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Abstract Menaquinone (MK) in bacterial membrane is an attractive target for the development of novel therapeutic agents. Mining the untapped chemical diversity encoded by Gram-negative bacteria presents an opportunity to identify additional MK-binding antibiotics (MBAs). By MK-binding motif searching of bioinformatically predicted linear non-ribosomal peptides from 14,298 sequenced genomes of 45 underexplored Gram-negative bacterial genera, here we identify a novel MBA structural family, including silvmeb and pseudomeb, using structure prediction-guided chemical synthesis. Both MBAs show rapid bacteriolysis by MK-dependent membrane depolarization to achieve their potent activities against a panel of Gram-positive pathogens. Furthermore, both MBAs are proven to be effective against methicillin-resistant Staphylococcus aureus in a murine peritonitis-sepsis model. Our findings suggest that MBAs are a kind of structurally diverse and still underexplored antibacterial lipodepsipeptide class. The interrogation of underexplored bacterial taxa using synthetic bioinformatic natural product methods is an appealing strategy for discovering novel biomedically relevant agents to confront the crisis of antimicrobial resistance.

Abstract To compare the efficacy and advantages of mini percutaneous nephrostomy (MPCN), micropercutaneous nephrostomy (MicroPCN), and retrograde ureteric stenting (RUS) in the treatment of acute upper urinary tract calculi (UUTC) obstruction with hydronephrosis and infection, and verify the safety and indications of clinical application of micropercutaneous nephrostomy. Clinical-epidemiological data of patients with acute upper urinary tract calculi obstruction and infection treated in Ningbo No.2 hospital were retrospectively collected from May 2019 to May 2023. 64 patients (20 patients in MPCN group, 13 patients in MicroPCN group, and 31 patients in RUS group) were eligible for analysis based on inclusion and exclusion criteria. P value

Abstract Understanding litter decomposition processes in coastal macrophyte habitats is critically important for predicting ecosystem functioning. However, decomposition processes of litter mixtures in coastal habitats remain largely unexplored. Here, we evaluated the litter mixture effects on the decomposition of six marine macrophytes (two seagrasses and four macroalgae) through in situ litter-mixing experiments with five levels of litter species richness and 36 different litter compositions. We found that the litter species identity and composition, rather than species richness, were crucial in structuring benthic faunal communities. Macroalgal litter, particularly Sargassum sp., hosted higher numbers of polychaetes and crustaceans than seagrass litter. More macroalgal presence induced faster decomposition rates of seagrass litter in the late stage, but not in the early stage. These findings suggest that changes in macrophyte diversity and composition can alter decomposition processes and, consequently, the sediment organic carbon stock through the transition of litter sources and benthic faunas.

Abstract Interannual global mean surface temperature (GMST) forecast provides critical insights into the economic and societal implications of climate variability. The pronounced GMST elevation in 2023–2024 indicates that the Earth may have accumulated enough heat to cause widespread disasters, underscoring the necessity for establishing accurate short-term GMST predictions to offer timely and sustainable public service. However, capturing high-frequency annual variability (ANV) component of GMST poses challenges due to its susceptibility to intraseasonal-to-interannual (ISI) noises, particularly across the Northern Hemisphere’s mid-to-high latitudes. Averaging these ISI variations in November and December effectively enhances signal clarity, especially over oceans, and masks unpredictable noises on land. By forecasting the average GMST for November and December to extract ANV predictability, a strategy for annual GMST prediction was established. This approach successfully advanced precise GMST hindcasts by up to 2-months during 1980–2022, exceeding performance of existing climate models and boosting early warning for interannual GMST shifts.

Abstract Biocatalysis has been widely employed for the generation of carbon-carbon/heteroatom stereocentres, yet its application in chiral C(sp3)–S bond construction is rare and limited to enzymatic kinetic resolutions. Herein, we describe the enantioselective construction of chiral C(sp3)–S bonds through ene-reductase biocatalyzed conjugate reduction of prochiral vinyl sulfides. A series of cooperative sequential/concurrent chemoenzymatic and biocatalytic cascades have been developed to access a broad range of chiral sulfides, including valuable β-hydroxysulfides bearing two adjacent C(sp3)–S and C(sp3)–O stereocentres, in a stereoconvergent manner with good to excellent yields (up to 96%) and enantioselectivities (up to >99% ee). Notably, this biocatalytic strategy allows to overcome the long-standing shortcomings of catalyst poisoning and C(sp2)/C(sp3)–S bond cleavage faced in transition-metal-catalyzed hydrogenation of vinyl sulfides. Finally, the potential of this methodology is also exemplified by its broader application in the stereoconvergent assembly of chiral C(sp3)–N/O/Se bonds with good to excellent enantioselctivities.

Abstract The continuous generation of multi-omics and phenotype data is propelling advancements in precision oncology. UCSCXenaShiny was developed as an interactive tool for exploring thousands of cancer datasets available on UCSC Xena. However, its capacity for comprehensive and personalized pan-cancer data analysis is being challenged by the growing demands. Here, we introduce UCSCXenaShiny v2, a milestone update through a variety of improvements. Firstly, by integrating multidimensional data and implementing adaptable sample settings, we create a suite of robust TPC (TCGA, PCAWG, CCLE) analysis pipelines. These pipelines empower users to conduct in-depth analyses of correlation, comparison, and survival in three modes: Individual, Pan-cancer and Batch screen. Additionally, the tool includes download interfaces that enable users to access diverse data and outcomes, several features also facilitate the joint analysis of drug sensitivity and multi-omics of cancer cell lines. UCSCXenaShiny v2 is an open-source R package and a web application, freely accessible at https://github.com/openbiox/UCSCXenaShiny .

Abstract Ossicular fixation disturbs the mobility of the ossicular chain and causes conductive hearing loss. To diagnose the lesion area, otologists typically assess ossicular mobility through intraoperative palpation. Quantification of ossicular mobility and evidence-based diagnostic criteria are necessary for accurate assessment of each pathology, because diagnosis via palpation can rely on the surgeons’ experiences and skills. In this study, ossicular mobilities were simulated in 92 pathological cases of ossicular fixation as compliances using a finite-element (FE) model of the human middle ear. The validity of the ossicular mobilities obtained from the FE model was verified by comparison with measurements of ossicular mobilities in cadavers using our newly developed intraoperative ossicular mobility measurement system. The fixation-induced changes in hearing were validated by comparison with changes in the stapedial velocities obtained from the FE model with measurements reported in patients and in temporal bones. The 92 cases were classified into four groups by conducting a cluster analysis based on the simulated ossicular compliances. Most importantly, the cases of combined fixation of the malleus and/or the incus with otosclerosis were classified into two different surgical procedure groups by degree of fixation, i.e., malleo-stapedotomy and stapedotomy. These results suggest that pathological characteristics can be detected using quantitatively measured ossicular compliances followed by cluster analysis, and therefore, an effective diagnosis of ossicular fixation is achievable.

