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Abstract The chromatin modifier GRAIN WEIGHT 6a (GW6a) enhances rice grain size and yield. However, little is known about its gene network determining grain size. Here, we report that MITOGEN-ACTIVED PROTEIN KINASE 6 (OsMAPK6) and E3 ligase CHANG LI GENG 1 (CLG1) interact with and target GW6a for phosphorylation and ubiquitylation, respectively. Unexpectedly, however, in vitro and in vivo assays reveal that both of the two post-translational modifications stabilize GW6a. Furthermore, we uncover two major GW6a phosphorylation sites (serine142 and threonine186) targeted by OsMAPK6 serving an important role in modulating grain size. In addition, our genetic and molecular results suggest that the OsMAPK6-GW6a and CLG1-GW6a axes are crucial and operate in a non-additive manner to control grain size. Overall, our findings identify a previously unknown mechanism by which phosphorylation and ubiquitylation non-additively stabilize GW6a to enhance grain size, and reveal correlations and interactions of these posttranslational modifications during rice grain development.

Summary: ATP-citrate lyase (ACLY) is a critical metabolic enzyme and promising target for drug development. The structure determinations of ACLY have revealed its homotetramer states with various subunit symmetries, but catalytic mechanism of ACLY tetramer and the importance of subunit symmetry have not been clarified. Here, we constructed the free energy landscape of ACLY tetramer with arbitrary subunit symmetries and investigated energetic and conformational coupling of subunits during citryl-CoA synthesis process. The optimal conformational pathway indicates that ACLY tetramer encounters three critical conformational barriers and undergoes a loss of rigid-D2 symmetry to gain an energetic advantage. Energetic coupling of conformational changes and biochemical reactions suggests that these biological events are not independent but rather coupled with each other, showing a comparable energy barrier to the experimental data for the rate-limiting step. These findings could contribute to further research on catalytic mechanism, functional modulation, and inhibitor design of ACLY.

ObjectiveThis retrospective study aims to investigate the treatment of tic disorder (TD) in Dongfang Hospital affiliated with Beijing University of Chinese Medicine, explore its underlying mechanism, and provide valuable insights for future research and clinical management of TD.MethodsThe electronic medical records of children with TD, from 2015 to 2021, were extracted from the information system of Dongfang Hospital affiliated with Beijing University of Chinese Medicine. The clinical characteristics of TD, utilization patterns of Chinese herbal medicine and synthetic drugs in prescriptions, as well as their pharmacological effects, were statistically described and categorized. In addition, association rules and network pharmacology were employed to identify core prescriptions (CPs) and elucidate their microscopic molecular mechanisms in treating TD.ResultsThe age range of the children was from 6 to 11 years, with a higher proportion of male participants than female ones. The average duration of treatment was 6 weeks. Regimen Z for the treatment of TD can be summarized as follows: Chinese herbal medicine [Saposhnikoviae Radix (FangFeng), Puerariae Lobatae Radix (GeGen), Uncariae Ramulus cum Uncis (GouTeng), Acori Tatarinowii Rhizoma (ShiChangPu), Chuanxiong Rhizoma (ChuanXiong)] and vitamins [lysine, inosite, and vitamin B12 oral solution] form the basic treatment, combined with immunomodulators, antibiotics, electrolyte-balancing agents, and antiallergic agents. CPs primarily exerted their effects through the modulation of gene expression (transcription), the immune system, and signal transduction pathways, with interleukin-4 and interleukin-13 pathways being particularly crucial. Among the lysine synthetic drugs used, inosite and vitamin B12 oral solution were the most frequently prescribed.ConclusionThe regimen Z drug treatment holds significant importance in the field, as it exerts its therapeutic effects through a multitude of pathways and intricate interventions. Chinese herbal medicine primarily regulates immune system–related pathways, while synthetic drugs predominantly consist of vitamins.

