Diversified Synthesis of Chiral Fluorinated Cyclobutane Derivatives Enabled by Regio- and Enantioselective Hydroboration.

The  diversified synthesis of chiral fluorinated cyclobutane derivatives has remained a tough task in synthetic chemistry. Herein, we present a switchable paradigm for asymmetric hydroboration and formal hydrodefluorination of gem-difluorinated cyclobutenes via rhodium catalysis, providing chiral gem-difluorinated α-boryl cyclobutanes and monofluorinated cyclobutenes with excellent regio- and enantioselectivity, respevtively. The key to the success of the two transformations relies on an efficient, mild and highly selective rhodium-catalyzed asymmetric hydroboration with HBPin (pinacolborane), in which the subsequent addition of a base, and a catalytic amount of palladium if necessary, results in the formation of formal hydrodefluorination products with the four-membered ring retained. The obtained chiral gem-difluorinated α-boryl cyclobutanes are versatile building blocks, which provides a platform for the synthesis of enantioenriched fluorinated cyclobutane derivatives to a great diversity.

Development and validation of a liquid chromatography tandem mass spectrometry method for the determination of 10 mycotoxins in beer of the Chinese market and exposure estimate.

Mycotoxins are important risk factors in beer. In this study, a liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed to determine 10 mycotoxins in beer within 6 min. The method is fast, efficient, and has a simple and quick sample preparation. Validation was conducted based on the performance standards specified in Commission Decision 657/2002/EC, and the results demonstrated excellent linearity (R2 > 0.99), repeatability (RSD < 5 %), quantification limits (0.005-20.246 µg/L), and recovery rates (77 %-118 %). The prevalence of the 10 mycotoxins in 96 beers purchased from the Chinese market was analyzed, and the exposure of the Chinese population to mycotoxins through beer consumption was assessed. Deoxynivalenol (DON) was detected in 93.75 % of the beers, and the incidence of fumonisins (FBs) and zearalenone (ZEN) exceeded 50 %. Beer intake contributed significantly to the exposure of aflatoxins (AFs) and DON, especially in males. Correlation analysis between mycotoxin content in beer, raw materials, and the brewing process revealed that the brewing process significantly affected the content of DON (P < 0.001), while auxiliary materials also had a significant impact on the content of FBs and DON (P < 0.001). This study holds great significance in producing higher quality and safer beer.

Association between abnormal lipid metabolism and Alzheimer's disease: New research has revealed significant findings on the APOE4 genotype in microglia.

APOE4 is widely recognized as a genetic risk factor for Alzheimer's disease (AD), implicated in 60-80% of all AD cases. Recent research suggests that microglia carrying the APOE4 genotype display abnormal lipid metabolism and accumulate lipid droplets, which may exacerbate the pathology of AD. Microglia play a critical role in immune surveillance within the central nervous system and are responsible for removing harmful particles and preserving neuronal function. The APOE4 genotype causes abnormal lipid metabolism in microglia, resulting in excessive accumulation of lipid droplets. This accumulation not only impairs the phagocytic and clearance capabilities of microglia but also disrupts their interactions with neurons, resulting in disorganization and neurodegenerative alterations at the neuronal network level. In addition, the presence of APOE4 modifies the metabolic landscape of microglia, particularly affecting purinergic signaling and lipid metabolism, thereby exacerbating the pathological processes of AD. In conclusion, the accumulation of lipid droplets and abnormal lipid metabolism may be critical mechanisms in the progression of AD in microglia carrying the APOE4 genotype.

Comprehensive assessment and treatment strategies for dysphagia in the elderly population: Current status and prospects.

As the population ages, the prevalence of dysphagia among older adults is a growing concern. Age-related declines in physiological function, coupled with neurological disorders and structural changes in the pharynx associated with aging, can result in weakened tongue propulsion, a prolonged reaction time of the submental muscles, delayed closure of the laryngeal vestibule, and delayed opening of the upper esophageal sphincter (UES), increasing the risk of dysphagia. Dysphagia impacts the physical health of the elderly, leading to serious complications such as dehydration, aspiration pneumonia, malnutrition, and even life-threatening conditions, and it also detrimentally affects their psychological and social well-being. There is a significant correlation between frailty, sarcopenia, and dysphagia in the elderly population. Therefore, older adults should be screened for dysphagia to identify both frailty and sarcopenia. A reasonable diagnostic approach for dysphagia involves screening, clinical assessment, and instrumental diagnosis. In terms of treatment, multidisciplinary collaboration, rehabilitation training, and the utilization of new technologies are essential. Future research will continue to concentrate on these areas to enhance the diagnosis and treatment of dysphagia, with the ultimate aim of enhancing the quality of life of the elderly population.

