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Abstract Purpose To develop and validate a preoperative prediction model based on multimodal ultrasound and biochemical indicator for identifying microvascular invasion (MVI) in patients with a single hepatocellular carcinoma (HCC) ≤ 5 cm. Methods From May 2022 to November 2023, a total of 318 patients with pathologically confirmed single HCC ≤ 5 cm from three institutions were enrolled. All of them underwent preoperative biochemical, conventional ultrasound (US), and contrast-enhanced ultrasound (CEUS) (Sonazoid, 0.6 mL, bolus injection) examinations. Univariate and multivariate logistic regression analyses on clinical information, biochemical indicator, and US imaging features were performed in the training set to seek independent predictors for MVI-positive. The models were constructed and evaluated using the area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis in both validation and test sets. Subgroup analyses in patients with different liver background and tumor sizes were conducted to further investigate the model’s performance. Results Logistic regression analyses showed that obscure tumor boundary in B-mode US, intra-tumoral artery in pulsed-wave Doppler US, complete Kupffer-phase agent clearance in Sonazoid-CEUS, and biomedical indicator PIVKA-II were independently correlated with MVI-positive. The combined model comprising all predictors showed the highest AUC, which were 0.937 and 0.893 in the validation and test sets. Good calibration and prominent net benefit were achieved in both sets. No significant difference was found in subgroup analyses. Conclusions The combination of biochemical indicator, conventional US, and Sonazoid-CEUS features could help preoperative MVI prediction in patients with a single HCC ≤ 5 cm. Critical relevance statement Investigation of imaging features in conventional US, Sonazoid-CEUS, and biochemical indicators showed a significant relation with MVI-positivity in patients with a single HCC ≤ 5 cm, allowing the construction of a model for preoperative prediction of MVI status to help treatment decision making. Key Points MVI status is important for patients with a single HCC ≤ 5 cm. The model based on conventional US, Sonazoid-CEUS and PIVKA-II performs best for MVI prediction. The combined model has potential for preoperative prediction of MVI status. Graphical Abstract

Objective Due to low prevalence and few studies, the morphologic risk factors for hip osteoarthritis (HOA) in Chinese population remain unknown. The purpose of this study was to investigate the relationship between 10 radiographic parameters measured via anteroposterior pelvic X‐ray radiography and HOA in Chinese population. Methods Thirty‐three patients who required total hip arthroplasty for unilateral HOA (2017–2022) and 132 healthy individuals were selected for this case–control study. We measured 10 radiological parameters via anteroposterior pelvic X‐ray radiography, which were sharp angle, center edge angle, sourcil angle, neck shaft angle, α angle, pelvic height, pelvic width, femoral head diameter, femoral neck width, and ratio of the femoral head diameter to the femoral neck width. After measurements were obtained, logistic regression analysis was utilized to calculate the adjusted odds ratios (ORs) for confounding variables such as age, sex, and body mass index (BMI). Receiver operating characteristic (ROC) curves were utilized to determine the proportional risk contribution (PRC) of each radiographic factor. Results After adjustment for confounding factors, individuals with a larger sourcil angle (SA) (OR = 4.89, 95% CI 1.66–14.42, p = 0.004), larger α angle (OR = 4.14, 95% CI 1.53–11.23, p = 0.005), and wider femoral neck (OR = 5.27, 95% CI 1.50–18.51, p = 0.01) were found to have a greater risk of developing HOA. Among all radiographic parameters, the SA demonstrated the greatest risk contribution (PRC = 13.695%). Conclusions Radiographic parameters correlate with the incidence of HOA. The SA is probably the most powerful of all the parameters related to HOA.

Abstract Immunotherapy successfully complements traditional cancer treatment. However, primary and acquired resistance might limit efficacy. Reduced antigen presentation by MHC-I has been identified as potential resistance factor. Here we show that the epigenetic regulator ubiquitin-like with PHD and ring finger domains 1 (UHRF1), exhibits altered expression and aberrant cytosolic localization in cancerous tissues, where it promotes MHC-I ubiquitination and degradation. Cytoplasmic translocation of UHRF1 is induced by its phosphorylation on a specific serine in response to signals provided by factors present in the tumor microenvironment (TME), such as TGF-β, enabling UHRF1 to bind MHC-I. Downregulation of MHC-I results in suppression of the antigen presentation pathway to establish an immune hostile TME. UHRF1 inactivation by genetic deletion synergizes with immune checkpoint blockade (ICB) treatment and induces an anti-tumour memory response by evoking low-affinity T cells. Our study adds to the understanding of UHRF1 in cancer immune evasion and provides a potential target to synergize with immunotherapy and overcome immunotherapeutic resistance.

Abstract To investigate the effect of Tetrasphaera’s enrichment on phosphorus removal mechanism, three micro-pressure swirl reactor (MPSR) groups were used to experiment on sewage treatment under different SRT (17.2, 50.8, and 68.2 d). Results showed that Tetrasphaera enrichment in the MPSR system was promoted by extending the SRT. After extending the SRT from 17.2 to 68.2 d, the relative abundance of Tetrasphaera increased from 3.1% to 12.1%, and the TP removal efficiency maintained above 92%. The internal circulation results indicated that after extending the SRT, glycogen and polyhydroxybutyrate were co-synthesized during the anaerobic stage, which enhanced the driving force of nutrient removal. Analysis of the microbial composition and functional gene prediction indicated that efficient phosphorus removal can be attributed to the enrichment of Tetrasphaera at long SRT. Overall, the synergistic mechanisms of Tetrasphaera in the organic matter degradation and phosphorus removal processes were integrated into the MPSR.

Abstract Background Corynebacterium striatum (C. striatum), a common skin and mucosal colonizer, is increasingly considered as an opportunistic pathogen causing bloodstream infections (BSIs). This study aims to investigate the clinical features and outcomes of C. striatum-BSI. Methods We included hospitalized cases with C. striatum-positive blood cultures from January 2014 to June 2022 and classified them into C. striatum-BSI group and contamination group; Clinical characteristics, treatments, and outcomes were compared between the C. striatum-BSI group and contamination group, Methicillin-resistant Staphylococcus aureus (MRSA)-BSI and Methicillin-resistant Staphylococcus epidermidis (MRSE)-BSI. Results Fifty-three patients with positive C. striatum blood cultures were identified. Among them, 25 patients were classified as C. striatum-BSI, with 21 as contamination cases. And 62 cases of MRSA-BSI and 44 cases of MRSE-BSI were identified. Compared to the contaminated group, the C. striatum-BSI group had a shorter time to positivity of blood cultures (27.0 h vs. 42.5 h, P = 0.011). C. striatum-BSI group had a longer time to positivity (27 h) when compared to both the MRSA (20 h) and MRSE groups (19 h) (p

Abstract The dynamics of soft microparticles enclosed in a droplet flowing in a channel is an unexplored fundamental problem that lies at the heart of numerous applications, including droplet-based microfluidics, tissue engineering and smart material synthesis. Here we show that enclosing a flexible capsule into a droplet can amplify the capsule’s deformation parameters in channel flow by up to two orders of magnitude. Previously unreported capsule equilibrium shapes in channel flow, including an oblate spheroid and a reversed bullet, have also been discovered. We propose two theoretical models to predict the equilibrium position of the capsule inside the droplet, and estimate the capsule deformation, respectively. The present study provides an effective but simple approach to enhance and control the deformation of soft particles in a flowing suspension, which may inspire widespread applications, from high-throughput single-cell mechanical phenotyping, enhanced cross-membrane drug delivery, to manufacturing shape-controlled non-spherical particles and artificial cells.

