, A-to-I, ac4C, Am, Cm, Um, Gm, hm5C, D and f5C) in 20 organisms (human, mouse, rat, zebrafish, maize, fruit fly, yeast, fission yeast, Arabidopsis, rice, chicken, goat, sheep, pig, cow, rhesus monkey, tomato, chimpanzee, green monkey and SARS-CoV-2). Among them, 14 749 disease- and 2441 trait-associated genetic variants may function via the perturbation of epitranscriptomic markers. RMDisease v2.0 should serve as a useful resource for studying the genetic drivers of phenotypes that lie within the epitranscriptome layer circuitry, and is freely accessible at: www.rnamd.org/rmdisease2.

Association of PLXND1 with a novel subtype of anomalous pulmonary venous return.

Anomalous pulmonary venous return (APVR) is a potentially lethal congenital heart disease. Elucidating the genetic etiology is crucial for understanding its pathogenesis and improving clinical practice, whereas its genetic basis remains largely unknown because of complex genetic etiology. We thus performed whole-exome sequencing for 144 APVR patients and 1636 healthy controls and report a comprehensive atlas of APVR-related rare genetic variants. Novel singleton, loss-of-function and deleterious missense variants (DVars) were enriched in patients, particularly for genes highly expressed in the developing human heart at the critical time point for pulmonary veins draining into the left atrium. Notably, PLXND1, encoding a receptor for semaphorins, represents a strong candidate gene of APVR (adjusted P = 1.1e-03, odds ratio: 10.9-69.3), accounting for 4.17% of APVR. We further validated this finding in an independent cohort consisting of 82 case-control pairs. In these two cohorts, eight DVars were identified in different patients, which convergently disrupt the GTPase-activating protein-related domain of PLXND1. All variant carriers displayed strikingly similar clinical features, in that all anomalous drainage of pulmonary vein(s) occurred on the right side and incorrectly connected to the right atrium, which may represent a novel subtype of APVR for molecular diagnosis. Studies in Plxnd1 knockout mice further revealed the effects of PLXND1 deficiency on severe heart and lung defects and cellular abnormalities related to APVR such as abnormal migration and vascular formation of vascular endothelial cells. These findings indicate the important role of PLXND1 in APVR pathogenesis, providing novel insights into the genetic etiology and molecular subtyping for APVR.

The immune cell transcriptome is modulated by vitamin D3 supplementation in people with a first demyelinating event participating in a randomized placebo-controlled trial.

Vitamin D deficiency is a risk factor for developing multiple sclerosis. The PrevANZ trial was conducted to determine if vitamin D3 supplementation can prevent recurrent disease activity in people with a first demyelinating event. As a sub-study of this trial, we investigated the effect of supplementation on peripheral immune cell gene expression. Participants were randomized to 1000, 5000 or 10,000 international units daily of vitamin D3 or placebo. Peripheral blood was collected at baseline and 12 weeks and sent for ribonucleic acid sequencing. Datasets from 55 participants were included. Gene expression was modulated by high dose supplementation. Antigen presentation and viral response pathways were upregulated. Oxidative phosphorylation and immune signaling pathways, including tumor necrosis factor-alpha and interleukin-17 signaling, were downregulated. Overall, vitamin D3 supplementation for 12 weeks modulated the peripheral immune cell transcriptome with induction of anti-inflammatory gene expression profiles. Our results support a dose-dependent effect of vitamin D3 supplementation on immune gene expression.

Differential inhibition of sildenafil and macitentan on saxagliptin metabolism.