Regional Inequality and Associated Factors of Emergency Medicine Beds Distribution in China.

Objective: The regional inequality of emergency medicine beds distribution has a great impact on population health as well as the accessibility of emergency services. This study aimed to explore the regional inequality of emergency medicine bed distribution and its influencing factors. Methods: The Gini coefficient and health resource agglomeration were used to analyze the regional inequality of emergency medicine beds distribution by area from 2012 to 2021 in China. Grey correlation models were used to explore the factors influencing the regional inequality of emergency medicine beds distribution. Results: From 2012 to 2021, Gini coefficients of emergency medicine beds distribution by geographic in China showed a worsening trend, rising from 0.6229 to 0.6636. The average HRAD index was 3.43 in the east and 0.44 in the west. Population structure factors have the greatest influence on the regional inequality of emergency medicine beds distribution. Conclusion: Health resources allocation strategy only according to population size should be changed. In formulating policies for emergency medicine beds allocation should take into account population structure, financial structure of expenditure, the inequality of geographical distribution and so on.

Drug repurposing for cancer therapy.

Cancer, a complex and multifactorial disease, presents a significant challenge to global health. Despite significant advances in surgical, radiotherapeutic and immunological approaches, which have improved cancer treatment outcomes, drug therapy continues to serve as a key therapeutic strategy. However, the clinical efficacy of drug therapy is often constrained by drug resistance and severe toxic side effects, and thus there remains a critical need to develop novel cancer therapeutics. One promising strategy that has received widespread attention in recent years is drug repurposing: the identification of new applications for existing, clinically approved drugs. Drug repurposing possesses several inherent advantages in the context of cancer treatment since repurposed drugs are typically cost-effective, proven to be safe, and can significantly expedite the drug development process due to their already established safety profiles. In light of this, the present review offers a comprehensive overview of the various methods employed in drug repurposing, specifically focusing on the repurposing of drugs to treat cancer. We describe the antitumor properties of candidate drugs, and discuss in detail how they target both the hallmarks of cancer in tumor cells and the surrounding tumor microenvironment. In addition, we examine the innovative strategy of integrating drug repurposing with nanotechnology to enhance topical drug delivery. We also emphasize the critical role that repurposed drugs can play when used as part of a combination therapy regimen. To conclude, we outline the challenges associated with repurposing drugs and consider the future prospects of these repurposed drugs transitioning into clinical application.

Heterogeneous sampled subgraph neural networks with knowledge distillation to enhance double-blind compound-protein interaction prediction.

Identifying binding compounds against a target protein is crucial for large-scale virtual screening in drug development. Recently, network-based methods have been developed for compound-protein interaction (CPI) prediction. However, they are difficult to be applied to unseen (i.e., never-seen-before) proteins and compounds. In this study, we propose SgCPI to incorporate local known interacting networks to predict CPI interactions. SgCPI randomly samples the local CPI network of the query compound-protein pair as a subgraph and applies a heterogeneous graph neural network (HGNN) to embed the active/inactive message of the subgraph. For unseen compounds and proteins, SgCPI-KD takes SgCPI as the teacher model to distillate its knowledge by estimating the potential neighbors. Experimental results indicate: (1) the sampled subgraphs of the CPI network introduce efficient knowledge for unseen molecular prediction with the HGNNs, and (2) the knowledge distillation strategy is beneficial to the double-blind interaction prediction by estimating molecular neighbors and distilling knowledge.

High-Valent Copper Catalysis Enables Regioselective Fluoroarylation of Gem-Difluorinated Cyclopropanes.