Abstract Background Lymph node (LN) metastasis is a significant prognostic factor for esophageal squamous cell carcinoma (ESCC), and there are no satisfactory methods for accurately predicting metastatic LNs. The present study aimed to assess the efficacy of 99mTc‐3PRGD2 single‐photon emission computed tomography (SPECT)/computed tomography (CT) for diagnosing metastatic LNs in ESCC. Methods A total of 15 enrolled patients with ESCC underwent 99mTc‐3PRGD2 SPECT/CT and 18F‐fluorodeoxyglucose positron emission tomography‐computed tomography (18F‐FDG PET/CT) examinations preoperatively. High‐definition bone carving reconstruction technology (HD‐xSPECT Bone) was applied to quantitatively assess the LN's SUVmax via SPECT/CT. The two methods were compared for diagnosing metastatic LNs with pathology as the gold standard. Results Among 15 patients, 23 metastatic lymph node stations (mLNSs) were predicted by SPECT/CT, with a mean SUVmax of 2.71 ± 1.34, of which 15 were pathologically confirmed; 32 mLNSs were predicted by PET/CT with a mean SUVmax of 4.41 ± 4.02, of which 17 were pathologically confirmed. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value of SPECT/CT for diagnosing metastatic LNs were 62.50%, 91.30%, 85.34%, 65.22%, and 90.32%, respectively, and those of PET/CT were 70.83%, 83.70%, 81.03%, 53.13%, and 91.67%, respectively. There was no significant difference in sensitivity (p = 0.061) or specificity (p = 0.058) between the two methods. The AUCSPECT/CT was 0.816 and the SUVmax threshold was 2.5. Conclusion 99mTc‐3PRGD2 SPECT/CT might be an effective method for diagnosing metastatic LNs in ESCC, especially in combination with HD‐xSPECT Bone. The diagnostic efficiency of this method was noninferior to that of 18F‐FDG PET/CT. The SUVmax threshold of 2.5 showed the highest agreement with the pathology findings.

Abstract Background The pericoronary fat attenuation index (FAI) has emerged as a novel and sensitive biomarker reflecting the degree of coronary artery inflammation. Semaglutide has been demonstrated to exert a cardiovascular protective effect independent of hypoglycemia; however, its impact on coronary artery inflammation remains elusive. This study aimed to investigate the association between semaglutide treatment and coronary artery inflammation based on FAI in patients with type 2 diabetes mellitus (T2DM). Methods This study enrolled 497 T2DM patients who underwent coronary computed tomography angiography (CCTA) at Hebei General Hospital, of whom 93 treated with semaglutide (Sema+) and 404 did not (Sema-). Clinical data, laboratory indicators, and CCTA parameters were collected and compared between the two groups at baseline. Propensity score matching (PSM) was used to adjust for confounders, and pericoronary FAI was compared. Multivariate linear regression models were used to analyze the association between semaglutide treatment and pericoronary FAI. Results Before PSM, pericoronary FAI of the LAD and LCX was lower in patients treated with semaglutide than those without semaglutide treatment. The results of the PSM analysis revealed a lower FAI in all three major coronary arteries in the Sema + group compared to the Sema- group. Multivariate linear regression analyses revealed an independent association between semaglutide treatment and reduced FAI in all three major coronary arteries. This association varied across T2DM patients of differing profiles. Conclusion Semaglutide treatment may be associated with lower coronary artery inflammation in patients with T2DM, which might partially explain its cardiovascular protective mechanism.

Abstract The pursuit of innovative therapeutic strategies in oncology remains imperative, given the persistent global impact of cancer as a leading cause of mortality. Immunotherapy is regarded as one of the most promising techniques for systemic cancer therapies among the several therapeutic options available. Nevertheless, limited immune response rates and immune resistance urge us on an augmentation for therapeutic efficacy rather than sticking to conventional approaches. Ferroptosis, a novel reprogrammed cell death, is tightly correlated with the tumor immune environment and interferes with cancer progression. Highly mutant or metastasis-prone tumor cells are more susceptible to iron-dependent nonapoptotic cell death. Consequently, ferroptosis-induction therapies hold the promise of overcoming resistance to conventional treatments. The most prevalent post-transcriptional modification, RNA m6A modification, regulates the metabolic processes of targeted RNAs and is involved in numerous physiological and pathological processes. Aberrant m6A modification influences cell susceptibility to ferroptosis, as well as the expression of immune checkpoints. Clarifying the regulation of m6A modification on ferroptosis and its significance in tumor cell response will provide a distinct method for finding potential targets to enhance the effectiveness of immunotherapy. In this review, we comprehensively summarized regulatory characteristics of RNA m6A modification on ferroptosis and discussed the role of RNA m6A-mediated ferroptosis on immunotherapy, aiming to enhance the effectiveness of ferroptosis-sensitive immunotherapy as a treatment for immune-resistant malignancies.

Abstract The advancement in extraterrestrial exploration has highlighted the crucial need for studying how the human cardiovascular system adapts to space conditions. Human development occurs under the influence of gravity, shielded from space radiation by Earth’s magnetic field, and within an environment characterized by 24-hour day-night cycles resulting from Earth’s rotation, thus deviating from these conditions necessitates adaptive responses for survival. With upcoming manned lunar and Martian missions approaching rapidly, it is essential to understand the impact of various stressors induced by outer-space environments on cardiovascular health. This comprehensive review integrates insights from both actual space missions and simulated experiments on Earth, to analyze how microgravity, space radiation, and disrupted circadian affect cardiovascular well-being. Prolonged exposure to microgravity induces myocardial atrophy and endothelial dysfunction, which may be exacerbated by space radiation. Mitochondrial dysfunction and oxidative stress emerge as key underlying mechanisms along with disturbances in ion channel perturbations, cytoskeletal damage, and myofibril changes. Disruptions in circadian rhythms caused by factors such as microgravity, light exposure, and irregular work schedules, could further exacerbate cardiovascular issues. However, current research tends to predominantly focus on disruptions in the core clock gene, overlooking the multifactorial nature of circadian rhythm disturbances in space. Future space missions should prioritize targeted prevention strategies and early detection methods for identifying cardiovascular risks, to preserve astronaut health and ensure mission success.

