Deep learning revealed the distribution and evolution patterns for invertible promoters across bacterial lineages.

Invertible promoters (invertons) are crucial regulatory elements in bacteria, facilitating gene expression changes under stress. Despite their importance, their prevalence and the range of regulated gene functions are largely unknown. We introduced DeepInverton, a deep learning model that identifies invertons across a broad phylogenetic spectrum without using sequencing reads. By analyzing 68 733 bacterial genomes and 9382 metagenomes, we have uncovered over 200 000 nonredundant invertons and have also highlighted their abundance in pathogens. Additionally, we identified a post-Cambrian Explosion increase of invertons, paralleling species diversification. Furthermore, we revealed that invertons regulate diverse functions, including antimicrobial resistance and biofilm formation, underscoring their role in environmental adaptation. Notably, the majority of inverton identifications by DeepInverton have been confirmed by the in vitro experiments. The comprehensive inverton profiles have deepened our understanding of invertons at pan-genome and pan-metagenome scales, enabling a broad spectrum of applications in microbial ecology and synthetic biology.

Paternal USP26 mutations raise Klinefelter syndrome risk in the offspring of mice and humans.

Current understanding holds that Klinefelter syndrome (KS) is not inherited, but arises randomly during meiosis. Whether there is any genetic basis for the origin of KS is unknown. Here, guided by our identification of some USP26 variations apparently associated with KS, we found that knockout of Usp26 in male mice resulted in the production of 41, XXY offspring. USP26 protein is localized at the XY body, and the disruption of Usp26 causes incomplete sex chromosome pairing by destabilizing TEX11. The unpaired sex chromosomes then result in XY aneuploid spermatozoa. Consistent with our mouse results, a clinical study shows that some USP26 variations increase the proportion of XY aneuploid spermatozoa in fertile men, and we identified two families with KS offspring wherein the father of the KS patient harbored a USP26-mutated haplotype, further supporting that paternal USP26 mutation can cause KS offspring production. Thus, some KS should originate from XY spermatozoa, and paternal USP26 mutations increase the risk of producing KS offspring.

Biological characteristics of pregnancy in captive Yangtze finless porpoises revealed by urinary metabolomics†.

The Yangtze finless porpoises (Neophocaena asiaeorientalis a.) are an endemic and critically endangered species in China. Intensive captive breeding is essential for understanding the biology of critically endangered species, especially their pregnancy characteristics, knowledge of which is crucial for effective breeding management. Urine metabolomics can reveal metabolic differences, arising from physiological changes across pregnancy stages. Therefore, we used the urinary metabolomic technology, to explore urinary metabolite changes in pregnant Yangtze finless porpoises. A total of 2281 metabolites were identified in all samples, which including organic acids and derivatives (24.45%), organoheterocyclic compounds (20.23%), benzenoids (18.05%), organic oxygen compounds (7.73%), and phenylpropanoids and polyketides (6.48%). There were 164, 387, and 522 metabolites demonstrating differential abundance during early pregnancy, mid pregnancy, and late pregnancy, respectively, from the levels observed in nonpregnancy. The levels of pregnenolone, 17α-hydroxyprogesterone, and tetrahydrocortisone were significantly higher during all pregnancy stages, indicating their important roles in fetal development. The differential metabolites between nonpregnancy and pregnancy were mainly associated with amino acid and carbohydrate metabolism. Moreover, metabolic activity varied across pregnancy stages; steroid hormone biosynthesis was predominant in early pregnancy, and amino acid biosynthesis and carbohydrate metabolism were predominant in mid pregnancy and late pregnancy, respectively. Our results provide new insights into metabolic characteristics in the Yangtze finless porpoises' urine during pregnancy, and indicate that the differential levels of urine metabolites can determine pregnancy in Yangtze finless porpoises, providing valuable information for the husbandry and management of pregnant Yangtze finless porpoises in captivity.

MORN2 regulates the morphology and energy metabolism of mitochondria and is required for male fertility in mice.