Abstract By dispensing with all the atoms and only focusing on dislocation lines, the computational method of Discrete Dislocation Dynamics (DDD) gains greatly over Molecular Dynamics (MD) in simulation efficiency of metal plasticity. But whereas in MD dislocations follow natural dynamics of atomic motion, DDD must rely on a dislocation mobility function to prescribe how a dislocation line should respond to the driving force exerted on it. However, reflecting our still incomplete understanding of ways in which dislocations move, mobility functions presently employed in DDD simulations entail simplifications and approximations of limited or, worse still, unknown accuracy and applicability. Here we introduce a data-driven approach in which the dislocation mobility function is modeled as a graph neural network (GNN) trained on large-scale MD simulations of crystal plasticity. We apply our proposed approach to predicting plastic strength of body-centered-cubic (BCC) metal tungsten and show that, once implemented in a DDD model, our GNN dislocation mobility function accurately reproduces the challenging tension/compression asymmetry of plastic flow observed both in ground-truth MD simulations and in experiment. Furthermore, subsequently validated by MD simulations, the same function accurately predicts plastic response of tungsten under conditions not previously seen in training. By demonstrating its ability to learn relevant physics of dislocation motion, our DDD+ML approach opens a promising avenue to bringing fidelity of DDD models closer in line with direct MD simulations at a much reduced computational cost.

Abstract Developing light yet strong aluminum (Al)-based alloys has been attracting unremitting efforts due to the soaring demand for energy-efficient structural materials. However, this endeavor is impeded by the limited solubility of other lighter components in Al. Here, we propose to surmount this challenge by converting multiple brittle phases into a ductile solid solution in Al-based complex concentrated alloys (CCA) by applying high pressure and temperature. We successfully develop a face-centered cubic single-phase Al-based CCA, Al55Mg35Li5Zn5, with a low density of 2.40 g/cm3 and a high specific yield strength of 344×103 N·m/kg (typically ~ 200×103 N·m/kg in conventional Al-based alloys). Our analysis reveals that formation of the single-phase CCA can be attributed to the decreased difference in atomic size and electronegativity between the solute elements and Al under high pressure, as well as the synergistic high entropy effect caused by high temperature and high pressure. The increase in strength originates mainly from high solid solution and nanoscale chemical fluctuations. Our findings could offer a viable route to explore lightweight single-phase CCAs in a vast composition-temperature-pressure space with enhanced mechanical properties.

Abstract Extreme myopia (EM), defined as a spherical equivalent (SE) ≤ −10.00 diopters (D), is one of the leading causes of sight impairment. Known EM-associated variants only explain limited risk and are inadequate for clinical decision-making. To discover risk genes, we performed a whole-exome sequencing (WES) on 449 EM individuals and 9606 controls. We find a significant excess of rare protein-truncating variants (PTVs) in EM cases, enriched in the retrograde vesicle-mediated transport pathway. Employing single-cell RNA-sequencing (scRNA-seq) and a single-cell polygenic burden score (scPBS), we pinpointed PI16 + /SFRP4+ fibroblasts as the most relevant cell type. We observed that KDELR3 is highly expressed in scleral fibroblast and involved in scleral extracellular matrix (ECM) organization. The zebrafish model revealed that kdelr3 downregulation leads to elongated ocular axial length and increased lens diameter. Together, our study provides insight into the genetics of EM in humans and highlights KDELR3’s role in EM pathogenesis.

Abstract Polyamorphic transition (PT) is a compelling and pivotal physical phenomenon in the field of glass and materials science. Understanding this transition is of scientific and technological significance, as it offers an important pathway for effectively tuning the structure and property of glasses. In contrast to the PT observed in conventional metallic glasses (MGs), which typically exhibit a pronounced first-order nature, herein we report a continuous PT (CPT) without first-order characteristics in high-entropy MGs (HEMGs) upon heating. This CPT behavior is featured by the continuous structural evolution at the atomic level and an increasing chemical concentration gradient with temperature, but no abrupt reduction in volume and energy. The continuous transformation is associated with the absence of local favorable structures and chemical heterogeneity caused by the high configurational entropy, which limits the distance and frequency of atomic diffusion. As a result of the CPT, numerous glass states can be generated, which provides an opportunity to understand the nature, atomic packing, formability, and properties of MGs. Moreover, this discovery highlights the implication of configurational entropy in exploring polyamorphic glasses with an identical composition but highly tunable structures and properties.

Abstract This retrospective study analyzed a large population of gastric cancer (GC) patients treated between 2010 and 2015 to investigate the clinical features and predictive risk factors for developing secondary primary malignancies (SPMs). The cumulative incidence of SPM was assessed using Kaplan–Meier analysis. Competing risk analyses adjusted for mortality were conducted using stratified Cox proportional hazard regression models and multivariate analyses to identify independent predictors of SPM. A total of 3289 out of 167,747 GC patients were included in the analytic cohort, with 155 patients diagnosed with SPM. Patients whose histologic type other than adenocarcinomas (AC) and signet ring cell carcinoma (SRCC) emerged as an independent risk factor for developing SPM (hazard ratio [HR] 2.262, 95% confidence interval [CI] 1.146–4.465, P = 0.019) in multivariate Cox regression analysis. The surgical method, including biopsy/local excision (HR 2.3, [CI] 1.291–4.095, P = 0.005) and subtotal/total resection ([HR] 1.947, [CI] 1.028–3.687, P = 0.041), chemotherapy ([HR] 1.527, [CI] 1.006–2.316, P = 0.047), and histologic type ([HR] 2.318, [CI] 1.193–4.504, P = 0.013)), were identified as independent risk factors in the competitive risk model. Subgroup analyses, stratified by chemotherapy, revealed an increased risk of SPM among older patients. Furthermore, a nomogram was developed and internally validated to predict the cumulative incidence of SPM in GC patients (C-index = 0.73 for 72 months). These findings suggested that in specific histologic types of GC, the lymph node infiltration region missed after local surgical resection, and concomitant chemotherapy would have an increased risk of SPM for cancer survivors.