Abstract Background GPNMB is a type I transmembrane protein, and emerging evidence supports the relationship between GPNMB and cancers. Objective Through a comprehensive pan-cancer analysis, we examined the expression levels, prognostic significance, and mutation profiles of GPNMB in different cancer types. Subsequently, utilizing in vitro experiments, we elucidated the impact of GPNMB in endometrial cancer (EC). Methods TIMER2, GEPIA2, UALCAN and cBioPortal were used to analyze the expression pattern, prognostic values, and mutation status of GPNMB. HEC-1B and Ishikawa cells were used to conduct in vitro analyses of GPNMB overexpression. GeneMANIA and TIMER2 were used to evaluate the potential functions and correlations between GPNMB expression and tumor-infiltrating immune cells in EC. Results GPNMB was found to be highly expressed in multiple cancers, where it was associated with poor prognosis. Additionally, GPNMB was downregulated at both mRNA and protein levels in EC. Overexpression of GPNMB inhibited the proliferation, migration, and invasion of HEC-1B and Ishikawa cells. Functional analysis showed that GPNMB was enriched in pathways associated with regulation of plasma lipoprotein particle levels. The expression of GPNMB was positively connected with B cell, CD8+ T cell, CD4+ T cell, Macrophage, Neutrophil, and Dendritic cell levels. Conclusion Through pan-cancer analysis, we identified the antitumor effect of GPNMB in EC and predicted the potential mechanisms between GPNMB expression and EC.

Abstract Miniaturized on-chip spectrometers with small footprints, lightweight, and low cost are in great demand for portable optical sensing, lab-on-chip systems, and so on. Such miniaturized spectrometers are usually based on engineered spectral response units and then reconstruct unknown spectra with algorithms. However, due to the limited footprints of computational on-chip spectrometers, the recovered spectral resolution is limited by the number of integrated spectral response units/filters. Thus, it is challenging to improve the spectral resolution without increasing the number of used filters. Here we present a computational on-chip spectrometer using electrochromic filter-based computational spectral units that can be electrochemically modulated to increase the efficient sampling number for higher spectral resolution. These filters are directly integrated on top of the photodetector pixels, and the spectral modulation of the filters results from redox reactions during the dual injection of ions and electrons into the electrochromic material. We experimentally demonstrate that the spectral resolution of the proposed spectrometer can be effectively improved as the number of applied voltages increases. The average difference of the peak wavelengths between the reconstructed and the reference spectra decreases from 1.61 nm to 0.29 nm. We also demonstrate the proposed spectrometer can be worked with only four or two filter units, assisted by electrochromic modulation. In addition, we also demonstrate that the electrochromic filter can be easily adapted for hyperspectral imaging, due to its uniform transparency. This strategy suggests a new way to enhance the performance of miniaturized spectrometers with tunable spectral filters for high resolution, low-cost, and portable spectral sensing, and would also inspire the exploration of other stimulus responses such as photochromic and force-chromic, etc, on computational spectrometers.

Abstract Aims Chronic liver disease (CLD) is increasingly recognized as a significant global public health threat, with morbidity and mortality rates remaining high. Evidence suggests that sarcopenia independently increases the risk of CLD and negatively impacts various clinical outcomes, including survival, quality of life, and the emergence of additional complications in patients with CLD. This study aimed to give a bibliometric analysis to examine the correlation between sarcopenia and CLD from a literature perspective. Methods To understand the structure of this research field, we employed VOSviewer. The research on the correlation between long‐term liver disease and sarcopenia was obtained from the Web of Science Core Collection. VOSviewer 1.6.19.0 was utilized to examine and illustrate these publications, encompassing yearly patterns in the domain, focal points of research, significant articles, authors, journals, and organizations. Moreover, according to the results of the cluster analysis of keywords, we further searched and classified related studies to discuss. Results This study provides a comprehensive analysis of current research trends, international collaboration models, fundamental understandings, key focus areas, and future research areas in the field of sarcopenia and CLD by reviewing publications from January 1, 2000 to December 31, 2023. Over the past 24 years, research in the field of sarcopenia and CLD has deepened, with a gradual increase in publications and citations from various countries, institutions, and authors. Keyword analysis of sarcopenia and CLD indicates that current research predominantly focuses on several key areas, including obesity, metabolic syndrome, hepatic steatosis, insulin resistance, inflammation, and nutrition therapy. Conclusion This study provided a visual representation of the current research on the correlation between CLD and sarcopenia, including publication trends, global collaboration patterns, and research hotspots. This research contributes significantly by summarizing and discussing current research trends in sarcopenia and CLD, offering valuable insights into the complex relationship, and highlighting research trends, collaborations, and future directions in clinical treatment.

Abstract Acquired resistance is inevitable in the treatment of non-small cell lung cancer (NSCLC) with osimertinib, and one of the primary mechanisms responsible for this resistance is the epithelial-mesenchymal transition (EMT). We identify upregulation of the proviral integration site for Moloney murine leukemia virus 1 (PIM1) and functional inactivation of glycogen synthase kinase 3β (GSK3β) as drivers of EMT-associated osimertinib resistance. Upregulation of PIM1 promotes the growth, invasion, and resistance of osimertinib-resistant cells and is significantly correlated with EMT molecules expression. Functionally, PIM1 suppresses the ubiquitin-proteasome degradation of snail family transcriptional repressor 1 (SNAIL) and snail family transcriptional repressor 2 (SLUG) by deactivating GSK3β through phosphorylation. The stability and accumulation of SNAIL and SLUG facilitate EMT and encourage osimertinib resistance. Furthermore, treatment with PIM1 inhibitors prevents EMT progression and re-sensitizes osimertinib-resistant NSCLC cells to osimertinib. PIM1/GSK3β signaling is activated in clinical samples of osimertinib-resistant NSCLC, and dual epidermal growth factor receptor (EGFR)/PIM1 blockade synergistically reverse osimertinib-resistant NSCLC in vivo. These data identify PIM1 as a driver of EMT-associated osimertinib-resistant NSCLC cells and predict that PIM1 inhibitors and osimertinib combination therapy will provide clinical benefit in patients with EGFR-mutant NSCLC.