The development of diabetes mellitus (DM) is generally accompanied by erectile dysfunction (ED) and pulmonary arterial hypertension (PAH), which increases the use of combination drug therapy and the risk of drug-drug interactions. Saxagliptin for the treatment of DM, sildenafil for the treatment of ED and PAH, and macitentan for the treatment of PAH are all substrates of CYP3A4, which indicates their potential involvement in drug-drug interactions. Therefore, we investigated potential pharmacokinetic interactions between saxagliptin and sildenafil/macitentan. We investigated this speculation both in vitro and in vivo, and explored the underlying mechanism using in vitro hepatic metabolic models and molecular docking assays. The results showed that sildenafil substantially inhibited the metabolism of saxagliptin by occupying the catalytic site of CYP3A4 in a competitive manner, leading to the alterations in the pharmacokinetic properties of saxagliptin in terms of increased maximum plasma concentration (Cmax), area under the plasma concentration-time curve from time 0 to 24 h (AUC(0-t)), area under the plasma concentration-time curve from time 0 extrapolated to infinite time (AUC(0-∞)), decreased clearance rate (CLz/F), and prolonged terminal half-life (t1/2). In contrast, a slight inhibition was observed in saxagliptin metabolism when concomitantly used with macitentan, as no pharmacokinetic parameters were altered, except for CLz/F. Thus, dosage adjustment of saxagliptin may be required in combination with sildenafil to achieve safe therapeutic plasma concentrations and reduce the risk of potential toxicity, but it is not necessary for co-administration with macitentan.

Comparing ocrelizumab to interferon/glatiramer acetate in people with multiple sclerosis over age 60.

BACKGROUND: Ongoing controversy exists regarding optimal management of disease modifying therapy (DMT) in older people with multiple sclerosis (pwMS). There is concern that the lower relapse rate, combined with a higher risk of DMT-related infections and side effects, may alter the risk-benefit balance in older pwMS. Given the lack of pwMS above age 60 in randomised controlled trials, the comparative efficacy of high-efficacy DMTs such as ocrelizumab has not been shown in older pwMS. We aimed to evaluate the comparative effectiveness of ocrelizumab, a high-efficacy DMT, versus interferon/glatiramer acetate (IFN/GA) in pwMS over the age of 60. METHODS: Using data from MSBase registry, this multicentre cohort study included pwMS above 60 who switched to or started on ocrelizumab or IFN/GA. We analysed relapse and disability outcomes after balancing covariates using an inverse probability treatment weighting (IPTW) method. Propensity scores were obtained based on age, country, disease duration, sex, baseline Expanded Disability Status Scale, prior relapses (all-time, 12 months and 24 months) and prior DMT exposure (overall number and high-efficacy DMTs). After weighting, all covariates were balanced. Primary outcomes were time to first relapse and annualised relapse rate (ARR). Secondary outcomes were 6-month confirmed disability progression (CDP) and confirmed disability improvement (CDI). RESULTS: A total of 248 participants received ocrelizumab, while 427 received IFN/GA. The IPTW-weighted ARR for ocrelizumab was 0.01 and 0.08 for IFN/GA. The IPTW-weighted ARR ratio was 0.15 (95% CI 0.06 to 0.33, p<0.001) for ocrelizumab compared with IFN/GA. On IPTW-weighted Cox regression models, HR for time to first relapse was 0.13 (95% CI 0.05 to 0.26, p<0.001). The hazard of first relapse was significantly reduced in ocrelizumab users after 5 months compared with IFN/GA users. However, the two groups did not differ in CDP or CDI over 3.57 years. CONCLUSION: In older pwMS, ocrelizumab effectively reduced relapses compared with IFN/GA. Overall relapse activity was low. This study adds valuable real-world data for informed DMT decision making with older pwMS. Our study also confirms that there is a treatment benefit in older people with MS, given the existence of a clear differential treatment effect between ocrelizumab and IFN/GA in the over 60 age group.