BackgroundInfluenza virus is one of the most common pathogens that cause viral pneumonia. During pneumonia, host immune inflammation regulation involves microbiota in the intestine and glycolysis in the lung tissues. In the clinical guidelines for pneumonia treatment in China, Ma Xing Shi Gan Decoction (MXSG) is a commonly prescribed traditional Chinese medicine formulation with significant efficacy, however, it remains unclear whether its specific mechanism of action is related to the regulation of intestinal microbiota structure and lung tissue glycolysis.ObjectiveThis study aimed to investigate the mechanism of action of MXSG in an animal model of influenza virus-induced pneumonia. Specifically, we aimed to elucidate how MXSG modulates intestinal microbiota structure and lung tissue glycolysis to exert its therapeutic effects on pneumonia.MethodsWe established a mouse model of influenza virus-induced pneumoni, and treated with MXSG. We observed changes in inflammatory cytokine levels and conducted 16S rRNA gene sequencing to assess the intestinal microbiota structure and function. Additionally, targeted metabolomics was performed to analyze lung tissue glycolytic metabolites, and Western blot and enzyme-linked immunosorbent assays were performed to assess glycolysis-related enzymes, lipopolysaccharides (LPSs), HIF-1a, and macrophage surface markers. Correlation analysis was conducted between the LPS and omics results to elucidate the relationship between intestinal microbiota and lung tissue glycolysis in pneumonia animals under the intervention of Ma Xing Shi Gan Decoction.ResultsMXSG reduced the abundance of Gram-negative bacteria in the intestines, such as Proteobacteria and Helicobacter, leading to reduced LPS content in the serum and lungs. This intervention also suppressed HIF-1a activity and lung tissue glycolysis metabolism, decreased the number of M1-type macrophages, and increased the number of M2-type macrophages, effectively alleviating lung damage caused by influenza virus-induced pneumonia.ConclusionMXSG can alleviate glycolysis in lung tissue, suppress M1-type macrophage activation, promote M2-type macrophage activation, and mitigate inflammation in lung tissue. This therapeutic effect appears to be mediated by modulating gut microbiota and reducing endogenous LPS production in the intestines. This study demonstrates the therapeutic effects of MXSG on pneumonia and explores its potential mechanism, thus providing data support for the use of traditional Chinese medicine in the treatment of respiratory infectious diseases.

Abstract Insulin receptor (IR) controls growth and metabolism. Insulin-like growth factor 2 (IGF2) has different binding properties on two IR isoforms, mimicking insulin’s function. However, the molecular mechanism underlying IGF2-induced IR activation remains unclear. Here, we present cryo-EM structures of full-length human long isoform IR (IR-B) in both the inactive and IGF2-bound active states, and short isoform IR (IR-A) in the IGF2-bound active state. Under saturated IGF2 concentrations, both the IR-A and IR-B adopt predominantly asymmetric conformations with two or three IGF2s bound at site-1 and site-2, which differs from that insulin saturated IR forms an exclusively T-shaped symmetric conformation. IGF2 exhibits a relatively weak binding to IR site-2 compared to insulin, making it less potent in promoting full IR activation. Cell-based experiments validated the functional importance of IGF2 binding to two distinct binding sites in optimal IR signaling and trafficking. In the inactive state, the C-terminus of α-CT of IR-B contacts FnIII-2 domain of the same protomer, hindering its threading into the C-loop of IGF2, thus reducing the association rate of IGF2 with IR-B. Collectively, our studies demonstrate the activation mechanism of IR by IGF2 and reveal the molecular basis underlying the different affinity of IGF2 to IR-A and IR-B.

Objective: To uncover the underlying mechanisms of action of the Yinlai decoction on high-calorie diet-induced pneumonia through proteomics analysis. Methods: Based on the Gene Expression Omnibus (GEO) database, lung tissue samples from normal and high-fat diet (HFD) fed mice in the GSE16377 dataset were selected as test cohorts to identify differentially expressed genes and conduct bioinformatics analyses. In the animal experiments, mice were randomly divided into the control (N), high-calorie diet pneumonia (M), and Yinlai decoction treatment (Y) groups. Mice in the M group received high-calorie feed and a 0.5 mg/mL lipopolysaccharide solution spray for 30 min for 3 d. The mice in the Y group were intragastrically administered 2 mL/10 g Yinlai decoction twice daily for 3 d. Pathological evaluation of the lung tissue was performed. Differentially expressed proteins (DEPs) in the lung tissue were identified using quantitative proteomics and bioinformatics analyses. The drug-target relationships between Yinlai decoction and core DEPs in the lung tissue were verified using AutoDock Vina and Molecular Graphics Laboratory (MGL) Tools. DEPs were verified by western blot. Results: GEO data mining showed that an HFD altered oxidative phosphorylation in mouse lung tissue. The Yinlai decoction alleviated pathological damage to lung tissue and pneumonia in mice that were fed a high-calorie diet. A total of 47 DEPs were identified between the Y and M groups. Enrichment analysis revealed their association with energy metabolism pathways such as the tricarboxylic acid cycle (TCA) and oxidative phosphorylation. The protein-protein interaction network revealed that Atp5a1, Pdha1, and Sdha were the target proteins mediating the therapeutic effects of Yinlai decoction. Molecular docking results suggested that the mechanism of the therapeutic effect of Yinlai decoction involves the binding of brassinolide, praeruptorin B, chrysoeriol, and other components in Yinlai decoction to Atp5a1. Conclusion: The Yinlai decoction alleviated lung tissue damage and pneumonia in mice that were fed a high-calorie diet by regulating the TCA and oxidative phosphorylation. Our study highlights the importance of a healthy diet for patients with pneumonia and provides a scientific basis for the prevention and treatment of pneumonia through dietary adjustments.