BACKGROUND: Mitochondria produce adenosine triphosphate through respiratory activities to power sperm differentiation and motility, and decreased mitochondrial respiratory activity can result in poor sperm motility and asthenospermia. The mitochondrial sheath is a component of the mid-piece of the sperm flagellum, and dysfunction of the sheath can reduce sperm motility and cause male infertility. The membrane occupation and recognition nexus-motif protein 2 (MORN2) is testis enriched in mice, and the MORN motif was reported to play a role in the regulation of bioelectrical signal homeostasis in cardiomyocytes. METHODS: We generated Morn2-/- mice using CRISPR/Cas9 and evaluated the potential functions of MORN2 in spermiogenesis through histological analysis, fertility examination, RT-PCR, CASA, immunofluorescence, TUNEL, electron microscopy analysis, mitochondrial energy metabolism analysis, etc. RESULTS: The Morn2-/- mice were infertile, and their sperm showed severe motility defects. Morn2-/- sperm also had abnormal morphology characterized by bent heads, aberrant mitochondrial sheath formation, lower mitochondrial membrane potential, higher levels of reactive oxygen species, and decreased mitochondrial respiratory activity. CONCLUSIONS: Our study demonstrates that MORN2 is essential for male fertility and indicates that MORN2 functions in mitochondrial sheath formation and regulates mitochondrial respiratory activity.

Large-Dynamic-Range Ocular Aberration Measurement Based on Deep Learning with a Shack-Hartmann Wavefront Sensor.

The Shack-Hartmann wavefront sensor (SHWFS) is widely utilized for ocular aberration measurement. However, large ocular aberrations caused by individual differences can easily make the spot move out of the range of the corresponding sub-aperture in SHWFS, rendering the traditional centroiding method ineffective. This study applied a novel convolutional neural network (CNN) model to wavefront sensing for large dynamic ocular aberration measurement. The simulation results demonstrate that, compared to the modal method, the dynamic range of our method for main low-order aberrations in ocular system is increased by 1.86 to 43.88 times in variety. Meanwhile, the proposed method also has the best measurement accuracy, and the statistical root mean square (RMS) of the residual wavefronts is 0.0082 ± 0.0185 λ (mean ± standard deviation). The proposed method generally has a higher accuracy while having a similar or even better dynamic range as compared to traditional large-dynamic schemes. On the other hand, compared with recently developed deep learning methods, the proposed method has a much larger dynamic range and better measurement accuracy.

Regiodivergent Functionalization of Protected and Unprotected Carbohydrates using Photoactive 4-Tetrafluoropyridinylthio Fragment as an Adaptive Activating Group.

The selective functionalization of carbohydrates holds a central position in synthetic carbohydrate chemistry, driving the ongoing quest for ideal approaches to manipulate these compounds. In this study, we introduce a general strategy that enables the regiodivergent functionalization of saccharides. The use of electron-deficient photoactive 4-tetrafluoropyridinylthio (SPyf) fragment as an adaptable activating group, facilitated efficient functionalization across all saccharide sites. More importantly, this activating group can be directly installed at the C1, C5 and C6 positions of biomass-derived carbohydrates in a single step and in a site-selective manner, allowing for the efficient and precision-oriented modification of unprotected saccharides and glycans.

NhaA facilitates the maintenance of bacterial envelope integrity and the evasion of complement attack contributing to extraintestinal pathogenic Escherichia coli virulence.

Extraintestinal pathogenic Escherichia coli (ExPEC) is responsible for severe bloodstream infections in humans and animals. However, the mechanisms underlying ExPEC's serum resistance remain incompletely understood. Through the transposon-directed insertion-site sequencing approach, our previous study identified nhaA, the gene encoding a Na+/H+ antiporter, as a crucial factor for infection in vivo. In this study, we investigated the role of NhaA in ExPEC virulence utilizing both in vitro models and systemic infection models involving avian and mammalian animals. Genetic mutagenesis analysis revealed that nhaA deletion resulted in filamentous bacterial morphology and rendered the bacteria more susceptible to sodium dodecyl sulfate, suggesting the role of nhaA in maintaining cell envelope integrity. The nhaA mutant also displayed heightened sensitivity to complement-mediated killing compared to the wild-type strain, attributed to augmented deposition of complement components (C3b and C9). Remarkably, NhaA played a more crucial role in virulence compared to several well-known factors, including Iss, Prc, NlpI, and OmpA. Our findings revealed that NhaA significantly enhanced virulence across diverse human ExPEC prototype strains within B2 phylogroups, suggesting widespread involvement in virulence. Given its pivotal role, NhaA could serve as a potential drug target for tackling ExPEC infections.