Local structural and functional MRI markers of compulsive behaviors and obsessive-compulsive disorder diagnosis within striatum-based circuits.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a classic disorder on the compulsivity spectrum, with diverse comorbidities. In the current study, we sought to understand OCD from a dimensional perspective by identifying multimodal neuroimaging patterns correlated with multiple phenotypic characteristics within the striatum-based circuits known to be affected by OCD. METHODS: Neuroimaging measurements of local functional and structural features and clinical information were collected from 110 subjects, including 51 patients with OCD and 59 healthy control subjects. Linked independent component analysis (LICA) and correlation analysis were applied to identify associations between local neuroimaging patterns across modalities (including gray matter volume, white matter integrity, and spontaneous functional activity) and clinical factors. RESULTS: LICA identified eight multimodal neuroimaging patterns related to phenotypic variations, including three related to symptoms and diagnosis. One imaging pattern (IC9) that included both the amplitude of low-frequency fluctuation measure of spontaneous functional activity and white matter integrity measures correlated negatively with OCD diagnosis and diagnostic scales. Two imaging patterns (IC10 and IC27) correlated with compulsion symptoms: IC10 included primarily anatomical measures and IC27 included primarily functional measures. In addition, we identified imaging patterns associated with age, gender, and emotional expression across subjects. CONCLUSIONS: We established that data fusion techniques can identify local multimodal neuroimaging patterns associated with OCD phenotypes. The results inform our understanding of the neurobiological underpinnings of compulsive behaviors and OCD diagnosis.

Schottky Junction Enhanced Photosynthesis of Hydrogen Peroxide by Ultrathin Porous Carbon Nitride Supported Ni Nanoparticles.

Artificial photosynthesis for high-value hydrogen peroxide (H2O2) through a two-electron reduction reaction is a green and sustainable strategy. However, the development of highly active H2O2 photocatalysts is impeded by severe carrier recombination, ineffective active sites, and low surface reaction efficiency. We developed a dual optimization strategy to load dense Ni nanoparticles onto ultrathin porous graphitic carbon nitride (Ni-UPGCN). In the absence and presence of sacrificial agents, Ni-UPGCN achieved H2O2 production rates of 169 and 4116 µmol g-1 h-1 with AQY (apparent quantum efficiency) at 420 nm of 3.14% and 17.71%. Forming a Schottky junction, the surface-modified Ni nanoparticles broaden the light absorption boundary and facilitate charge separation, which act as active sites, promoting O2 adsorption and reducing the formation energy of *OOH (reaction intermediate). This results in a substantial improvement in both H2O2 generation activity and selectivity. The Schottky junction of dual modulation strategy provides novel insights into the advancement of highly effective photocatalytic agents for the photosynthesis of H2O2.

Assembly and Applications of Macrocyclic-Confinement-Derived Supramolecular Organic Luminescent Emissions from Cucurbiturils.

Cucurbit[n]urils (Q[n]s or CB[n]s), as a classical of artificial organic macrocyclic hosts, were found to have excellent advantages in the fabricating of tunable and smart organic luminescent materials in aqueous media and the solid state with high emitting efficiency under the rigid pumpkin-shaped structure-derived macrocyclic-confinement effect in recent years. This review aims to give a systematically up-to-date overview of the Q[n]-based supramolecular organic luminescent emissions from the confined spaces triggered host-guest complexes, including the assembly fashions and the mechanisms of the macrocycle-based luminescent complexes, as well as their applications. Finally, challenges and outlook are provided. Since this class of Q[n]-based supramolecular organic luminescent emissions, which have essentially derived from the cavity-dependent confinement effect and the resulting assembly fashions, emerged only a few years ago, we hope this review will provide valuable information for the further development of macrocycle-based light-emitting materials and other related research fields.

Music training affects listeners' processing of different types of accentuation information: Evidence from ERPs.

Previous studies found that prolonged musical training can promote language processing, but few studies have examined whether and how musical training affects the processing of accentuation in spoken language. In this study, a vocabulary detection task was conducted, with Chinese single sentences as materials, to investigate how musicians and non-musicians process corrective accent and information accent in the sentence-middle and sentence-final positions. In the sentence-middle position, results of the cluster-based permutation t-tests showed significant differences in the 574-714 ms time window for the control group. In the sentence-final position, the cluster-based permutation t-tests revealed significant differences in the 612-810 ms time window for the music group and in the 616-812 ms time window for the control group. These significant positive effects were induced by the processing of information accent relative to that of corrective accent. These results suggest that both groups were able to distinguish corrective accent from information accent, but they processed the two accent types differently in the sentence-middle position. These findings show that musical training has a cross-domain effect on spoken language processing and that the accent position also affects its processing.

m5C-Atlas: a comprehensive database for decoding and annotating the 5-methylcytosine (m5C) epitranscriptome.