Abstract In this paper, we study the phase tranisions in the extended holographic thermodynamics of Born–Infeld AdS black holes. The extended gravitational thermodynamics of black holes is related to the thermodynamics of the dual field theory by varying both cosmological constant and Newton’s constant. With topological analysis and numerical calculation, we find that the reentrant large-small-large black hole phase transition still exists in $$D=4$$ D = 4 . Interestingly, a similar reentrant phase transition is also observed in the dual field theory, between the high-, low- and high-entropy thermal states. For higher dimension $$D>4$$ D > 4 , only the van der Waals like phase transition is observed, both in the bulk and the dual field theory.

BackgroundThe efficacy of Chinese herbal medicine (CHM) in managing irritable bowel syndrome with diarrhea (IBS-D) accompanied by anxiety and depression remains uncertain. Thus, a systematic review was carried out employing meta-analysis and network pharmacology to ascertain the efficacy and underlying mechanisms of CHM therapy.MethodsBy conducting a systematic review, including literature search, screening, and data extraction, we identified 25 randomized controlled trials to assess CHM’s effectiveness in treating irritable bowel syndrome alongside anxiety and depression. Network pharmacology was utilized to scrutinize the metabolite utility of CHM in addressing this condition. Potential primary mechanisms were synthesized using information sourced from the PubMed database.ResultsTwenty-five studies, including 2055 patients, were analyzed, revealing significant treatment efficacy for IBS-D in the trial group compared to controls [OR = 4.01, 95% CI (2.99, 5.36), I2 = 0%] Additionally, treatment for depression [SMD = −1.08, 95% CI (-1.30, −0.86), p < 0.00001, I2 = 68%; SDS: SMD = -1.69, 95% CI (-2.48, −0.90), p < 0.0001, I2 = 96%] and anxiety [HAMA: SMD = -1.29, 95% CI (-1.68, −0.91), p < 0.00001, I2 = 89%; SAS: SMD = -1.75, 95% CI (-2.55, −0.95), p < 0.00001, I2 = 96%] significantly improved in the trial group. Furthermore, the trial group exhibited a significantly lower disease relapse rate [OR = 0.30, 95% CI (0.20, 0.44), p < 0.00001, I2 = 0%]. CHM treatment consistently improved IBS severity (IBS-SSS) and symptom scores. Network pharmacology analysis identified key chemical metabolites in traditional Chinese medicine formulations, including Beta-sitosterol, Stigmasterol, Quercetin, Naringenin, Luteolin, Kaempferol, Nobiletin, Wogonin, Formononetin, and Isorhamnetin. Utilizing the STRING database and Cytoscape v3.9.0 software, a protein-protein interaction (PPI) network revealed the top eight key targets: IL-6, TNF, PPARG, PTGS2, ESR1, NOS3, MAPK8, and AKT1, implicated in anti-inflammatory responses, antioxidant stress modulation, and neurotransmitter homeostasis maintenance.ConclusionChinese Herbal Medicine (CHM) offers a promising and safe treatment approach for patients dealing with Diarrheal Irritable Bowel Syndrome (IBS-D) accompanied by anxiety and depression; thus, indicating its potential for practical implementation. The most active metabolites of CHM could simultaneously act on the pathological targets of IBS-D, anxiety, and depression.The diverse scope of CHM’s therapeutic role includes various aspects and objectives, underscoring its potential for broad utilization.