Direct wavefront sensing with a plenoptic sensor based on deep learning.

Traditional plenoptic wavefront sensors (PWS) suffer from the obvious step change of the slope response which leads to the poor performance of phase retrieval. In this paper, a neural network model combining the transformer architecture with the U-Net model is utilized to restore wavefront directly from the plenoptic image of PWS. The simulation results show that the averaged root mean square error (RMSE) of residual wavefront is less than 1/14λ (Marechal criterion), proving the proposed method successfully breaks through the non-linear problem existed in PWS wavefront sensing. In addition, our model performs better than the recently developed deep learning models and traditional modal approach. Furthermore, the robustness of our model to turbulence strength and signal level is also tested, proving the good generalizability of our model. To the best of our knowledge, it is the first time to perform direct wavefront detection with a deep-learning-based method in PWS-based applications and achieve the state-of-the-art performance.

The Relation Between the Power of Prefrontal Gamma in Rest-state EEG Under Normal Sleep and Reactive Aggression Behaviour After Sleep Deprivation.

Whether sleep deprivation affects aggressive behaviour is still under debate. The present study examined the influence of individual differences in reactive aggressive behaviour after sleep deprivation and preliminarily explored an electrophysiological marker to identify individuals with more aggressive behaviour after sleep deprivation. Thirty participants performed the Taylor Aggression Paradigm task under two sleep conditions: normal sleep (NS, one night of regular sleep) and total sleep deprivation (SD, 30 h of wakefulness), and 5-minute resting-state electroencephalogram (EEG) acquisition was completed under the NS condition. The results found that although sleep deprivation did not have significant effects on aggressive behaviour in the overall analysis, the participants can be classified as an increased group (n = 16) and a no-increased group (n = 14) by different changes in the two sleep conditions (SD-NS). In addition, prefrontal gamma (γ) power was significantly lower in the increased group than in the no-increased group, which may reflect the difference in ability on inhibition. Furthermore, more critical is that γ power was significantly negatively correlated with change in the reactive aggressive behaviour. These results indicate that the effect of SD on reactive aggression varies between individuals, and prefrontal γ power may be an effective electrophysiological marker for identifying people at risk of aggressive behaviour after SD.

Mitofusins: from mitochondria to fertility.

Germ cell formation and embryonic development require ATP synthesized by mitochondria. The dynamic system of the mitochondria, and in particular, the fusion of mitochondria, are essential for the generation of energy. Mitofusin1 and mitofusin2, the homologues of Fuzzy onions in yeast and Drosophila, are critical regulators of mitochondrial fusion in mammalian cells. Since their discovery mitofusins (Mfns) have been the source of significant interest as key influencers of mitochondrial dynamics, including membrane fusion, mitochondrial distribution, and the interaction with other organelles. Emerging evidence has revealed significant insight into the role of Mfns in germ cell formation and embryonic development, as well as the high incidence of reproductive diseases such as asthenospermia, polycystic ovary syndrome, and gestational diabetes mellitus. Here, we describe the key mechanisms of Mfns in mitochondrial dynamics, focusing particularly on the role of Mfns in the regulation of mammalian fertility, including spermatogenesis, oocyte maturation, and embryonic development. We also highlight the role of Mfns in certain diseases associated with the reproductive system and their potential as therapeutic targets.

Three-wave differential locking scheme in a 12-m-perimeter large-scale passive laser gyroscope.