5-Methylcytosine (m5C) is one of the most prevalent covalent modifications on RNA. It is known to regulate a broad variety of RNA functions, including nuclear export, RNA stability and translation. Here, we present m5C-Atlas, a database for comprehensive collection and annotation of RNA 5-methylcytosine. The database contains 166 540 m5C sites in 13 species identified from 5 base-resolution epitranscriptome profiling technologies. Moreover, condition-specific methylation levels are quantified from 351 RNA bisulfite sequencing samples gathered from 22 different studies via an integrative pipeline. The database also presents several novel features, such as the evolutionary conservation of a m5C locus, its association with SNPs, and any relevance to RNA secondary structure. All m5C-atlas data are accessible through a user-friendly interface, in which the m5C epitranscriptomes can be freely explored, shared, and annotated with putative post-transcriptional mechanisms (e.g. RBP intermolecular interaction with RNA, microRNA interaction and splicing sites). Together, these resources offer unprecedented opportunities for exploring m5C epitranscriptomes. The m5C-Atlas database is freely accessible at https://www.xjtlu.edu.cn/biologicalsciences/m5c-atlas.

Geographic encoding of transcripts enabled high-accuracy and isoform-aware deep learning of RNA methylation.

As the most pervasive epigenetic mark present on mRNA and lncRNA, N6-methyladenosine (m6A) RNA methylation regulates all stages of RNA life in various biological processes and disease mechanisms. Computational methods for deciphering RNA modification have achieved great success in recent years; nevertheless, their potential remains underexploited. One reason for this is that existing models usually consider only the sequence of transcripts, ignoring the various regions (or geography) of transcripts such as 3'UTR and intron, where the epigenetic mark forms and functions. Here, we developed three simple yet powerful encoding schemes for transcripts to capture the submolecular geographic information of RNA, which is largely independent from sequences. We show that m6A prediction models based on geographic information alone can achieve comparable performances to classic sequence-based methods. Importantly, geographic information substantially enhances the accuracy of sequence-based models, enables isoform- and tissue-specific prediction of m6A sites, and improves m6A signal detection from direct RNA sequencing data. The geographic encoding schemes we developed have exhibited strong interpretability, and are applicable to not only m6A but also N1-methyladenosine (m1A), and can serve as a general and effective complement to the widely used sequence encoding schemes in deep learning applications concerning RNA transcripts.

The antennal transcriptome analysis and characterizations of odorant-binding proteins in Megachile saussurei (Hymenoptera, Megachilidae).

BACKGROUND: Odorant-binding proteins (OBPs) are essential in insect's daily behaviors mediated by olfactory perception. Megachile saussurei Radoszkowski (Hymenoptera, Megachilidae) is a principal insect pollinating alfalfa (Medicago sativa) in Northwestern China. The olfactory function have been less conducted, which provides a lot of possibilities for our research. RESULTS: Our results showed that 20 OBPs were identified in total. Multiple sequence alignment analysis indicated MsauOBPs were highly conserved with a 6-cysteine motif pattern and all belonged to the classic subfamily, coding 113-196 amino acids and sharing 41.32%-99.12% amino acid identity with known OBPs of other bees. Phylogenetic analysis indicated there were certain homologies existed among MsauOBPs and most sequences were clustered with that of Osmia cornuta (Hymenoptera, Megachilidae). Expression analysis showed the identified OBPs were mostly enriched in antennae instead of other four body parts, especially the MsauOBP2, MsauOBP3, MsauOBP4, MsauOBP8, MsauOBP11 and MsauOBP17, in which the MsauOBP2, MsauOBP4 and MsauOBP8 presented obvious tissue-biased expression pattern. Molecular docking results indicated MsauOBP4 might be the most significant protein in recognizing alfalfa flower volatile 3-Octanone, while MsauOBP13 might be the most crucial protein identifying (Z)-3-hexenyl acetate. It was also found the lysine was a momentous hydrophilic amino acid in docking simulations. CONCLUSION: In this study, we identified and analyzed 20 OBPs of M. saussurei. The certain homology existed among these OBPs, while some degree of divergence could also be noticed, indicating the complex functions that different MsauOBPs performed. Besides, the M. saussurei and Osmia cornuta were very likely to share similar physiological functions as most of their OBPs were clustered together. MsauOBP4 might be the key protein in recognizing 3-Octanone, while MsauOBP13 might be the key protein in binding (Z)-3-hexenyl acetate. These two proteins might contribute to the alfalfa-locating during the pollination process. The relevant results may help determine the highly specific and effective attractants for M. saussurei in alfalfa pollination and reveal the molecular mechanism of odor-evoked pollinating behavior between these two species.