BackgroundThe use of Intra-aortic Balloon Pump (IABP) and Impella devices as a bridge to heart transplantation (HTx) has increased significantly in recent times. This study aimed to create and validate an explainable machine learning (ML) model that can predict the failure of status two listings and identify the clinical features that significantly impact this outcome.MethodsWe used the UNOS registry database to identify HTx candidates listed as UNOS Status 2 between 2018 and 2022 and supported with either Impella (5.0 or 5.5) or IABP. We used the eXtreme Gradient Boosting (XGBoost) algorithm to build and validate ML models. We developed two models: (1) a comprehensive model that included all patients in our cohort and (2) separate models designed for each of the 11 UNOS regions.ResultsWe analyzed data from 4,178 patients listed as Status 2. Out of them, 12% had primary outcomes indicating Status 2 failure. Our ML models were based on 19 variables from the UNOS data. The comprehensive model had an area under the curve (AUC) of 0.71 (±0.03), with a range between 0.44 (±0.08) and 0.74 (±0.01) across different regions. The models' specificity ranged from 0.75 to 0.96. The top five most important predictors were the number of inotropes, creatinine, sodium, BMI, and blood group.ConclusionUsing ML is clinically valuable for highlighting patients at risk, enabling healthcare providers to offer intensified monitoring, optimization, and care escalation selectively.

Abstract Using the high‐time‐resolution data from the Magnetospheric Multiscale mission, precursor waves upstream of foreshock transient (FT) shocks are statistically investigated using the four‐spacecraft timing method. The wave frequencies and wave vectors determined in the plasma rest frame (PRF) are shown to follow the cold plasma dispersion relation for whistler waves. Combining with the feature of the right‐hand polarization in the PRF, the precursors are identified as whistler‐mode waves around the lower hybrid frequency. The occurrence of whistler precursors is independent of the Alfvén Mach number and the FT shock normal angle. More importantly, all the whistler precursors have group velocities pointing upstream in the shock frame, suggesting the dispersive radiation to be a possible generation mechanism. The study improves the understanding of not only the whistler precursors but also the overall FT shock dynamics.

Extensive regulation of microRNAs (miRNAs) that belong to a type of endogenous small noncoding RNAs on gene expression in sheep has been recognised. Meanwhile, utilisation of water extract of Allium mongolicum Regel (WEA) in diet of sheep has been proved to regulate fatty acid composition and flavour in mutton. However, the regulatory mechanism remains unclear. We conducted miRNA and mRNA sequencing in this study. Briefly, 30 male small-tailed Han sheep (4.5 months old) were randomly assigned to two groups. A basal diet with 3.4 g·sheep−1·d−1 WEA supplementation (WEA group) or with no WEA supplementation (CON group) was fed to sheep, respectively. Subcutaneous and visceral adipose tissue samples were collected during slaughter after 75-day feeding experiment. We obtained 30 differentially expressed miRNAs (DE-miRNAs) after application of WEA in diet of sheep in subcutaneous adipose tissue. Likewise, 15 DE-miRNAs in visceral adipose tissue were identified. A total of 746 differentially expressed mRNAs (DE-mRNAs) with 90 lipid-related DE-mRNAs in subcutaneous adipose tissue and 569 DE-mRNAs with 73 lipid-related DE-mRNAs in visceral adipose tissue were identified after WEA supplementation. The intersection genes from predicted target genes of DE-miRNAs by databases and actual DE-mRNAs by mRNA sequencing were enriched in several lipid-related pathways both in subcutaneous adipose and in visceral adipose tissue. We constructed differential miRNAs-mRNAs networks by Cytoscape software. Our results will help to explain regulatory mechanism of fatty acid composition in mutton by dietary WEA and will provide a theoretical basis for rational use of the plant extract in diet of sheep.HIGHLIGHTS Utilisation of Allium mongolicum Regel water extract led to alterations of endogenous miRNA and gene expression profiles in subcutaneous and visceral adipose tissue of sheep. Allium mongolicum Regel water extract improved nutritional value and flavour of mutton by changing fatty acid composition in adipose tissue. Establishment of miRNA-mRNA regulatory network with regard to manipulation of fatty acid composition in mutton by Allium mongolicum Regel water extract, and provided a theoretical basis for rational utilisation of this plant extract in diet of sheep.