Abstract Cisplatin is a widely used chemotherapeutic drug that can induce ovarian damage. Icariin (ICA), a natural antioxidant derived from Epimedium brevicornum Maxim., has been found to protect against organ injury. The aim of the present study was to investigate whether ICA can exert an ovarian-protective effect on cisplatin induced premature ovarian failure (POF) and the underlying mechanism involved. The preventive effect of ICA was evaluated using body weight, the oestrous cycle, ovarian histological analysis, and follicle counting. ICA treatment increased body weight, ovarian weight, and the number of follicles and improved the oestrous cycle in POF mice. ICA reduced cisplatin-induced oxidative damage and upregulated the protein expression levels of Nrf2, GPX4 and HO-1. Moreover, ICA reduced the expression levels of Bax and γH2AX and inhibited ovarian apoptosis. In addition, ICA activated the Nrf2 pathway in vitro and reversed changes in the viability of cisplatin-induced KGN cells, reactive oxygen species (ROS) levels, lipid peroxidation, and apoptosis, and these effects were abrogated when Nrf2 was knocked down or inhibited. Molecular docking confirmed that ICA promotes the release of Nrf2 by competing with Nrf2 for binding to Keap1. The inhibitory effects of ICA on cisplatin-induced oxidative stress, ferroptosis, and apoptosis may be mediated by its modulatory effects on the Nrf2 pathway, providing a novel perspective on the potential mechanisms by which ICA prevents POF.

Abstract We propose an effective method for removing thermal vibrations that complicate the task of analyzing complex dynamics in atomistic simulation of condensed matter. Our method iteratively subtracts thermal noises or perturbations in atomic positions using a denoising score function trained on synthetically noised but otherwise perfect crystal lattices. The resulting denoised structures clearly reveal underlying crystal order while retaining disorder associated with crystal defects. Purely geometric, agnostic to interatomic potentials, and trained without inputs from explicit simulations, our denoiser can be applied to simulation data generated from vastly different interatomic interactions. The denoiser is shown to improve existing classification methods, such as common neighbor analysis and polyhedral template matching, reaching perfect classification accuracy on a recent benchmark dataset of thermally perturbed structures up to the melting point. Demonstrated here in a wide variety of atomistic simulation contexts, the denoiser is general, robust, and readily extendable to delineate order from disorder in structurally and chemically complex materials.

Abstract FVP is a polysaccharide extracted from Flammulina velutipes with immunomodulatory, anti-tumor, and anti-oxidation activities. In this study, we obtained the crude polysaccharide FVP-C from the water extract of Flammulina velutipes, and its main component FVP-S1 was obtained after further purification. Upon structural identification, we found that FVP-C is a neutral polysaccharide, and FVP-S1 was an acidic golden mushroom polysaccharide, consisting of glucuronic acid, xylose, and glucose. Lung adenocarcinoma (A549) was treated with FVP-S1 and FVP-C, respectively, and we found that FVP-S1 and FVP-C inhibited the proliferation and migration ability of tumor cells, as well as changed the morphology of the tumor cells and caused chromosome sheteropythosis, among which FVP-S1 had the best inhibition effect. The results of flow cytometry experiments and mitochondrial membrane potential, RT-qPCR, and Western blot showed that FVP-S1 and FVP-C were able to decrease the mitochondrial membrane potential, increase the expression level of apoptotic proteins Casepase-3 and Casepase-9 proteins, and at the same time, increase the ratio of Bax and Bcl-2, which promoted apoptosis of tumor cells. In conclusion, these data indicated that FVP-S1 and FVP-C were able to induce apoptosis in A549 cells through the mitochondrial pathway, which played an important role in inhibiting tumor cells.

Abstract Previous studies that focused on univariate correlations between neuroanatomy and cognition in schizophrenia identified some inconsistent findings. Moreover, antipsychotic medication may impact the brain-behavior profiles in affected individuals. It remains unclear whether unmedicated and medicated individuals with schizophrenia would share common neuroanatomy-cognition associations. Therefore, we aimed to investigate multivariate neuroanatomy-cognition relationships in both groups. A sample of 59 drug-naïve individuals with first-episode schizophrenia (FES) and a sample of 115 antipsychotic-treated individuals with schizophrenia were finally included. Multivariate modeling was conducted in the two patient samples between multiple cognitive domains and neuroanatomic features, such as cortical thickness (CT), cortical surface area (CSA), and subcortical volume (SV). We observed distinct multivariate correlational patterns between the two samples of individuals with schizophrenia. In the FES sample, better performance in token motor, symbol coding, and verbal fluency tests was associated with greater thalamic volumes but lower CT in the prefrontal and anterior cingulate cortices. Two significant multivariate correlations were identified in antipsychotic-treated individuals: 1) worse verbal memory performance was related to smaller volumes for the most subcortical structures and smaller CSA mainly in the temporal regions and inferior parietal lobule; 2) a lower symbol coding test score was correlated with smaller CSA in the right parahippocampal gyrus but greater volume in the right caudate. These multivariate patterns were sample-specific and not confounded by imaging quality, illness duration, antipsychotic dose, or psychopathological symptoms. Our findings may help to understand the neurobiological basis of cognitive impairments and the development of cognition-targeted interventions.

Abstract In contemporary manufacturing, the processing of structural materials plays a pivotal role in enabling the creation of robust, tailor-made, and precise components suitable for diverse industrial applications. Nonetheless, current material forming technologies face challenges due to internal stress and defects, resulting in a substantial decline in both mechanical properties and processing precision. We herein develop a processing strategy toward graphene superstructure with a curvature gradient, which allows us to fabricate robust structural materials with meticulously designed functional shapes. The structure consists of an arc-shaped assembly of graphene nanosheets positioned at co-axial curvature centers. During the dehydration-based evaporate-casting process, the assembly is tightened via capillary effect, inducing local bending. By precisely tuning the axis-center distance and tilt angle, we achieve accurate control over the shape of obtained structure. Notably, internal stress is harnessed to reinforce a designed mortise and tenon structure, resulting in a high joining strength of up to ~200 MPa. This innovative approach addresses the challenges faced by current material forming technologies and opens up more possibilities for the manufacturing of robust and precisely shaped components.