Large-scale laser gyroscopes with sufficiently high sensitivity for measurement of the rotation rate of the Earth Ω E are inertial sensors with the capability to provide Earth orientation parameters, i.e., rotation rate and polar motion in near real time. Larger-scale passive resonant gyroscopes (PRGs) theoretically have a lower shot-noise limit. However, the cavity perimeter fluctuations and laser frequency noise become challenges in a passive gyro. In this paper, we introduce a three-wave differential locking scheme for large-scale PRGs, resulting in an in situ measurement of the cavity perimeter with nanometer resolution. Furthermore, the laser frequency noise is effectively suppressed with an additional gain of 30 dB by a double-stage locking system, based on the three-wave differential locking scheme. Finally, the rotation rate resolution of our 3m×3m gyroscope improves to 1.1×10-9 r a d/s over 200 s. The simplicity, robustness, and effectiveness of the locking scheme are important to the long-term operation of large-scale PRGs aiming for applications in the geosciences.

The Design of Rapid Self-Healing Alginate Hydrogel with Dendritic Crosslinking Network.

Self-healing alginate hydrogels play important roles in the biological field due to their biocompatibility and ability to recover after cracking. One of the primary targets for researchers in this field is to increase the self-healing speed. Sodium alginate was oxidized, generating aldehyde groups on the chains, which were then crosslinked by poly(amino) amine (PAMAM) via Schiff base reaction. The dendritic structure was introduced to the alginate hydrogel in this work, which was supposed to promote intermolecular interactions and accelerate the self-healing process. Results showed that the hydrogel (ADA-PAMAM) formed a gel within 2.5 min with stable rheological properties. Within 25 min, the hydrogel recovered under room temperature. Furthermore, the aldehyde degree of alginate dialdehyde with a different oxidation degree was characterized through gel permeation chromatograph aligned with multi-angle laser light scattering and ultraviolet (UV) absorption. The chemical structure of the hydrogel was characterized through Fourier transform infrared spectroscopy and UV-vis spectra. The SEM and laser scanning confocal microscope (CLSM) presented the antibiotic ability of ADA-PAMAM against both S. aureus and E. coli when incubated with 10-7 CFU microorganism under room temperature for 2 h. This work presented a strategy to promote the self-healing of hydrogel through forming a dendritic dynamic crosslinking network.

The 3A protein of coxsackievirus B3 acts as a viral suppressor of RNA interference.

RNA interference (RNAi) is a potent antiviral defence mechanism in eukaryotes, and numerous viruses have been found to encode viral suppressors of RNAi (VSRs). Coxsackievirus B3 (CVB3) belongs to the genus Enterovirus in the family Picornaviridae, and has been reported to be a major causative pathogen for viral myocarditis. Despite the importance of CVB3, it is unclear whether CVB3 can also encode proteins that suppress RNAi. Here, we showed that the CVB3 nonstructural protein 3A suppressed RNAi triggered by either small hairpin RNAs (shRNAs) or small interfering RNAs (siRNAs) in mammalian cells. We further uncovered that CVB3 3A interacted directly with double-stranded RNAs (dsRNAs) and siRNAs in vitro. Through mutational analysis, we found that the VSR activity of CVB3 3A was significantly reduced by mutations of D24A/L25A/L26A, Y37A/C38A and R60A in conserved residues. In addition, the 3A protein encoded by coxsackievirus B5 (CVB5), another member of Enterovirus, also showed VSR activity. Taken together, our findings showed that CVB3 3A has in vitro VSR activity, thereby providing insights into the pathogenesis of CVB3 and other enteroviruses.

A meta-analysis for Kuanxiong Aerosol on the treatment of angina pectoris.