Genomic imprinting is essential for mammalian growth and embryogenesis. High-throughput bisulfite sequencing accompanied with parental haplotype-specific information allows analysis of imprinted genes and imprinting control regions (ICRs) on a large scale. Currently, although several allelic methylated regions (AMRs) detection software were developed, methods for detecting imprinted AMRs is still limited. Here, we developed a SNP-independent statistical approach, AIMER, to detect imprinting-like AMRs. By using the mouse frontal cortex methylome as input, we demonstrated that AIMER performs very well in detecting known germline ICRs compared with other methods. Furthermore, we found the putative parental AMRs AIMER detected could be distinguished from sequence-dependent AMRs. Finally, we found a novel germline imprinting-like AMR using WGBS data from 17 distinct mouse tissue samples. The results indicate that AIMER is a good choice for detecting imprinting-like (parent-of-origin-dependent) AMRs. We hope this method will be helpful for future genomic imprinting studies. The Python source code for our project is now publicly available on both GitHub (https://github.com/ZhaoLab-TMU/AIMER) and Gitee (https://gitee.com/zhaolab_tmu/AIMER).

The use of geopolymers for the solidification/stabilization (S/S) of municipal solid waste incineration fly ash (MSWI FA) is promising because the Cao in MSWI FA can provide an alkaline environment to facilitate geopolymer reactions and help to form the gel phase in the solidified body. This study investigated the role of CaO in MSWI FA in immobilizing common heavy metals, especially Cd2+ and Pb2+. Tests were performed to evaluate the effect of CaO on the unconfined compressive strength (UCS) of the polymer and the leaching of heavy metals. The findings revealed that as the CaO content increased, the UCS of the geopolymer samples also rose, reaching a maximum 28-day UCS of 24.8 MPa at a CaO content of 31.5%. Additionally, higher CaO levels resulted in lower leaching concentrations of heavy metals in the stabilized material. When the CaO level is 32%, the levels of heavy metals that leach out are very low, with Pb2+ at 0. 02 mg/L and Cd2+ at 0. 01 mg/L, achieving a stabilization rate of over 93.6% for these ions. Moreover, the geopolymer’s characteristics were analyzed by XRD, FTIR, and SEM, and the immobilization mechanisms of Cd2+ and Pb2+ were identified as gelation, physical encapsulation, and chemical substitution.

Arctic warming played a dominant role in recent occurrences of extreme events over the Northern Hemisphere, but climate models cannot accurately simulate the relationship. Here a significant positive correlation (0.33–0.95) between extreme precipitation and Arctic amplification (AA) is found using observations and CMIP5/6 multi-model ensembles. However, CMIP6 models are superior to CMIP5 models in simulating the temporal evolution of extreme precipitation and AA. According to 14 optimal CMIP6 models, the maximum latitude of planetary waves and the strength of Northern Hemisphere annular mode (NAM) will increase with increasing AA, contributing to increased extreme precipitation over the Northern Hemisphere. Under the Shared Socioeconomic Pathway SSP5-8.5, AA is expected to increase by 0.85 °C per decade while the maximum latitude of planetary waves will increase by 2.82° per decade. Additionally, the amplitude of the NAM will increase by 0.21 hPa per decade, contributing to a rise in extreme precipitation of 1.17% per decade for R95pTOT and 0.86% per decade for R99pTOT by 2100.

Abstract Background Klebsiella pneumoniae is the most commonly encountered pathogen in clinical practice. Widespread use of broad-spectrum antibiotics has led to the current global dissemination of carbapenem-resistant K. pneumoniae, which poses a significant threat to antibacterial treatment efficacy and public health. Outer membrane vesicles (OMVs) have been identified as carriers capable of facilitating the transfer of virulence and resistance genes. However, the role of OMVs in carbapenem-resistant K. pneumoniae under external pressures such as antibiotic and phage treatments remains unclear. Methods To isolate and purify OMVs under the pressure of phages and tigecycline, we subjected K. pneumoniae 0692 harboring plasmid-mediated bla NDM-1 and bla KPC-2 genes to density gradient separation. The double-layer plate method was used to isolate MJ1, which efficiently lysed K. pneumoniae 0692 cells. Transmission electron microscopy (TEM) was used to characterize the isolated phages and extract OMV groups for relevant morphological identification. Determination of protein content of each OMV group was conducted through bicinchoninic acid assay (BCA) and proteomic analysis. Results K. pneumoniae 0692 released OMVs in response to different environmental stimuli, which were characterized through TEM as having the typical structure and particle size of OMVs. Phage or tigecycline treatment alone resulted in a slight increase in the mean protein concentration of OMVs secreted by K. pneumoniae 0692 compared to that in the untreated group. However, when phage treatment was combined with tigecycline, there was a significant reduction in the average protein concentration of OMVs compared to tigecycline treatment alone. Proteomics showed that OMVs encapsulated numerous functional proteins and that under different external stresses of phages and tigecycline, the proteins carried by K. pneumoniae 0692-derived OMVs were significantly upregulated or downregulated compared with those in the untreated group. Conclusions This study confirmed the ability of OMVs to carry abundant proteins and highlighted the important role of OMV-associated proteins in bacterial responses to phages and tigecycline, representing an important advancement in microbial resistance research.

Abstract Background Apoprotein A-I (ApoA-I) and Apoprotein B (ApoB) have emerged as novel cardiovascular risk biomarkers influenced by feeding behavior. Hypothalamic appetite peptides regulate feeding behavior and impact lipoprotein levels, which effects vary in different weight states. This study explores the intricate relationship between body mass index (BMI), hypothalamic appetite peptides, and apolipoproteins with emphasis on the moderating role of body weight in the association between neuropeptide Y (NPY), ghrelin, orexin A (OXA), oxytocin in cerebrospinal fluid (CSF) and peripheral ApoA-I and ApoB. Methods In this cross-sectional study, we included participants with a mean age of 31.77 ± 10.25 years, categorized into a normal weight (NW) (n = 73) and an overweight/obese (OW/OB) (n = 117) group based on BMI. NPY, ghrelin, OXA, and oxytocin levels in CSF were measured. Results In the NW group, peripheral ApoA-I levels were higher, while ApoB levels were lower than in the OW/OB group (all p

Abstract Employing machine learning methods for mapping surface ocean pCO2 has reduced the uncertainty in estimating sea-air CO2 flux. However, a general discrepancy exists between the Southern Ocean carbon sinks derived from pCO2 products and those from biogeochemistry models. Here, by performing a boosting ensemble learning feed-forward neural networks method, we have identified an underestimation of the surface Southern Ocean pCO2 due to notably uneven density of pCO2 measurements between summer and winter, which resulted in about 16% overestimating of Southern Ocean carbon sink over the past three decades. In particular, the Southern Ocean carbon sink since 2010 was notably overestimated by approximately 29%. This overestimation can be mitigated by a winter correction in algorithms, with the average Southern Ocean carbon sink during 1992-2021 corrected to −0.87 PgC yr−1 from the original −1.01 PgC yr−1. Furthermore, the most notable underestimation of surface ocean pCO2 mainly occurred in regions south of 60°S and was hiding under ice cover. As the surface ocean pCO2 under sea ice coverage in the winter is much higher than the atmosphere, if sea ice melts completely, there could be a further reduction of about 0.14 PgC yr−1 in the Southern Ocean carbon sink.