Abstract Although the chloroplast genome (cpDNA) of higher plants is known to exist as a large protein-DNA complex called ‘plastid nucleoid’, researches on its DNA state and regulatory elements are limited. In this study, we performed the assay for transposase-accessible chromatin sequencing (ATAC-seq) on five common tissues across five grasses, and found that the accessibility of different regions in cpDNA varied widely, with the transcribed regions being highly accessible and accessibility patterns around gene start and end sites varying depending on the level of gene expression. Further analysis identified a total of 3970 putative protein binding footprints on cpDNAs of five grasses. These footprints were enriched in intergenic regions and co-localized with known functional elements. Footprints and their flanking accessibility varied dynamically among tissues. Cross-species analysis showed that footprints in coding regions tended to overlap non-degenerate sites and contain a high proportion of highly conserved sites, indicating that they are subject to evolutionary constraints. Taken together, our results suggest that the accessibility of cpDNA has biological implications and provide new insights into the transcriptional regulation of chloroplasts.

Abstract To determine the dietary structure and its associated factors of tuberculosis (TB) patients in the community. This cross-sectional study analysed the dietary intake of 300 TB patients in two impoverished counties in China. Food intake was collected by using food frequency and two consecutive 24-h dietary review (24hdr) methods. The dietary composition and dietary structure of TB patients were compared with China’s 2022 Dietary Reference Intake (DRIs) and the average reference value of dietary composition (ARC) in China in 2013. Binary logistic regression models were used to explore the factors associated with inadequate intake of animal food, insufficient protein and fat energy supply in patients with TB. The daily intake of various foods in TB patients was measured and the results were as follows: staple foods—median 372.12 g (interquartile range [IQR] 315.87 g); vegetables—median 200.00 g (IQR 205.55 g); fruits—median 20.22 g (IQR 36.82 g); animal foods—median 100.82 g (IQR 180.74 g); dairy products—median 0.00 g (IQR 0.00 g); nuts—median 17.10 g (IQR 29.75 g). The average daily intakes of vegetables, fruits, animal food, dairy products, soy and nuts were lower than those recommended by the DRIs (P

Abstract This study aimed to investigate the impact of tactical formations on the physical and technical performance of professional football players in the Chinese Super League (CSL). A sample of 800 games from the 2015–2021 CSL was analyzed, and players' physical (total distance covered, distance covered while ball in play, number of sprints, sprint distance, and high/middle/low-speed running) and technical (gain/loss of possession, ball retention percentage, challenges, challenge success percentage, passes, and pass success percentage) performance was assessed across six team formations: 3-5-2 (n = 137), 4-3-3 (n = 77), 4-2-3-1 (n = 391), 4-4-2 (n = 257), 3-4-3 (n = 41), and 4-1-4-1 (n = 107). Linear mixed models were used to assess variations in performance indicators across positions and formations. The results demonstrated that central defenders traveled significantly more total and low-speed running distances in the 3-5-2 formation than in the 4-2-3-1 formation (ES range: 0.33–0.34, p

Abstract Circular RNAs (circRNAs) are linked to cancer, but it's still not clear what role they play in prostatic cancer. Through high-throughput sequencing, the goal of this study was to compare how circRNAs are expressed at different stages of prostate cancer. 12 patients attending the Department of Urology at the Second Affiliated Hospital of Nanchang University between June 2020 and October 2021 were used for RNA sequencing, and 14 patients were used for real-time fluorescent quantitative PCR (qRT-PCR). The expression profiles of prostate cancer circRNAs were constructed by sequencing with the help of next-generation high-throughput sequencing technology, and the differentially expressed circRNAs were analyzed by targeting microRNA (miRNA) loci and Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of the genes from which circRNAs originated. Finally, the expression of target circRNAs in two prostate tissues was verified by qRT-PCR. Following high-throughput sequencing, 13,047 circRNAs were identified, and 605 circRNAs with significant differential expression were identified, of which 361 circRNAs were up-regulated, and 244 circRNAs were down-regulated. Analysis of circRNA-originated genes using GO and the KEGG enrichment analysis showed that circRNA host genes can regulate and influence multiple signaling pathways in prostate cancer with important biological functions. And the circRNA–miRNA network was constructed. The highest number of differentially expressed circRNA-binding miRNAs were: hsa_circ_000 7582 (52), hsa_circ_000 6198 (37), hsa_circ_000 6759 (28), hsa_circ_000 5675 (25), and hsa_circ_000 2172 (22). Moreover, we further screened out the circRNA (hsa_circ_0005692) that was significantly differentially expressed and common to all groups and verified by qRT-PCR that the expression of the target circRNA (hsa_circ_0005692) was significantly downregulated in prostate cancer compared with benign prostatic hyperplasia (BPH) tissues.

Abstract Sarcopenia is a disease characterized by decreased muscle mass and strength, affecting 20–70% of patients with cirrhosis, and is associated with poor prognosis, complications, and high mortality. At present, the epidemiological investigation of sarcopenia in patients with liver cirrhosis is relatively limited, and because of the differences in population characteristics, regions, diagnostic criteria and diagnostic tools, the prevalence of sarcopenia in various studies varies greatly. The definition of sarcopenia in this study adopted the criteria of the Asian Working Group on Sarcopenia (AWGS 2019), including muscle mass and muscle strength / physical performance. A total of 271 patients with liver cirrhosis were included in this cross-sectional study to explore the influencing factors of sarcopenia in patients with liver cirrhosis. The prevalence of sarcopenia was 27.7%, 27.3% in male and 28.4% in female. The results of binary logistic regression analysis showed that age, physical activity, BMI, mid-upper arm muscle circumference, hepatic encephalopathy, nutritional status, alkaline phosphatase, albumin and total cholesterol were significantly correlated with the occurrence of sarcopenia in patients with liver cirrhosis. After adjusting for the potential influencing factors, it was found that the correlation between age and sarcopenia was weakened (OR = 0.870, 95% CI 0.338–2.239). The current findings show that sarcopenia is common in patients with cirrhosis and is independently associated with age, physical activity, BMI, nutritional status, and albumin, and serum alkaline phosphatase and total cholesterol are associated with the development of sarcopenia. Regular exercise may help maintain the grip strength of patients with cirrhosis and delay the deterioration of liver function.