BACKGROUND: Kuanxiong Aerosol (KA) has been used in patients with angina pectoris (AP) attacks for many years, this systematic review and meta-analysis aims to evaluate the clinical efficacy and safety of KA versus nitrates in the treatment of AP. METHODS: Seven databases (PubMed, EMBASE, CENTRAL, CNKI, VIP, CBM and Wanfang) were searched from inception to November 2019 to include randomized controlled trials (RCTs) that compare the efficacy and safety of KA with nitrates on the treatment of AP. And two reviewers independently assessed the risk of bias. RESULT: A total of 12 RCTs were eventually included, involving 2001 patients. Compared with the Nitrates group, the KA group showed great significant improvement on the 3-min [relative risk (RR) = 1.12, 95% confidence interval (CI) (1.03,1.23), P < .05;11 studies,1875 patients] and 5-min [RR = 1.05, 95%CI (1.01,1.08), P < 0.05; 11 studies,1875 patients] angina remission rates, the incidence of adverse reactions [RR = 0.42,95% CI (0.33,0.54), P < 0.00001; 8 studies, 1350 patients], endothelin(ET) [SMD = -0.40, 95%CI (-0.74,-0.07), P < 0.05; 2 studies, 143 patients] and c-reactive protein (CRP) [SMD = -0.58, 95%CI (-0.87,-0.30), P < 0.00001;2 studies, 200 patients],but no significant improvement on electrocardiogram efficacy [RR = 1.03, 95%CI (0.98,1.10), P = 0.26;11 studies, 1549 patients], nitric oxide (NO) [SMD = -0.08, 95%CI (-0.61,0.45), P = 0.76;2 studies, 143 patients]. CONCLUSION: The clinical use of KA is effective and safe on the treatment of AP, which appears to be better than nitrates in terms of efficiency, adverse reactions, endothelial function and inflammatory response. Nevertheless, due to some limitations in the sample size and quality of the included studies, more high-quality RCTs were still needed for further verification.

Variation analysis of SOX8 gene in Chinese men with non-obstructive azoospermia or oligozoospermia.

Sox8, encoding a SRY-related HMG box transcription factor, is essential in Sertoli cells for germ cell differentiation via regulation of integrity of the blood-testis barrier (BTB) as well as Sertoli-germ cell adhesion. Inactivation of Sox8 gene in mice causes postnatal progressive spermatogenic failure, resulting in male infertility. This study aims to investigate whether variants of SOX8 contribute to pathogenesis of idiopathic non-obstructive azoospermia (NOA) or oligozoospermia. A case-control genetic study was conducted in which all exons and exon-intron boundaries of SOX8 gene were screened in 190 NOA and 139 oligozoospermia cases by Sanger sequencing. The detected variants were examined in 284 normospermic controls. Nine known single-nucleotide polymorphisms (SNPs) of SOX8 gene were identified, and four of them exist simultaneously in oligo/azoospermia patients. A comparison of allele/genotype frequencies of these variants showed no significant difference between oligo/azoospermia cases and controls. The results indicate that deleterious variants in SOX8 gene may not be a common cause for oligo/azoospermia in Chinese men. Considering ethnic diversity, SOX8 could not be ruled out as a candidate gene for male infertility. The role of SOX8-mediated Sertoli cell function and BTB integrity played in the pathogenesis of male infertility needs to be further explored in other populations.

Identification of Host Adaptation Genes in Extraintestinal Pathogenic Escherichia coli during Infection in Different Hosts.

Extraintestinal pathogenic Escherichia coli (ExPEC) is an important human and animal pathogen. Despite the apparent similarities in their known virulence attributes, some ExPEC strains can cross the host species barrier and present a zoonotic potential, whereas other strains exhibit host specificity, suggesting the existence of unknown mechanisms that remain to be identified. We applied a transposon-directed insertion site sequencing (TraDIS) strategy to investigate the ExPEC XM strain, which is capable of crossing the host species barrier, and to screen for virulence-essential genes in both mammalian (mouse) and avian (duck) models of E. coli-related septicemia. We identified 151 genes essential for systemic infection in both mammalian and avian models, 97 required only in the mammalian model, and 280 required only in the avian model. Ten genes/gene clusters were selected for further validation, and their contributions to ExPEC virulence in both mammalian and avian models or mammalian- or avian-only models were confirmed by animal tests. This represents the first comprehensive genome-wide analysis of virulence-essential genes required for systemic infections in two different host species and provides a further comprehensive understanding of ExPEC-related virulence, host specificity, and adaptation.