Abstract Background Rickettsia and related diseases have been identified as significant global public health threats. This study involved comprehensive field and systematic investigations of various rickettsial organisms in Yunnan Province. Methods Between May 18, 2011 and November 23, 2020, field investigations were conducted across 42 counties in Yunnan Province, China, encompassing small mammals, livestock, and ticks. Preliminary screenings for Rickettsiales involved amplifying the 16S rRNA genes, along with additional genus- or species-specific genes, which were subsequently confirmed through sequencing results. Sequence comparisons were carried out using the Basic Local Alignment Search Tool (BLAST). Phylogenetic relationships were analyzed using the default parameters in the Molecular Evolutionary Genetics Analysis (MEGA) program. The chi-squared test was used to assess the diversities and component ratios of rickettsial agents across various parameters. Results A total of 7964 samples were collected from small mammals, livestock, and ticks through Yunnan Province and submitted for screening for rickettsial organisms. Sixteen rickettsial species from the genera Rickettsia, Anaplasma, Ehrlichia, Neoehrlichia, and Wolbachia were detected, with an overall prevalence of 14.72%. Among these, 11 species were identified as pathogens or potential pathogens to humans and livestock. Specifically, 10 rickettsial organisms were widely found in 42.11% (24 out of 57) of small mammal species. High prevalence was observed in Dremomys samples at 5.60%, in samples from regions with latitudes above 4000 m or alpine meadows, and in those obtained from Yuanmou County. Anaplasma phagocytophilum and Candidatus Neoehrlichia mikurensis were broadly infecting multiple genera of animal hosts. In contrast, the small mammal genera Neodon, Dremomys, Ochotona, Anourosorex, and Mus were carrying individually specific rickettsial agents, indicating host tropism. There were 13 rickettsial species detected in 57.14% (8 out of 14) of tick species, with the highest prevalence (37.07%) observed in the genus Rhipicephalus. Eight rickettsial species were identified in 2375 livestock samples. Notably, six new Rickettsiales variants/strains were discovered, and Candidatus Rickettsia longicornii was unambiguously identified. Conclusions This large-scale survey provided further insight into the high genetic diversity and overall prevalence of emerging Rickettsiales within endemic hotspots in Yunnan Province. The potential threats posed by these emerging tick-borne Rickettsiales to public health warrant attention, underscoring the need for effective strategies to guide the prevention and control of emerging zoonotic diseases in China. Graphical Abstract

AIM: To observe the effects of femtosecond laser-assisted excimer laser in situ keratomileusis combined with accelerated corneal cross-linking (FS-LASIK Xtra) on corneal densitometry after correcting for high myopia. METHODS: In this prospectively study, 130 patients underwent FS-LASIK or FS-LASIK Xtra for high myopia. Their right eyes were selected for inclusion in the study, of which 65 cases of 65 eyes in the FS-LASIK group, 65 patients with 65 eyes in the FS-LASIK Xtra group. Patients were evaluated for corneal densitometry at 1, 3, and 6mo postoperatively using Pentacam Scheimpflug imaging. RESULTS: Preoperative differences in corneal densitometry between the FS-LASIK and FS-LASIK Xtra groups in different ranges were not statistically significant (P>0.05). Layer-by-layer analysis revealed statistically significant differences in the anterior (120 μm), central, and total layer corneal densitometry between the FS-LASIK and FS-LASIK Xtra groups at 1 and 3mo postoperatively (all P0.05). CONCLUSION: There is an increase in internal corneal densitometry during the early postoperative period after FS-LASIK Xtra for correction of high myopia. However, the densitometry values decreased to the level of conventional FS-LASIK at 6mo after surgery, with the most significant changes observed in the superficial central zone.

Microbial phospholipase D (PLD) showed a more competent potential for phospholipids production due to its higher catalytic activity and broader substrate specificity. In this study, the PLD from Acinetobacter sp. DUT-2 (ADPLD) was used as the research object. Firstly, bioinformatics was used to examine the protein sequence characteristics. Then, the recombinant plasmid was generated and heterologously expressed in Escherichia coli. The enzyme protein was purified further, and the substrate selectivity of ADPLD to phosphatidylcholine (PC) with various acyl chains was investigated. Finally, the substrate recognition mechanism of ADPLD was investigated using molecular docking and molecular dynamics simulation. Multiple sequence alignment and phylogenetic tree analysis of ADPLD and other microbial-derived PLDs revealed that the sequence similarity between ADPLD and Streptomyces-derived PLDs was less than 30%, and there was only one conserved HKD motif, indicating that the catalytic mechanism of ADPLD might differ from the reaction mechanism in traditional cognition, which required two HKD motifs to complete the PLD catalytic process. ADPLD was mostly produced as a soluble protein, and a relatively uniform protein could be purified using Ni2+ affinity chromatography at a low concentration of 50 mmol/L imidazole. When soybean PC was utilized as a substrate, the specific activity of ADPLD was about 4.09 U/mg. ADPLD showed relatively high activity in neutralizing short-chain PC (C6~C14), with a specific activity of 13.2 U/mg for 8:0/8:0-PC, which was higher than that of other PC substrates with long acyl chains. The activity of ADPLD on PC reduced dramatically when the acyl chain length of PC grew from C14 to C16. Molecular dynamics simulation and molecular docking experiments revealed that the ADPLD amino acid residues Thr205, Pro209, Phe293, Ala324, Lys329, and Phe453 might form hydrophobic interactions with PC. Arg383 and Gly326 could form hydrogen bonds with PC when the distance between Arg383 (N), Gly326 (N), and PC (P) was

Reducing the formation of large carbon clusters during the combustion of energetic materials (EMs) and improving their comprehensive performance hold great significance. With fluororubber (F2604) as a binder, this study prepared HNS/n-Al microspheres with different n-Al contents (5%, 10%, and 15%) using droplet microfluidic technology. Then, it characterized and tested the morphology, particle size distribution, dispersibility, crystal structure, thermal properties, mechanical sensitivity, and combustion behavior of the microspheres. The results show that the prepared microspheres had regular shapes, uniform particle sizes, and excellent dispersibility and contained more homogeneous components than physically mixed samples. Furthermore, the microspheres retained the crystal structures of the raw materials, enjoying high safety performance. The thermal analysis shows that HNS/n-Al microspheres had high heat resistance (thermal decomposition temperature: over 354 °C) and that a higher n-Al content was associated with more thorough thermal decomposition reactions of HNS (HNS: 83%, HNS/n-Al: 84%, 86%, and 93%). The ignition experiments show that the HNS/n-Al microspheres possessed excellent and stable combustion performance, as evidenced by more complete combustion reactions and significantly elevated energy release efficiency. Therefore, it is expected to achieve high-energy and high-speed responses of carbon-rich EMs and promote their practical applications.