Transition-metal (TM) catalyzed reaction of gem-difluorinated cyclopropanes (gem-DFCPs) has drawn much attention recently. The reaction generally occurs via the activation of the distal C─C bond in gem-DFCPs by a low-valent TM through oxidative addition, eventually producing mono-fluoro olefins as the coupling products. However, achieving regioselective activation of the proximal C─C bond in gem-DFCPs that overcomes the intrinsic reactivity via TM catalysis remains elusive. Here, a new reaction mode of gem-DFCPs enabled by high-valent copper catalysis, which allows exclusive activation of the congested proximal C─C bond is presented. The reaction that achieves fluoroarylation of gem-DFCPs uses NFSI (N-fluorobenzenesulfonimide) as electrophilic fluoro reagent and arenes as the C─H nucleophiles, enabling the synthesis of diverse CF3 -containing scaffolds. It is proposed that a high-valent copper species plays an important role in the regioselective activation of the proximal C─C bond possibly via a σ-bond metathesis.

Uncovering lupus nephritis-specific genes and the potential of TNFRSF17-targeted immunotherapy: a high-throughput sequencing study.

Introduction: Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE). This study aimed to identify LN specific-genes and potential therapeutic targets. Methods: We performed high-throughput transcriptome sequencing on peripheral blood mononuclear cells (PBMCs) from LN patients. Healthy individuals and SLE patients without LN were used as controls. To validate the sequencing results, qRT-PCR was performed for 5 upregulated and 5 downregulated genes. Furthermore, the effect of the TNFRSF17-targeting drug IBI379 on patient plasma cells and B cells was evaluated by flow cytometry. Results: Our analysis identified 1493 and 205 differential genes in the LN group compared to the control and SLE without LN groups respectively, with 70 genes common to both sets, marking them as LN-specific. These LN-specific genes were significantly enriched in the 'regulation of biological quality' GO term and the cell cycle pathway. Notably, several genes including TNFRSF17 were significantly overexpressed in the kidneys of both LN patients and NZB/W mice. TNFRSF17 levels correlated positively with urinary protein levels, and negatively with complement C3 and C4 levels in LN patients. The TNFRSF17-targeting drug IBI379 effectively induced apoptosis in patient plasma cells without significantly affecting B cells. Discussion: Our findings suggest that TNFRSF17 could serve as a potential therapeutic target for LN. Moreover, IBI379 is presented as a promising treatment option for LN.

Selectivity in Rh-catalysis with gem-difluorinated cyclopropanes.

Small-ring chemistry is a fascinating field in organic chemistry. gem-Difluorinated cyclopropanes, a unique class of cyclopropanes, have garnered significant interest due to their intrinsic high reactivity. In this context, gem-difluorinated cyclopropanes have been extensively investigated as fluoroallylic synthons in Pd-catalyzed ring-opening/cross-coupling reactions for the synthesis of monofluoroalkenes with linear or branched selectivity. In contrast, Rh-catalysis has revealed diverse selectivity in the reaction of gem-difluorinated cyclopropanes, such as regioselectivity, enantioselectivity, and chemoselectivity. This feature article aims to summarize our efforts towards developing Rh-catalyzed reactions of gem-difluorinated cyclopropanes, briefly discussing the design, selectivity, reaction mechanisms and future research prospects.

MAP3K1 regulates female reproductive tract development.

Mitogen-activated protein 3 kinase 1 (MAP3K1) has a plethora of cell type-specific functions not yet fully understood. Herein, we describe a role for MAP3K1 in female reproductive tract (FRT) development. MAP3K1 kinase domain-deficient female mice exhibited an imperforate vagina, labor failure and infertility. These defects corresponded with shunted Müllerian ducts (MDs), the embryonic precursors of FRT, that manifested as a contorted caudal vagina and abrogated vaginal-urogenital sinus fusion in neonates. The MAP3K1 kinase domain is required for optimal activation of the Jun-N-terminal kinase (JNK) and cell polarity in the MD epithelium, and for upregulation of WNT signaling in the mesenchyme surrounding the caudal MD. The MAP3K1-deficient epithelial cells and MD epithelium had reduced expression of WNT7B ligands. Correspondingly, conditioned media derived from MAP3K1-competent, but not -deficient, epithelial cells activated a TCF/Lef-luciferase reporter in fibroblasts. These observations indicate that MAP3K1 regulates MD caudal elongation and FRT development, in part through the induction of paracrine factors in the epithelium that trans-activate WNT signaling in the mesenchyme.