Single-nucleus transcriptome sequencing reveals hepatic cell atlas in pigs.

BACKGROUND: As the largest substantive organ of animals, the liver plays an essential role in the physiological processes of digestive metabolism and immune defense. However, the cellular composition of the pig liver remains poorly understood. This investigation used single-nucleus RNA sequencing technology to identify cell types from liver tissues of pigs, providing a theoretical basis for further investigating liver cell types in pigs. RESULTS: The analysis revealed 13 cells clusters which were further identified 7 cell types including endothelial cells, T cells, hepatocytes, Kupffer cells, stellate cells, B cells, and cholangiocytes. The dominant cell types were endothelial cells, T cells and hepatocytes in the liver tissue of Dahe pigs and Dahe black pigs, which accounts for about 85.76% and 82.74%, respectively. The number of endothelial cells was higher in the liver tissue of Dahe pigs compared to Dahe black pigs, while the opposite tendency was observed for T cells. Moreover, functional enrichment analysis demonstrated that the differentially expressed genes in pig hepatic endothelial cells were significantly enriched in the protein processing in endoplasmic reticulum, MAPK signaling pathway, and FoxO signaling pathway. Functional enrichment analysis demonstrated that the differentially expressed genes in pig hepatic T cells were significantly enriched in the thyroid hormone signaling pathway, B cell receptor signaling pathway, and focal adhesion. Functional enrichment analysis demonstrated that the differentially expressed genes in pig hepatic hepatocytes were significantly enriched in the metabolic pathways. CONCLUSIONS: In summary, this study provides a comprehensive cell atlas of porcine hepatic tissue. The number, gene expression level and functional characteristics of each cell type in pig liver tissue varied between breeds.

The hypothalamic steroidogenic pathway mediates susceptibility to inflammation-evoked depression in female mice.

BACKGROUND: Depression is two-to-three times more frequent among women. The hypothalamus, a sexually dimorphic area, has been implicated in the pathophysiology of depression. Neuroinflammation-induced hypothalamic dysfunction underlies behaviors associated with depression. The lipopolysaccharide (LPS)-induced mouse model of depression has been well-validated in numerous laboratories, including our own, and is widely used to investigate the relationship between neuroinflammation and depression. However, the sex-specific differences in metabolic alterations underlying depression-associated hypothalamic neuroinflammation remain unknown. METHODS: Here, we employed the LPS-induced mouse model of depression to investigate hypothalamic metabolic changes in both male and female mice using a metabolomics approach. Through bioinformatics analysis, we confirmed the molecular pathways and biological processes associated with the identified metabolites. Furthermore, we employed quantitative real-time PCR, enzyme-linked immunosorbent assay, western blotting, and pharmacological interventions to further elucidate the underlying mechanisms. RESULTS: A total of 124 and 61 differential metabolites (DMs) were detected in male and female mice with depressive-like behavior, respectively, compared to their respective sex-matched control groups. Moreover, a comparison between female and male model mice identified 37 DMs. We capitalized on biochemical clustering and functional enrichment analyses to define the major metabolic changes in these DMs. More than 55% of the DMs clustered into lipids and lipid-like molecules, and an imbalance in lipids metabolism was presented in the hypothalamus. Furthermore, steroidogenic pathway was confirmed as a potential sex-specific pathway in the hypothalamus of female mice with depression. Pregnenolone, an upstream component of the steroid hormone biosynthesis pathway, was downregulated in female mice with depressive-like phenotypes but not in males and had considerable relevance to depressive-like behaviors in females. Moreover, exogenous pregnenolone infusion reversed depressive-like behaviors in female mice with depression. The 5α-reductase type I (SRD5A1), a steroidogenic hub enzyme involved in pregnenolone metabolism, was increased in the hypothalamus of female mice with depression. Its inhibition increased hypothalamic pregnenolone levels and ameliorated depressive-like behaviors in female mice with depression. CONCLUSIONS: Our study findings demonstrate a marked sexual dimorphism at the metabolic level in depression, particularly in hypothalamic steroidogenic metabolism, identifying a potential sex-specific pathway in female mice with depressive-like behaviors.