Glaciers have retreated and shrunk in High Mountain Asia since the mid-20th century because of global warming, leading to glacier instability and hazardous ice–snow avalanches. However, the complex relationship between ice–snow avalanches and factors such as climate and potential triggers are difficult to understand because of the lack of observational data. Here, we addressed ice–snow avalanches on the Annapurna II glacier in Nepal, Central Himalaya. We constructed an ice–snow avalanche history using long-term multi-source remote sensing images (1988–2021) and mapped the velocity fields of glaciers using cross-correlation analysis on SAR and optical images. Then, we investigated the impact of climate change and earthquakes on the frequency and size of ice–snow avalanches. The results demonstrate that the frequency of ice–snow avalanches has increased from 10 in 1988 to 27 in 2020, but the average area of ice–snow avalanche deposits has decreased by approximately 70%, from 3.4 × 105 m2 in 1988 to 1.2 × 105 m2 in 2020. The evolutionary characteristic of ice avalanches is linked to the impact of glacier retreat (reduction in ice material supply) and increased activity under climate change. The glacier movement velocity controls the size of ice–snow avalanches and can be set as an indicator for ice–snow avalanche warnings. On the Annapurna II glacier, an ice–snow avalanche occurred when the glacier velocities were greater than 1.5 m d−1. These results offer insights into ice–snow avalanche risk assessment and prediction in high-mountain areas, particularly in regions characterised by dense glacier distribution.

Abstract Aging and obesity pose significant threats to public health and are major contributors to muscle atrophy. The trends in muscle fiber types under these conditions and the transcriptional differences between different muscle fiber types remain unclear. Here, we demonstrate distinct responses of fast/glycolytic fibers and slow/oxidative fibers to aging and obesity. We found that in muscles dominated by oxidative fibers, the proportion of oxidative fibers remains unchanged during aging and obesity. However, in muscles dominated by glycolytic fibers, despite the low content of oxidative fibers, a significant decrease in proportion of oxidative fibers was observed. Consistently, our study uncovered that during aging and obesity, fast/glycolytic fibers specifically increased the expression of genes associated with muscle atrophy and inflammation, including Dkk3, Ccl8, Cxcl10, Cxcl13, Fbxo32, Depp1, and Chac1, while slow/oxidative fibers exhibit elevated expression of antioxidant protein Nqo-1 and downregulation of Tfrc. Additionally, we noted substantial differences in the expression of calcium-related signaling pathways between fast/glycolytic fibers and slow/oxidative fibers in response to aging and obesity. Treatment with a calcium channel inhibitor thapsigargin significantly increased the abundance of oxidative fibers. Our study provides additional evidence to support the transcriptomic differences in muscle fiber types under pathophysiological conditions, thereby establishing a theoretical basis for modulating muscle fiber types in disease treatment.

Soybean (Glycine max) is a short-day crop whose flowering time is regulated by photoperiod. The long-juvenile trait extends its vegetative phase and increases yield under short-day conditions. Natural variation in J, the major locus controlling this trait, modulates flowering time. We report that the three J-family genes influence soybean flowering time, with the triple mutant Guangzhou Mammoth-2 flowering late under short days by inhibiting transcription of E1-family genes. J-family genes offer promising allelic combinations for breeding.

Abstract High-quality ocean in situ profile observations are fundamental for ocean and climate research and operational oceanographic applications. Here we describe a new global ocean subsurface temperature profile database named the Chinese Academy of Science (CAS) Oceanography Data Center version 1 (CODC-v1). This database contains over 17 million temperature profiles between 1940–2023 from all available instruments. The major data source is the World Ocean Database (WOD), but CODC-v1 also includes some data from some Chinese institutes which are not available in WOD. The data are quality-controlled (QC-ed) by a new QC system that considers the skewness of local temperature distributions, topographic barriers, and the shift of temperature distributions due to climate change. Biases in Mechanical Bathythermographs (MBTs), eXpendable Bathythermographs (XBTs), and Bottle data (OSD) are all corrected using recently proposed correction schemes, which makes CODC-v1 a bias-corrected dataset. These aspects ensure the data quality of the CODC-v1 database, making it suitable for a wide spectrum of ocean and climate research and applications.

Abstract Respiratory syncytial virus (RSV) is the major cause of bronchiolitis and pneumonia in young children and the elderly. There are currently no approved RSV-specific therapeutic small molecules available. Using high-throughput antiviral screening, we identified an oral drug, the prenylation inhibitor lonafarnib, which showed potent inhibition of the RSV fusion process. Lonafarnib exhibited antiviral activity against both the RSV A and B genotypes and showed low cytotoxicity in HEp-2 and human primary bronchial epithelial cells (HBEC). Time-of-addition and pseudovirus assays demonstrated that lonafarnib inhibits RSV entry, but has farnesyltransferase-independent antiviral efficacy. Cryo-electron microscopy revealed that lonafarnib binds to a triple-symmetric pocket within the central cavity of the RSV F metastable pre-fusion conformation. Mutants at the RSV F sites interacting with lonafarnib showed resistance to lonafarnib but remained fully sensitive to the neutralizing monoclonal antibody palivizumab. Furthermore, lonafarnib dose-dependently reduced the replication of RSV in BALB/c mice. Collectively, lonafarnib could be a potential fusion inhibitor for RSV infection.