Abstract Improving regeneration of damaged thymus is important for reconstituting T-cell immunity. Interleukin-22 (IL-22) was proved to improve thymus regeneration through recovering thymic epithelial cells (TECs). The IL-22 receptor IL-22RA1 is crucial for mediating IL-22 functions. Mechanism that regulates IL-22RA1 expression is unknown. Through using TECs-conditional knockout mice, we found aryl hydrocarbon receptor (AHR) is important for thymus regeneration, because Foxn1-cre-mediated AHR knockout (AhrKO) significantly blocks recovery of thymus cells. Giving mice the AHR inhibitor CH-223191 or the AHR agonist FICZ blocks or accelerates thymus regeneration, respectively. AhrKO-mediated blockade of thymus regeneration could not be rescued by giving exogenous IL-22. Mechanistically, AhrKO mice shows decreased IL-22RA1 expression. In the murine TECs cell line mTEC1 cells, targeting AHR shows an impact on IL-22RA1 mRNA levels. Using chromatin immunoprecipitation and luciferase reporter assays, we find AHR co-operates with STAT3, binds the promotor region of IL-22RA1 gene and transcriptionally increases IL-22RA1 expression in mTEC1 cells. Foxn1-cre-mediated IL-22RA1 knockout (Il22ra1KO) blocks thymus regeneration after irradiation. Furthermore, targeting AHR or IL-22RA1 has significant impacts on severity of murine chronic graft-versus-host disease (cGVHD), which is an autoimmune-like complication following allogeneic hematopoietic cell transplantation. Giving FICZ decreases cGVHD, whereas Il22ra1KO exacerbates cGVHD. The impacts on cGVHD are associated with thymus regeneration and T-cell immune reconstitution. In conclusion, we report an unrecognized function of TECs-expressed AHR in thymus regeneration and AHR transcriptionally regulates IL-22RA1 expression, which have implications for improving thymus regeneration and controlling cGVHD.

Abstract Magnesium ions (Mg2+) play an essential role in cellular physiology. In mitochondria, protein and ATP synthesis and various metabolic pathways are directly regulated by Mg2+. MRS2, a magnesium channel located in the inner mitochondrial membrane, mediates the influx of Mg2+ into the mitochondrial matrix and regulates Mg2+ homeostasis. Knockdown of MRS2 in human cells leads to reduced uptake of Mg2+ into mitochondria and disruption of the mitochondrial metabolism. Despite the importance of MRS2, the Mg2+ translocation and regulation mechanisms of MRS2 are still unclear. Here, using cryo-EM we report the structures of human MRS2 in the presence and absence of Mg2+ at 2.8 Å and 3.3 Å, respectively. From the homo-pentameric structures, we identify R332 and M336 as major gating residues, which are then tested using mutagenesis and two cellular divalent ion uptake assays. A network of hydrogen bonds is found connecting the gating residue R332 to the soluble domain, potentially regulating the gate. Two Mg2+-binding sites are identified in the MRS2 soluble domain, distinct from the two sites previously reported in CorA, a homolog of MRS2 in prokaryotes. Altogether, this study provides the molecular basis for understanding the Mg2+ translocation and regulatory mechanisms of MRS2.

Abstract Glutamate, the major excitatory neurotransmitter in the central nervous system, has also been found to play a role in embryonic stem (ES) cells. However, the exact mechanism and function of glutamatergic signaling in ES cells remain poorly understood. In this study, we identified a glutamatergic transmission circuit in ES cells that operates through an autocrine mechanism and regulates cell proliferation. We performed biological analyses to identify the key components involved in glutamate biosynthesis, packaging for secretion, reaction, and reuptake in ES cells, including glutaminase, vesicular glutamate transporter, glutamate N-methyl-d-aspartate (NMDA) receptor, and cell membrane excitatory amino-acid transporter (EAAT). We directly quantified the released glutamate signal using microdialysis-high performance liquid chromatography-tandem mass spectrometry (MD–HPLC–MS–MS). Pharmacological inhibition of endogenous glutamate release and the resulting tonic activation of NMDA receptors significantly affected ES cell proliferation, suggesting that ES cells establish a glutamatergic autocrine niche via releasing and responding to the transmitter for their own regulation.

Abstract DNA tiles serve as the fundamental building blocks for DNA self-assembled nanostructures such as DNA arrays, origami, and designer crystals. Introducing additional binding arms to DNA crossover tiles holds the promise of unlocking diverse nano-assemblies and potential applications. Here, we present one-, two-, and three-layer T-shaped crossover tiles, by integrating T junction with antiparallel crossover tiles. These tiles carry over the orthogonal binding directions from T junction and retain the rigidity from antiparallel crossover tiles, enabling the assembly of various 2D tessellations. To demonstrate the versatility of the design rules, we create 2-state reconfigurable nanorings from both single-stranded tiles and single-unit assemblies. Moreover, four sets of 4-state reconfiguration systems are constructed, showing effective transformations between ladders and/or rings with pore sizes spanning ~20 nm to ~168 nm. These DNA tiles enrich the design tools in nucleic acid nanotechnology, offering exciting opportunities for the creation of artificial dynamic DNA nanopores.

Abstract Transposable elements (TEs) comprise ~85% of the common wheat genome, which are highly diverse among subgenomes, possibly contribute to polyploid plasticity, but the causality is only assumed. Here, by integrating data from gene expression cap analysis and epigenome profiling via hidden Markov model in common wheat, we detect a large proportion of enhancer-like elements (ELEs) derived from TEs producing nascent noncoding transcripts, namely ELE-RNAs, which are well indicative of the regulatory activity of ELEs. Quantifying ELE-RNA transcriptome across typical developmental stages reveals that TE-initiated ELE-RNAs are mainly from RLG_famc7.3 specifically expanded in subgenome A. Acquisition of spike-specific transcription factor binding likely confers spike-specific expression of RLG_famc7.3-initiated ELE-RNAs. Knockdown of RLG_famc7.3-initiated ELE-RNAs resulted in global downregulation of spike-specific genes and abnormal spike development. These findings link TE expansion to regulatory specificity and polyploid developmental plasticity, highlighting the functional impact of TE-driven regulatory innovation on polyploid evolution.