The Collision between g-C3 N4 and QDs in the Fields of Energy and Environment: Synergistic Effects for Efficient Photocatalysis.

Recently, graphitic carbon nitride (g-C3 N4 ) has attracted increasing interest due to its visible light absorption, suitable energy band structure, and excellent stability. However, low specific surface area, finite visible light response range (<460 nm), and rapid photogenerated electron-hole (e- -h+ ) pairs recombination of the pristine g-C3 N4 limit its practical applications. The small size of quantum dots (QDs) endows the properties of abundant active sites, wide absorption spectrum, and adjustable bandgap, but inevitable aggregation. Studies have confirmed that the integration of g-C3 N4 and QDs not only overcomes these limitations of individual component, but also successfully inherits each advantage. Encouraged by these advantages, the synthetic strategies and the fundamental of QDs/g-C3 N4 composites are briefly elaborated in this review. Particularly, the synergistic effects of QDs/g-C3 N4 composites are analyzed comprehensively, including the enhancement of the photocatalytic performance and the avoidance of aggregation. Then, the photocatalytic applications of QDs/g-C3 N4 composites in the fields of environment and energy are described and further combined with DFT calculation to further reveal the reaction mechanisms. Moreover, the stability and reusability of QDs/g-C3 N4 composites are analyzed. Finally, the future development of these composites and the solution of existing problems are prospected.

iCysMod: an integrative database for protein cysteine modifications in eukaryotes.

As important post-translational modifications, protein cysteine modifications (PCMs) occurring at cysteine thiol group play critical roles in the regulation of various biological processes in eukaryotes. Due to the rapid advancement of high-throughput proteomics technologies, a large number of PCM events have been identified but remain to be curated. Thus, an integrated resource of eukaryotic PCMs will be useful for the research community. In this work, we developed an integrative database for protein cysteine modifications in eukaryotes (iCysMod), which curated and hosted 108 030 PCM events for 85 747 experimentally identified sites on 31 483 proteins from 48 eukaryotes for 8 types of PCMs, including oxidation, S-nitrosylation (-SNO), S-glutathionylation (-SSG), disulfide formation (-SSR), S-sulfhydration (-SSH), S-sulfenylation (-SOH), S-sulfinylation (-SO2H) and S-palmitoylation (-S-palm). Then, browse and search options were provided for accessing the dataset, while various detailed information about the PCM events was well organized for visualization. With human dataset in iCysMod, the sequence features around the cysteine modification sites for each PCM type were analyzed, and the results indicated that various types of PCMs presented distinct sequence recognition preferences. Moreover, different PCMs can crosstalk with each other to synergistically orchestrate specific biological processes, and 37 841 PCM events involved in 119 types of PCM co-occurrences at the same cysteine residues were finally obtained. Taken together, we anticipate that the database of iCysMod would provide a useful resource for eukaryotic PCMs to facilitate related researches, while the online service is freely available at http://icysmod.omicsbio.info.