Abstract The long non-coding RNA (lncRNA) Small Nucleolar RNA Host Gene 4 (SNHG4) has been demonstrated to be significantly downregulated in various inflammatory conditions, yet its role in chronic obstructive pulmonary disease (COPD) remains elusive. This study aims to elucidate the biological function of SNHG4 in COPD and to unveil its potential molecular targets. Our findings reveal that both SNHG4 and Four and a Half LIM Domains 1 (FHL1) were markedly downregulated in COPD, whereas microRNA-409-3p (miR-409-3p) was upregulated. Importantly, SNHG4 exhibited a negative correlation with inflammatory markers in patients with COPD, but a positive correlation with forced expiratory volume in 1s percentage (FEV1%). SNHG4 distinguished COPD patients from non-smokers with high sensitivity, specificity, and accuracy. Overexpression of SNHG4 ameliorated cigarette smoke extract (CSE)-mediated inflammation, apoptosis, oxidative stress, and airway remodeling in 16HBE bronchial epithelial cells. These beneficial effects of SNHG4 overexpression were reversed by the overexpression of miR-409-3p or the silencing of FHL1. Mechanistically, SNHG4 competitively bound to miR-409-3p, mediating the expression of FHL1, and consequently improving inflammation, apoptosis, oxidative stress, and airway remodeling in 16HBE cells. Additionally, SNHG4 regulated the miR-409-3p/FHL1 axis to inhibit the activation of the mitogen-activated protein kinase (MAPK) pathway induced by CSE. In a murine model of COPD, knockdown of SNHG4 exacerbated CSE-induced pulmonary inflammation, apoptosis, and oxidative stress. In summary, our data affirm that SNHG4 mitigates pulmonary inflammation, apoptosis, and oxidative damage mediated by COPD through the regulation of the miR-409-3p/FHL1 axis. Graphical Abstract

Abstract Precise neurostimulation can revolutionize therapies for neurological disorders. Electrode-based stimulation devices face challenges in achieving precise and consistent targeting due to the immune response and the limited penetration of electrical fields. Ultrasound can aid in energy propagation, but transcranial ultrasound stimulation in the deep brain has limited spatial resolution caused by bone and tissue scattering. Here, we report an implantable piezoelectric ultrasound stimulator (ImPULS) that generates an ultrasonic focal pressure of 100 kPa to modulate the activity of neurons. ImPULS is a fully-encapsulated, flexible piezoelectric micromachined ultrasound transducer that incorporates a biocompatible piezoceramic, potassium sodium niobate [(K,Na)NbO3]. The absence of electrochemically active elements poses a new strategy for achieving long-term stability. We demonstrated that ImPULS can i) excite neurons in a mouse hippocampal slice ex vivo, ii) activate cells in the hippocampus of an anesthetized mouse to induce expression of activity-dependent gene c-Fos, and iii) stimulate dopaminergic neurons in the substantia nigra pars compacta to elicit time-locked modulation of nigrostriatal dopamine release. This work introduces a non-genetic ultrasound platform for spatially-localized neural stimulation and exploration of basic functions in the deep brain.

Introduction: Vascular neointimal hyperplasia, a pathological process observed in cardiovascular diseases such as atherosclerosis and pulmonary hypertension, involves the abundant presence of vascular smooth muscle cells (VSMCs). The proliferation, migration, and autophagy of VSMCs are associated with the development of neointimal lesions. Circular RNAs (circRNAs) play critical roles in regulating VSMC proliferation and migration, thereby participating in neointimal hyperplasia. However, the regulatory roles of circRNAs in VSMC autophagy remain unclear. Objectives: We aimed to identify circRNAs that are involved in VSMC autophagy-mediated neointimal hyperplasia, as well as elucidate the underlying mechanisms. Methods: Dual-luciferase reporter gene assay was performed to validate two competing endogenous RNA axes, hsa_circ_0001402/miR-183-5p/FKBP prolyl isomerase like (FKBPL) and hsa_circ_0001402/miR-183-5p/beclin 1 (BECN1). Cell proliferation and migration analyses were employed to investigate the effects of hsa_circ_0001402, miR-183-5p, or FKBPL on VSMC proliferation and migration. Cell autophagy analysis was conducted to reveal the role of hsa_circ_0001402 or miR-183-5p on VSMC autophagy. The role of hsa_circ_0001402 or miR-183-5p on neointimal hyperplasia was evaluated using a mouse model of common carotid artery ligation. Results: Hsa_circ_0001402 acted as a sponge for miR-183-5p, leading to the suppression of miR-183-5p expression. Through direct interaction with the coding sequence (CDS) of FKBPL, miR-183-5p promoted VSMC proliferation and migration by decreasing FKBPL levels. Besides, miR-183-5p reduced BECN1 levels by targeting the 3′-untranslated region (UTR) of BECN1, thus inhibiting VSMC autophagy. By acting as a miR-183-5p sponge, overexpression of hsa_circ_0001402 increased FKBPL levels to inhibit VSMC proliferation and migration, while simultaneously elevating BECN1 levels to activate VSMC autophagy, thereby alleviating neointimal hyperplasia. Conclusion: Hsa_circ_0001402, acting as a miR-183-5p sponge, increases FKBPL levels to inhibit VSMC proliferation and migration, while enhancing BECN1 levels to activate VSMC autophagy, thus alleviating neointimal hyperplasia. The hsa_circ_0001402/miR-183-5p/FKBPL axis and hsa_circ_0001402/miR-183-5p/BECN1 axis may offer potential therapeutic targets for neointimal hyperplasia.

This paper proposes an efficient method for quantifying the stratigraphic uncertainties and modeling the geological formations based on boreholes. Two Markov chains are used to describe the soil transitions along different directions, and the transition probability matrices (TPMs) of the Markov chains are analytically expressed by copulas. This copula expression is efficient since it can represent a large TPM by a few unknown parameters. Due to the analytical expression of the TPMs, the likelihood function of the Markov chain model is given in an explicit form. The estimation of the TPMs is then re-casted as a multi-objective constrained optimization problem that aims to maximize the likelihoods of two independent Markov chains subject to a set of parameter constraints. Unlike the method which determines the TPMs by counting the number of transitions between soil types, the proposed method is more statistically sound. Moreover, a random path sampling method is presented to avoid the directional effect problem in simulations. The soil type at a location is inferred from its nearest known neighbors along the cardinal directions. A general form of the conditional probability, based on Pickard's theorem and Bayes rule, is presented for the soil type generation. The proposed stratigraphic characterization and simulation method is applied to real borehole data collected from a construction site in Wuhan, China. It is illustrated that the proposed method is accurate in prediction and does not show an inclination during simulation.