Rhodium-Catalyzed Enantio- and Regioselective Allylation of Indoles with gem-Difluorinated Cyclopropanes.

The use of gem-difluorinated cyclopropanes (gem-DFCPs) as fluoroallyl surrogates under transition-metal catalysis has drawn considerable attention recently but such reactions are restricted to producing achiral or racemic mono-fluoroalkenes. Herein, we report the first enantioselective allylation of indoles under rhodium catalysis with gem-DFCPs. This reaction shows exceptional branched regioselectivity towards rhodium catalysis with gem-DFCPs, which provides an efficient route to enantioenriched fluoroallylated indoles with wide substrate scope and good functional group tolerance.

Genome assemblies of 11 bamboo species highlight diversification induced by dynamic subgenome dominance.

Polyploidy (genome duplication) is a pivotal force in evolution. However, the interactions between parental genomes in a polyploid nucleus, frequently involving subgenome dominance, are poorly understood. Here we showcase analyses of a bamboo system (Poaceae: Bambusoideae) comprising a series of lineages from diploid (herbaceous) to tetraploid and hexaploid (woody), with 11 chromosome-level de novo genome assemblies and 476 transcriptome samples. We find that woody bamboo subgenomes exhibit stunning karyotype stability, with parallel subgenome dominance in the two tetraploid clades and a gradual shift of dominance in the hexaploid clade. Allopolyploidization and subgenome dominance have shaped the evolution of tree-like lignified culms, rapid growth and synchronous flowering characteristic of woody bamboos as large grasses. Our work provides insights into genome dominance in a remarkable polyploid system, including its dependence on genomic context and its ability to switch which subgenomes are dominant over evolutionary time.

A comprehensive survey on protein-ligand binding site prediction.

Protein-ligand binding site prediction is critical for protein function annotation and drug discovery. Biological experiments are time-consuming and require significant equipment, materials, and labor resources. Developing accurate and efficient computational methods for protein-ligand interaction prediction is essential. Here, we summarize the key challenges associated with ligand binding site (LBS) prediction and introduce recently published methods from their input features, computational algorithms, and ligand types. Furthermore, we investigate the specificity of allosteric site identification as a particular LBS type. Finally, we discuss the prospective directions for machine learning-based LBS prediction in the near future.

The rapid proximity labeling system PhastID identifies ATP6AP1 as an unconventional GEF for Rheb.

Rheb is a small G protein that functions as the direct activator of the mechanistic target of rapamycin complex 1 (mTORC1) to coordinate signaling cascades in response to nutrients and growth factors. Despite extensive studies, the guanine nucleotide exchange factor (GEF) that directly activates Rheb remains unclear, at least in part due to the dynamic and transient nature of protein-protein interactions (PPIs) that are the hallmarks of signal transduction. Here, we report the development of a rapid and robust proximity labeling system named Pyrococcus horikoshii biotin protein ligase (PhBPL)-assisted biotin identification (PhastID) and detail the insulin-stimulated changes in Rheb-proximity protein networks that were identified using PhastID. In particular, we found that the lysosomal V-ATPase subunit ATP6AP1 could dynamically interact with Rheb. ATP6AP1 could directly bind to Rheb through its last 12 amino acids and utilizes a tri-aspartate motif in its highly conserved C-tail to enhance Rheb GTP loading. In fact, targeting the ATP6AP1 C-tail could block Rheb activation and inhibit cancer cell proliferation and migration. Our findings highlight the versatility of PhastID in mapping transient PPIs in live cells, reveal ATP6AP1's role as an unconventional GEF for Rheb, and underscore the importance of ATP6AP1 in integrating mTORC1 activation signals through Rheb, filling in the missing link in Rheb/mTORC1 activation.

Silencing PinX1 enhances radiosensitivity and antitumor-immunity of radiotherapy in non-small cell lung cancer.