Short large-amplitude magnetic field structures (SLAMSs) are often seen upstream of quasi-parallel shocks. They play vital roles near the quasi-parallel shock, such as decelerating solar wind ions and contributing to the dissipation and reformation of the shock. The formation process of these structures has attracted great attention and has long been realized in simulation. However, their formation mechanism is still full of mysteries. Here, using magnetospheric multiscale mission (MMS) observation, we provide direct observations of the SLAMS formation and destruction processes. SLAMS growth is powered by solar wind ions and shock-reflected ions through the ion-ion non-resonant mode. Reconnection occurs between and inside SLAMSs during their growth; however, these cumulative changes in magnetic field topology and the dissipation of the magnetic field energy contribute to the destruction of the SLAMS. These observations shed new light on the dissipation and reformation of the shock both in space physics and astrophysics.

It is long observed that females tend to live longer than males in nearly every country. However, the underlying mechanism remains elusive. In this study, we discovered that genetic associations with longevity are on average stronger in females than in males through bio-demographic analyses of genome-wide association studies (GWAS) dataset of 2178 centenarians and 2299 middle-age controls of Chinese Longitudinal Healthy Longevity Study (CLHLS). This discovery is replicated across North and South regions of China, and is further confirmed by North-South discovery/replication analyses of different and independent datasets of Chinese healthy aging candidate genes with CLHLS participants who are not in CLHLS GWAS, including 2972 centenarians and 1992 middle-age controls. Our polygenic risk score analyses of eight exclusive groups of sex-specific genes, analyses of sex-specific and not-sex-specific individual genes, and Genome-wide Complex Trait Analysis using all SNPs all reconfirm that genetic associations with longevity are on average stronger in females than in males. Our discovery/replication analyses are based on genetic datasets of in total 5150 centenarians and compatible middle-age controls, which comprises the worldwide largest sample of centenarians. The present study's findings may partially explain the well-known male-female health-survival paradox and suggest that genetic variants may be associated with different reactions between males and females to the same vaccine, drug treatment and/or nutritional intervention. Thus, our findings provide evidence to steer away from traditional view that “one-size-fits-all” for clinical interventions, and to consider sex differences for improving healthcare efficiency. We suggest future investigations focusing on effects of interactions between sex-specific genetic variants and environment on longevity as well as biological function.

The central player for chromosome segregation in both mitosis and meiosis is the macromolecular kinetochore structure, which is assembled by >100 structural and regulatory proteins on centromere DNA. Kinetochores play a crucial role in cell division by connecting chromosomal DNA and microtubule polymers. This connection helps in the proper segregation and alignment of chromosomes. Additionally, kinetochores can act as a signaling hub, regulating the start of anaphase through the spindle assembly checkpoint, and controlling the movement of chromosomes during anaphase. However, the role of various kinetochore proteins in plant meiosis has only been recently elucidated, and these proteins differ in their functionality from those found in animals. In this review, our current knowledge of the functioning of plant kinetochore proteins in meiosis will be summarized. In addition, the functional similarities and differences of core kinetochore proteins in meiosis between plants and other species are discussed, and the potential applications of manipulating certain kinetochore genes in meiosis for breeding purposes are explored.

Abstract Due to the relatively brief domestication history of sugar beet (Beta vulgaris ssp. vulgaris), our understanding of the genomic diversity and functional genes in its cultivars is limited, resulting in slow breeding progress. To address this issue, a total of 306 germplasm materials of major cultivars and breeding lines from China, the USA, and Europe were selected for genome resequencing. We investigated population structure and genetic diversity and performed selective scanning of genomic regions, identifying six novel genes associated with important agronomic traits: the candidate genes DFAX2 and P5CS for skin roughness; the candidate genes FRO5, GL24, and PPR91 for root yield and sugar yield, and the pleiotropic candidate gene POLX for flourishing growth vigour, plant height, crown size, flesh coarseness, and sugar yield. In addition, we constructed a protein–protein interaction network map and a phenotype-gene network map, which provide valuable information for identifying and characterizing functional genes affecting agronomic traits in sugar beet. Overall, our study sheds light on the future improvement of sugar beet agronomic traits at the molecular level.