Abstract The HIV-1 entry inhibitor temsavir prevents the viral receptor CD4 (cluster of differentiation 4) from interacting with the envelope glycoprotein (Env) and blocks its conformational changes. To do this, temsavir relies on the presence of a residue with small side chain at position 375 in Env and is unable to neutralize viral strains like CRF01_AE carrying His375. Here we investigate the mechanism of temsavir resistance and show that residue 375 is not the sole determinant of resistance. At least six additional residues within the gp120 inner domain layers, including five distant from the drug-binding pocket, contribute to resistance. A detailed structure-function analysis using engineered viruses and soluble trimer variants reveals that the molecular basis of resistance is mediated by crosstalk between His375 and the inner domain layers. Furthermore, our data confirm that temsavir can adjust its binding mode to accommodate changes in Env conformation, a property that likely contributes to its broad antiviral activity.

Abstract DddA-derived cytosine base editors (DdCBEs) greatly facilitated the basic and therapeutic research of mitochondrial DNA mutation diseases. Here we devise a saturated spacer library and successfully identify seven DddA homologs by performing high-throughput sequencing based screen. DddAs of Streptomyces sp. BK438 and Lachnospiraceae bacterium sunii NSJ-8 display high deaminase activity with a strong GC context preference, and DddA of Ruminococcus sp. AF17-6 is highly compatible to AC context. We also find that different split sites result in wide divergence on off-target activity and context preference of DdCBEs derived from these DddA homologs. Additionally, we demonstrate the orthogonality between DddA and DddIA, and successfully minimize the nuclear off-target editing by co-expressing corresponding nuclear-localized DddIA. The current study presents a comprehensive and unbiased strategy for screening and characterizing dsDNA cytidine deaminases, and expands the toolbox for mtDNA editing, providing additional insights for optimizing dsDNA base editors.

Abstract High-risk neuroblastoma (HR-NB) has a significantly lower survival rate compared to low- and intermediate-risk NB (LIR-NB) due to the lack of risk classification diagnostic models and effective therapeutic targets. The present study aims to characterize the differences between neuroblastomas with different risks through transcriptomic and metabolomic, and establish an early diagnostic model for risk classification of neuroblastoma.Plasma samples from 58 HR-NB and 38 LIR-NB patients were used for metabolomics analysis. Meanwhile, NB tissue samples from 32 HR-NB and 23 LIR-NB patients were used for transcriptomics analysis. In particular, integrative metabolomics and transcriptomic analysis was performed between HR-NB and LIR-NB. A total of 44 metabolites (P 1.5) were altered, including 12 that increased and 32 that decreased in HR-NB. A total of 1,408 mRNAs (P 1) showed significantly altered in HR-NB, of which 1,116 were upregulated and 292 were downregulated. Joint analysis of both omic data identified 4 aberrant pathways (P

Abstract Exploring optimized processes of thermodynamics at microscale is vital to exploitation of quantum advantages relevant to microscopic machines and quantum information processing. Here, we experimentally execute a reinforcement learning strategy, using a single trapped 40Ca+ ion, for engineering quantum state evolution out of thermal equilibrium. We consider a qubit system coupled to classical and quantum baths, respectively, the former of which is achieved by switching on the spontaneous emission relevant to the qubit and the latter of which is made based on a Jaynes-Cummings model involving the qubit and the vibrational degree of freedom of the ion. Our optimized operations make use of the external control on the qubit, designed by the reinforcement learning approach. In comparison to the conventional situation of free evolution subject to the same Hamiltonian of interest, our experimental implementation presents the evolution of the states with higher fidelity while with less consumption of entropy production and work, highlighting the potential of reinforcement learning in accomplishment of optimized nonequilibrium thermodynamic processes at atomic level.

Abstract The traditional surgical technique for esophageal cancer is mainly open esophagectomy. With the innovation of surgical instruments, it is necessary to re-optimize the minimally invasive surgery. Therefore, single-port thoracoscopic minimally invasive esophagectomy (SPTE) is an important direction of development. This study retrospectively analyzed 202 patients with esophageal squamous cell carcinoma undergoing SPTE. Surgical variables and postoperative complications were further evaluated. All procedures were performed using SPTE. The number of patients who received R0 resection was 201 (99.5%). The total number of resected lymph nodes during the whole operation was on average 32.01 ± 12.15, and the mean number of positive lymph nodes was 1.56 ± 2.51. In 170 cases (84.2%), intraoperative blood loss did not exceed 100 ml (ml), while 1 case had postoperative bleeding. Only 1 patient (0.5%) required reoperation after surgery. Postoperative complications included 42 cases of pneumonia (20.8%), 9 cases of anastomotic leak (4.5%), 7 cases of pleural effusion (3.8%), and 1 case (0.5%) of both pleural hemorrhage and acute gastrointestinal hemorrhagic ulcer. Besides, we also recorded the time to remove the drain tube, which averaged 9.13 ± 5.31 days. In our study, we confirmed that the application of SPTE in clinical practice is feasible, and that the postoperative complications are at a low level.

Abstract The flame of converter mouth can well reflect the change of temperature and composition of molten steel in the furnace. The flame characteristics of converter mouth collected by device can well predict the smelting process of converter. Based on the flame spectrum data set of converter mouth, this paper uses the BEADS algorithm and rough set attribute reduction algorithm optimized by genetic algorithm to extract the features of 2048-dimensional wavelength data. Through the model, eight indexes that contribute greatly to temperature and carbon content are selected, which are f-507, f-520, f-839, f-1073, f-1371, f-1528, f-1727 and f-1826. The MIC coefficients of the eight indicators with temperature and carbon content are calculated, and the MIC coefficients of the variables is small, and the selected indicators are representative. There was a significant correlation between temperature and C content. In BP neural network of temperature prediction model, it is found that the prediction accuracy of the training set is 0.99, the prediction accuracy of the test set is 0.99, the prediction accuracy of the verification set is 0.99, and the prediction accuracy of the whole set is 0.99. Through statistics, it is found that the hit rate of the temperature model in the range of ± 5 K is 88.7%, and the hit rate in the range of ± 10 K is 98.4%. and the RMSE parameter analysis shows that the average prediction error is 3.85 K. In BP neural network of carbon content prediction model, it is found that the prediction accuracy of the training set is 0.99, the prediction accuracy of the test set is 0.99, the prediction accuracy of the verification set is 0.98, and the prediction accuracy of the whole set is 0.99. Through statistics, it is found that the hit rate of the carbon contents model in the range of ± 0.05% is 94.0%, and the hit rate in the range of ± 0.10% is 98.3%, and the RMSE parameter analysis shows that the average prediction error is 0.021%. Finally, the universality of the model is verified by MIV algorithm.