Development of a heart-cutting supercritical fluid chromatography-high-performance liquid chromatography coupled to tandem mass spectrometry for the determination of four tobacco-specific nitrosamines in mainstream smoke.

This paper proposed a newly developed heart-cutting two-dimensional supercritical fluid chromatography-high-performance liquid chromatography system coupled to tandem mass spectrometry (SFC-HPLC-MS/MS) for the determination of four tobacco-specific nitrosamines (TSNAs) in cigarette mainstream smoke. The orthogonality of five SFC columns and two HPLC columns was evaluated. The 1-AA column was applied for the first dimensional (1D) SFC separation to isolate the target compounds from the complex cigarette smoke matrices, and a trapping column in conjunction with an isocratic pump was employed to capture the 1D elutes. Then, the trapped 1D elutes were transferred into the C18 column through a two-position/six-port valve for the second dimensional (2D) analysis. The ion suppression was significantly reduced by the established SFC-HPLC system; meanwhile, the matrix interferences were eliminated as the results demonstrated. A dynamic range between 0.1 and 20 ng/mL was achieved with LOQs of 0.72 µg/cig for N-nitrosonornicotine (NNN), 0.66 µg/cig for nicotine-derived nitrosamine ketone (NNK), 0.81 µg/cig for N-nitrosoanatabine (NAT), and 0.39 µg/cig for N-nitrosoanabasine (NAB). All the results revealed that the presented method exhibited good repeatabilities and recoveries and could be used as a rapid and reliable approach for routine analysis of TSNAs in mainstream smoke.

On-Demand Bioadhesive Dendrimers with Reduced Cytotoxicity.

Tissue adhesives based on polyamidoamine (PAMAM) dendrimer, grafted with UV-sensitive aryldiazirine (PAMAM-g-diazirine) are promising new candidates for light active adhesion on soft tissues. Diazirine carbene precursors form interfacial and intermolecular covalent crosslinks with tissues after UV light activation that requires no premixing or inclusion of free radical initiators. However, primary amines on the PAMAM dendrimer surface present a potential risk due to their cytotoxic and immunological effects. PAMAM-g-diazirine formulations with cationic pendant amines converted into neutral amide groups were evaluated. In vitro toxicity is reduced by an order of magnitude upon amine capping while retaining bioadhesive properties. The in vivo immunological response to PAMAM-g-diazirine formulations was found to be optimal in comparison to standard poly(lactic-co-glycolic acid) (PLGA) thin films.

A genome-wide association study reveals that variants within the HLA region are associated with risk for nonobstructive azoospermia.

A genome-wide association study of Han Chinese subjects was conducted to identify genetic susceptibility loci for nonobstructive azoospermia (NOA). In the discovery stage, 802 azoospermia cases and 1,863 controls were screened for genetic variants in the genome. Promising SNPs were subsequently confirmed in two independent sets of subjects: 818 azoospermia cases and 1,755 controls from northern China, and 606 azoospermia cases and 958 controls from central and southern China. We detected variants at human leukocyte antigen (HLA) regions that were independently associated with NOA (HLA-DRA, rs3129878, p(combine) = 3.70 × 10(-16), odds ratio [OR] = 1.37; C6orf10 and BTNL2, rs498422, p(combine) = 2.43 × 10(-12), OR = 1.42). These findings provide additional insight into the pathogenesis of NOA.

Mutations in KISS1 are not responsible for idiopathic hypogonadotropic hypogonadism in Chinese patients.

PURPOSE: To investigate whether mutations in the KISS1 gene are present in 170 Chinese patients with idiopathic hypogonadotropic hypogonadism (IHH). METHODS: Mutational screening of the KISS1 gene was performed in 170 Chinese patients with IHH (133 male cases and 37 female cases) and 187 matched controls (94 males and 93 females). RESULTS: Two known single-nucleotide polymorphisms (SNP), c. 58G > A in exon 1 and c. 242C > G in exon 2, were identified. However, no difference of genotype and allelic frequencies between cases and controls was observed. CONCLUSIONS: The results suggest that mutations in the coding sequence of KISS1 are not common in patients with IHH in this Chinese population.