BACKGROUND: We aimed to investigate the effects of PinX1 on non-small cell lung cancer(NSCLC) radiosensitivity and radiotherapy-associated tumor immune microenvironment and its mechanisms. METHODS: The effect of PinX1 silencing on radiosensitivity in NSCLC was assessed by colony formation and CCK8 assay, immunofluorescence detection of γ- H2AX and micronucleus assay. Western blot was used to assess the effect of PinX1 silencing on DNA damage repair pathway and cGAS-STING pathway. The nude mouse and Lewis lung cancer mouse model were used to assess the combined efficacy of PinX1 silencing and radiotherapy in vivo. Changes in the tumor immune microenvironment were assessed by flow cytometry for different treatment modalities in the Lewis luuse model. The interaction protein RBM10 was screened by immunoprecipitation-mass spectrometry. RESULTS: Silencing PinX1 enhanced radiosensitivity and activation of the cGAS-STING pathway while attenuating the DNA damage repair pathway. Silencing PinX1 further increases radiotherapy-stimulated CD8+ T cell infiltration and activation, enhances tumor control and improves survival in vivo; Moreover, PinX1 downregulation improves the anti-tumor efficacy of radioimmunotherapy, increases radioimmune-stimulated CD8+ T cell infiltration, and reprograms M2-type macrophages into M1-type macrophages in tumor tissues. The interaction of PinX1 and RBM10 may promote telomere maintenance by assisting telomerase localization to telomeres, thereby inhibiting the immunostimulatory effects of IR. CONCLUSIONS: In NSCLC, silencing PinX1 significantly contributed to the radiosensitivity and promoted the efficacy of radioimmunotherapy. Mechanistically, PinX1 may regulate the transport of telomerase to telomeres through interacting with RBM10, which promotes telomere maintenance and DNA stabilization. Our findings reveal that PinX1 is a potential target to enhance the efficacy of radioimmunotherapy in NSCLC patients.

Exploring the impact of ITGB2 on glioma progression and treatment: Insights from non-apoptotic cell death and immunotherapy.

In the realm of glioma treatment, our groundbreaking research has uncovered the pivotal role of Integrin Beta 2 (ITGB2) in non-apoptotic cell death and its profound implications for immunotherapy efficacy. Gliomas, known for their aggressive and infiltrative nature, demand innovative therapeutic strategies for improved patient outcomes. Our study bridges a critical gap by examining the interplay between non-apoptotic cell death and immunotherapy response in gliomas. Through comprehensive analysis of ten diverse glioma datasets, we developed a unique death enrichment score and identified ITGB2 as a significant risk marker. This study demonstrates that ITGB2 can predict immune activity, mutation characteristics, and drug response in glioma patients. We reveal that ITGB2 not only mediates glioma proliferation and migration but also crucially influences immunotherapy responses by modulating the interaction between gliomas and macrophages by single-cell sequencing analysis (iTalk and ICELLNET). Employing a variety of molecular and cellular methodologies, including in vitro models, our findings highlight ITGB2 as a potent marker in glioma biology, particularly impacting macrophage migration and polarization. We present compelling evidence of ITGB2's dual role in regulating tumor cell behavior and shaping the immune landscape, thereby influencing therapeutic outcomes. The study underlines the potential of ITGB2-targeted strategies in enhancing the efficacy of immunotherapy and opens new avenues for personalized treatment approaches in glioma management. In conclusion, this research marks a significant stride in understanding glioma pathology and therapy, positioning ITGB2 as a key biomarker and a promising target in the quest for effective glioma treatments.