Abstract A recent surge of patent applications among public hospitals in China has aroused significant research interest. A country’s healthcare innovation capacity can be measured by its number of patents. This paper explores the link between the number of patents and ten independent variables. Multicollinearity was carefully detected and removed by using the variable selection method and LASSO regression, respectively. The Poisson model and the negative binomial model were proposed to analyze the patent data. Three goodness of fit tests, the Pearson test, the deviance test, and the DHARMa non-parametric dispersion test, were conducted to investigate if the model has a good fit. After discovering four clusters by conducting agglomerative hierarchical clustering, these two models were replaced by the negative binomial mixed model. The likelihood ratio test was used to determine which model is more appropriate and the results reveal that the negative binomial mixed model outperforms both the Poisson model and the negative binomial model. Three variables, number of health technicians per 10,000 people, financial expenditure on science and technology as well as number of patent applications per 10,000 health personnel, have a significantly positive relationship with the number of patents in Chinese tertiary public hospitals.

Abstract Immune-based checkpoint therapy has made significant progress in cancer treatment, but its therapeutic effect is limited. A replication-defective adenovirus (Ad) vaccine encoding tumor antigen carbonic anhydrase IX (CAIX) combined with Ad-encoding immune checkpoint PD-L1 was developed to treat renal carcinoma. Three tumor models, subcutaneous, lung metastasis and orthotopic tumor were established, and Ad vaccines were used to immunize them and evaluate the vaccine’s therapeutic effect. Compared to the single Ad vaccine group, the subcutaneous tumor growth was significantly reduced in Ad-CAIX/Ad-PD-L1 combination group. Co-immunization of Ad-CAIX/Ad-PD-L1 enhanced the induction and maturation of CD11c+ or CD8+CD11c+ DCs in the spleen and tumor and promoted the strong tumor-specific CD8+ T cell immune responses. In vivo CD8 T cell deletion assay showed that the anti-tumor effect of the Ad-CAIX/Ad-PD-L1 vaccine was mainly dependent on functional CD8+ T cell immune responses. Furthermore, the Ad-CAIX/Ad-PD-L1 vaccine effectively inhibited tumor growth and lung metastasis in metastatic or orthotopic models. These results indicate that the combination strategy of the immune checkpoint vaccine shows promising potential as an approach for malignant tumor therapy.

Abstract The growth in world population, climate change, and resource scarcity necessitate a sustainable increase in crop productivity. Photosynthesis in major crops is limited by the inefficiency of the key CO2-fixing enzyme Rubisco, owing to its low carboxylation rate and poor ability to discriminate between CO2 and O2. In cyanobacteria and proteobacteria, carboxysomes function as the central CO2-fixing organelles that elevate CO2 levels around encapsulated Rubisco to enhance carboxylation. There is growing interest in engineering carboxysomes into crop chloroplasts as a potential route for improving photosynthesis and crop yields. Here, we generate morphologically correct carboxysomes in tobacco chloroplasts by transforming nine carboxysome genetic components derived from a proteobacterium. The chloroplast-expressed carboxysomes display a structural and functional integrity comparable to native carboxysomes and support autotrophic growth and photosynthesis of the transplastomic plants at elevated CO2. Our study provides proof-of-concept for a route to engineering fully functional CO2-fixing modules and entire CO2-concentrating mechanisms into chloroplasts to improve crop photosynthesis and productivity.

Abstract Solution growth of single-crystal ferroelectric oxide films has long been pursued for the low-cost development of high-performance electronic and optoelectronic devices. However, the established principles of vapor-phase epitaxy cannot be directly applied to solution epitaxy, as the interactions between the substrates and the grown materials in solution are quite different. Here, we report the successful epitaxy of single-domain ferroelectric oxide films on Nb-doped SrTiO3 single-crystal substrates by solution reaction at a low temperature of ~200 oC. The epitaxy is mainly driven by an electronic polarization screening effect at the interface between the substrates and the as-grown ferroelectric oxide films, which is realized by the electrons from the doped substrates. Atomic-level characterization reveals a nontrivial polarization gradient throughout the films in a long range up to ~500 nm because of a possible structural transition from the monoclinic phase to the tetragonal phase. This polarization gradient generates an extremely high photovoltaic short-circuit current density of ~2.153 mA/cm2 and open-circuit voltage of ~1.15 V under 375 nm light illumination with power intensity of 500 mW/cm2, corresponding to the highest photoresponsivity of ~4.306×10−3 A/W among all known ferroelectrics. Our results establish a general low-temperature solution route to produce single-crystal gradient films of ferroelectric oxides and thus open the avenue for their broad applications in self-powered photo-detectors, photovoltaic and optoelectronic devices.

Abstract Chrysanthemum (Chrysanthemum morifolium Ramat.) is a globally important ornamental plant with great economic, cultural, and symbolic value. However, research on chrysanthemum is challenging due to its complex genetic background. Here, we report a near-complete assembly and annotation for C. morifolium comprising 27 pseudochromosomes (8.15 Gb; scaffold N50 of 303.69 Mb). Comparative and evolutionary analyses reveal a whole-genome triplication (WGT) event shared by Chrysanthemum species approximately 6 million years ago (Mya) and the possible lineage-specific polyploidization of C. morifolium approximately 3 Mya. Multilevel evidence suggests that C. morifolium is likely a segmental allopolyploid. Furthermore, a combination of genomics and transcriptomics approaches demonstrate the C. morifolium genome can be used to identify genes underlying key ornamental traits. Phylogenetic analysis of CmCCD4a traces the flower colour breeding history of cultivated chrysanthemum. Genomic resources generated from this study could help to accelerate chrysanthemum genetic improvement.

Usual methods for optical encryption suffer from a tradeoff between the level of security and the complexity of operation given by multiple optical measurements or digital postprocessing. Here, the authors show a multi-d.o.f. metasurface-based vector optical manipulation protocol enabling secure decryption in real time.

Long non-coding RNA AABR07053481 is shown to inhibit hypoxia-induced apoptosis of bone marrow mesenchymal stem cells in rats by regulating the miR-664-2-5p/Notch1 pathway, promote the repair efficacy of BMSCs on early steroid-induced avascular necrosis of the femoral head.

Abstract Micro-nano biorobots based on bacteria have demonstrated great potential for tumor diagnosis and treatment. The bacterial gene expression and drug release should be spatiotemporally controlled to avoid drug release in healthy tissues and undesired toxicity. Herein, we describe an alternating magnetic field-manipulated tumor-homing bacteria developed by genetically modifying engineered Escherichia coli with Fe3O4@lipid nanocomposites. After accumulating in orthotopic colon tumors in female mice, the paramagnetic Fe3O4 nanoparticles enable the engineered bacteria to receive and convert magnetic signals into heat, thereby initiating expression of lysis proteins under the control of a heat-sensitive promoter. The engineered bacteria then lyse, releasing its anti-CD47 nanobody cargo, that is pre-expressed and within the bacteria. The robust immunogenicity of bacterial lysate cooperates with anti-CD47 nanobody to activate both innate and adaptive immune responses, generating robust antitumor effects against not only orthotopic colon tumors but also distal tumors in female mice. The magnetically engineered bacteria also enable the constant magnetic field-controlled motion for enhanced tumor targeting and increased therapeutic efficacy. Thus, the gene expression and drug release behavior of tumor-homing bacteria can be spatiotemporally manipulated in vivo by a magnetic field, achieving tumor-specific CD47 blockage and precision tumor immunotherapy.

Abstract In view of the alarming increase in the burden of diabetes mellitus (DM) today, a rising number of patients with diabetic kidney disease (DKD) is forecasted. Current DKD predictive models often lack reliable biomarkers and perform poorly. In this regard, serum myoglobin (Mb) identified by machine learning (ML) may become a potential DKD indicator. We aimed to elucidate the significance of serum Mb in the pathogenesis of DKD. Electronic health record data from a total of 728 hospitalized patients with DM (286 DKD vs. 442 non-DKD) were used. We developed DKD ML models incorporating serum Mb and metabolic syndrome (MetS) components (insulin resistance and β-cell function, glucose, lipid) while using SHapley Additive exPlanation (SHAP) to interpret features. Restricted cubic spline (RCS) models were applied to evaluate the relationship between serum Mb and DKD. Serum Mb-mediated renal function impairment induced by MetS components was verified by causal mediation effect analysis. The area under the receiver operating characteristic curve of the DKD machine learning models incorporating serum Mb and MetS components reached 0.85. Feature importance analysis and SHAP showed that serum Mb and MetS components were important features. Further RCS models of DKD showed that the odds ratio was greater than 1 when serum Mb was > 80. Serum Mb showed a significant indirect effect in renal function impairment when using MetS components such as HOMA-IR, HGI and HDL-C/TC as a reason. Moderately elevated serum Mb is associated with the risk of DKD. Serum Mb may mediate MetS component-caused renal function impairment.

Minimizing toxicity of herpes simplex virus 1 (HSV) based tools for anterograde tracing is important for functional studies. Here the authors generate an anterograde monosynaptic tracer system based on HSV amplicon, which shows fast tracing, bright labeling, low toxicity, input-defined postsynaptic neurons’ anterograde monosynaptic tracing feature, and has potential for functional mapping.

Abstract Oxidative stress had been linked to hypertensive renal impairment in previous investigations. Superoxide dismutase (SOD) was a clinically available oxidative stress biomarker. The association between SOD and the microalbuminuria in hypertensive patients has not been established. From January 2017 to December 2018, data on 690 patients with essential hypertension were collected retrospectively at Shandong Provincial Qianfoshan Hospital. Patients were divided into hypertension with microalbuminuria group (HM) and hypertension without microalbuminuria group (NHM). Clinical data from patients were collected and compared between the two groups. Spearman correlation analysis was used to analyze the correlation between UACR and SOD. Univariate and multivariate logistic regression analyses were used to screen for the risk factors for HM. Our research included 556 patients in the NHM group and 134 patients in the HM group. Spearman correlation analysis showed a negative correlation between SOD and UACR (P

Abstract Sorghum is a high-quality raw material for brewing white wine, and the starch content in seeds has a large impact on brewing quality. Transcriptomic data obtained from a glutinous variety (Liaonian3) and a non-glutinous variety (Liaoza10) at 3, 18, and 30 days after pollination were analyzed to identify genes associated with starch accumulation. The amylopectin content was significantly higher in Liaonian3 compared to Liaoza10, but the amylose content and total starch content were lower. There were 6634 differentially expressed genes found in Liaoza10 between 3 and 18 d after pollination, and 779 differentially expressed genes between 18 and 30 d after pollination. In Liaonian3, there were 6768 differentially expressed genes between 3 and 18 d after pollination, and 7630 differentially expressed genes between 18 and 30 d after pollination. Genes were grouped by expression profiles over the three time points and the profiles were analyzed for enrichment of gene ontology terms and biochemical pathways. Profile 1 (decreasing expression from 3 to 30 d) for Liaoza10 was enriched in ribosomes, metabolic pathways, and carbon metabolic pathways. Profile 0 (decreasing expression from 3 to 18 d and consistent expression from 18 to 30 d) was enriched in pathways related to sugar or starch metabolism. Although the starch accumulation rate in Liaonian3 and Liaoza10 showed a profile of increasing and then decreasing, the expression of genes related to starch synthesis gradually decreased with time since pollination, demonstrating the complexity of starch synthesis. According to orthologous gene alignment and expression analysis, 19 genes such as entrzID_8068390 and entrzID_8066807 were found to be the key genes for starch synthesis and glutinous and non-glutinous differentiation in sorghum grains.

From modern seasonal to the deep time, global data show that continental hydrology has a direct and consistent effect on river and marine Li isotope compositions, highlighting a crucial role of climate on Earth’s weathering and the carbon cycle.

Glass-to-glass transitions can help understanding the glass nature, but it remains difficult to tune metallic glasses into significantly different glass states. Here the authors demonstrate the high-entropy effects in glass-to-glass transitions of high-entropy metallic glasses.

Artificial systems to control the transport of molecules across biomembranes can be useful for biosensing or drug delivery. Here, the authors assemble a DNA channel enabling the precisely timed, stimulus-controlled transport of functional proteins across bilayer membranes.