Genetic Ablation of STE20-Type Kinase MST4 Does Not Alleviate Diet-Induced MASLD Susceptibility in Mice.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its advanced subtype, metabolic dysfunction-associated steatohepatitis (MASH), have emerged as the most common chronic liver disease worldwide, yet there is no targeted pharmacotherapy presently available. This study aimed to investigate the possible in vivo function of STE20-type protein kinase MST4, which was earlier implicated in the regulation of hepatocellular lipotoxic milieu in vitro, in the control of the diet-induced impairment of systemic glucose and insulin homeostasis as well as MASLD susceptibility. Whole-body and liver-specific Mst4 knockout mice were generated by crossbreeding conditional Mst4fl/fl mice with mice expressing Cre recombinase under the Sox2 or Alb promoters, respectively. To replicate the environment in high-risk subjects, Mst4-/- mice and their wild-type littermates were fed a high-fat or a methionine-choline-deficient (MCD) diet. Different in vivo tests were conducted in obese mice to describe the whole-body metabolism. MASLD progression in the liver and lipotoxic damage to adipose tissue, kidney, and skeletal muscle were analyzed by histological and immunofluorescence analysis, biochemical assays, and protein and gene expression profiling. In parallel, intracellular fat storage and oxidative stress were assessed in primary mouse hepatocytes, where MST4 was silenced by small interfering RNA. We found that global MST4 depletion had no effect on body weight or composition, locomotor activity, whole-body glucose tolerance or insulin sensitivity in obese mice. Furthermore, we observed no alterations in lipotoxic injuries to the liver, adipose, kidney, or skeletal muscle tissue in high-fat diet-fed whole-body Mst4-/- vs. wild-type mice. Liver-specific Mst4-/- mice and wild-type littermates displayed a similar severity of MASLD when subjected to an MCD diet, as evidenced by equal levels of steatosis, inflammation, hepatic stellate cell activation, fibrosis, oxidative/ER stress, and apoptosis in the liver. In contrast, the in vitro silencing of MST4 effectively protected primary mouse hepatocytes against ectopic lipid accumulation and oxidative cell injury triggered by exposure to fatty acids. In summary, these results suggest that the genetic ablation of MST4 in mice does not mitigate the initiation or progression of MASLD and has no effect on systemic glucose or insulin homeostasis in the context of nutritional stress. The functional compensation for the genetic loss of MST4 by yet undefined mechanisms may contribute to the apparent discrepancy between in vivo and in vitro phenotypic consequences of MST4 silencing.

Cell-type-specific optogenetic fMRI on basal forebrain reveals functional network basis of behavioral preference.

The basal forebrain (BF) is a complex structure that plays key roles in regulating various brain functions. However, it remains unclear how cholinergic and non-cholinergic BF neurons modulate large-scale functional networks and their relevance in intrinsic and extrinsic behaviors. With an optimized awake mouse optogenetic fMRI approach, we revealed that optogenetic stimulation of four BF neuron types evoked distinct cell-type-specific whole-brain BOLD activations, which could be attributed to BF-originated low-dimensional structural networks. Additionally, optogenetic activation of VGLUT2, ChAT, and PV neurons in the BF modulated the preference for locomotion, exploration, and grooming, respectively. Furthermore, we uncovered the functional network basis of the above BF-modulated behavioral preference through a decoding model linking the BF-modulated BOLD activation, low-dimensional structural networks, and behavioral preference. To summarize, we decoded the functional network basis of differential behavioral preferences with cell-type-specific optogenetic fMRI on the BF and provided an avenue for investigating mouse behaviors from a whole-brain view.

Assessing inter-intraspecific variability of leaf vulnerability to embolism for 10 alpine Rhododendron species growing in Southwestern China.

Alpine Rhododendron species are prominent constituents and renowned ornamental plants in alpine ecosystems. Consequently, evaluating the genetic variation in embolism resistance within the genus Rhododendron and predicting their adaptability to future climate change is important. Nevertheless, the assessment of embolism resistance in Rhododendron species remains limited. This investigation aimed to examine leaf vulnerability to embolism across ten alpine Rhododendron species, which are frequently employed as ornamental species in Rhododendron forests in Southwest China. The study analyzed the correlation between embolism resistance and various morphological traits, while also conducting water control experiments to evaluate the relationship between embolism resistance and drought resistance. The outcomes indicated pronounced variations in leaf vulnerability to embolism among species, as reflected by the water potential at 50% of embolized pixels (P50 ). Furthermore, the leaf P50 exhibited a significant positive correlation with vessel diameter (D) (R2 = 0.44, P = 0.03) and vessel wall span (b) (R2 = 0.64, P = 0.005), while displaying a significant negative correlation with vessel reinforcement ((t/b)2 ) (R2 = 0.67, P = 0.004). These findings underscore the reliability of selecting species based on embolism vulnerability to preserve the diversity of alpine ecosystems and foster resilience to climate change.