ABSTRACT This study explores the effects of disinfectant and antibiotic exposure on gut health, focusing on gut microbiota balance and gut immune function. Our analysis indicates that disinfectants increase the proportion of Gram-positive bacteria, particularly increasing Staphylococcus levels, while antibiotics increase the proportion of Gram-negative bacteria, especially Bacteroides levels. These changes disrupt microbial harmony and affect the gut microbiome’s functional capacity. Additionally, our research reveals that both disinfectants and antibiotics reduce colon length and cause mucosal damage. A significant finding is the downregulation of NLRC4, a key immune system regulator in the gut, accompanied by changes in immune factor expression. This interaction between chemical exposure and immune system dysfunction increases susceptibility to inflammatory bowel disease and other gut conditions. Given the importance of disinfectants in disease prevention, this study advocates for a balanced approach to their use, aiming to protect public health while minimizing adverse effects on the gut microbiome and immune function.IMPORTANCEDisinfectants are extensively employed across various sectors, such as the food sector. Disinfectants are widely used in various sectors, including the food processing industry, animal husbandry, households, and pharmaceuticals. Their extensive application risks environmental contamination, impacting water and soil quality. However, the effect of disinfectant exposure on the gut microbiome and the immune function of animals remains a significant, unresolved issue with profound public health implications. This highlights the need for increased scrutiny and more regulated use of disinfectants to mitigate unintended consequences on gut health and maintain immune system integrity.

Summary: Low doses of general anesthetics like ketamine and dexmedetomidine have anxiolytic properties independent of their sedative effects, but the underlying mechanisms remain unclear. We discovered a population of GABAergic neurons in the oval division of the bed nucleus of the stria terminalis that are activated by multiple anesthetics and the anxiolytic drug diazepam (ovBNSTGA). The majority of ovBNSTGA neurons express neurotensin receptor 1 (Ntsr1) and form circuits with brain regions known to regulate anxiety and stress responses. Optogenetic activation of ovBNSTGA or ovBNSTNtsr1 neurons significantly attenuated anxiety-like behaviors in both naive animals and mice with inflammatory pain, while inhibition of these cells elevated anxiety. Activation of these neurons decreased heart rate and increased heart rate variability, suggesting that they reduce anxiety by modulating autonomic responses. Our study identifies ovBNSTGA/ovBNSTNtsr1 neurons as a common neural substrate mediating the anxiolytic effect of low-dose anesthetics and a potential therapeutic target for treating anxiety-related disorders.

Summary: Background: Accurate staging of liver fibrosis (LF) is essential for clinical management in chronic liver disease. While non-contrast MRI (NC-MRI) yields valuable information for liver assessment, its effectiveness in predicting LF remains underexplored. This study aimed to develop and validate artificial intelligence (AI)-powered models utilizing NC-MRI for staging LF. Methods: A total of 1726 patients from Shengjing Hospital of China Medical University, registered between October 2003 and October 2022, were retrospectively collected, and divided into development (n = 1208) and internal test (n = 518) cohorts. An external test cohort consisting of 337 individuals from six centers, registered between June 2015 and November 2022, were also included. All participants underwent NC-MRI (T1-weighted imaging, T1WI; and T2-fat-suppressed imaging, T2FS) and liver biopsies. Two classification models (CMs), named T1 and T2FS, were trained on respective image types using 3D contextual transformer networks and evaluated on both test cohorts. Additionally, three CMs—Clinic, Image, and Fusion—were developed using clinical features, T1 and T2FS scores, and their integration via logistic regression. Classification effectiveness of CMs was assessed using the area under the receiver operating characteristic curve (AUC). A comparison was conducted between the optimal models (OMs) with highest AUC and other methods (transient elastography, five serum biomarkers, and six radiologists). Findings: Fusion models (i.e., OM) yielded the highest AUC among the CMs, achieving AUCs of 0.810 for significant fibrosis, 0.881 for advanced fibrosis, and 0.918 for cirrhosis in the internal test cohort, and 0.808, 0.868, and 0.925, respectively, in the external test cohort. The OMs demonstrated superior performance in AUC, significantly surpassing transient elastography (only for staging ≥ F2 and ≥ F3 grades), serum biomarkers, and three junior radiologists for staging LF. Radiologists, with the aid of the OMs, can achieve a higher AUC in LF assessment. Interpretation: AI-powered models utilizing NC-MRI, including T1WI and T2FS, accurately stage LF. Funding: National Natural Science Foundation of China (No. 82071885); General Program of the Liaoning Provincial Department of Education (LJKMZ20221160); Liaoning Province Science and Technology Joint Plan (2023JH2/101700127); the Leading Young Talent Program of Xingliao Yingcai in Liaoning Province (XLYC2203037).

PI3Kδ is a key signal transduction molecule in normal and malignant B cells, as well as in T-regulatory cells, making it a promising target for treatment of hematologic malignancies through both direct killing and anti-tumor immunity regulation. BGB-10188 is a highly selective inhibitor of PI3Kδ, showing more than 3000 folds selectivity over other PI3K isoforms and no significant inhibition across tested kinases. BGB-10188 potently inhibited PI3Kδ with IC50s ranging from 1.7-16 nM through various in vitro assays and showed a long-lasting and strong target inhibition in mouse B cells in vivo. BGB-10188 showed significant antitumor effects in human B cell lymphoma xenograft models as single agent or in combination with the BTK inhibitor zanubrutinib. BGB-10188 showed significant Treg inhibition in blood but not in colon, along with less drug accumulation in colon compared with idelalisib, which is an approved PI3Kdelta inhibitor with high incidence of gastrointestinal side effects in clinic. In summary, BGB-10188 is a novel PI3Kδ inhibitor with high selectivity, potency and improved safety profile shown in preclinical studies, which is showing the potential as a best-in-class PI3Kδ inhibitor.

Cancer-associated fibroblasts (CAFs) are known to play an important role in cancer progression, but their effects on tumor cell dormancy and the underlying mechanisms remain to be explored. Here, we aimed to dissect the intercellular communication between CAFs and oral squamous cell carcinoma (OSCC) cells under cellular dormancy. In this study, we investigated 61 OSCC patients and found that low expression of Differentiated Embryonic Chondrocyte gene 2 (DEC2) was closely associated with tumor recurrence, cisplatin chemotherapy administration, and infiltration of CAFs. Overexpression of DEC2 promoted the invasion and migration ability of OSCC cells but inhibited their proliferation and glucose metabolism, and characterized them as dormant and cisplatin-resistant cells. C-X-C motif ligand 1 (CXCL1) from CAFs was found to down-regulate DEC2 expression in OSCC cells, ultimately awakening dormant cells and leading to tumor recurrence, which was validated in vitro and in vivo. In conclusion, CAFs-derived CXCL1 downregulated DEC2 and “interrupted” DEC2-mediated OSCC cell dormancy, which may be a mechanism by which CAFs modulate OSCC cell dormancy and contribute to the development of new therapies for OSCC.

High-energy density dielectrics for electrostatic capacitors are in urgent demand for advanced electronics and electrical power systems. Poly(vinylidene fluoride) (PVDF) based nanocomposites have attracted remarkable attention by intrinsic high polarization, flexibility, low density, and outstanding processability. However, it is still challenging to achieve significant improvement in energy density due to the common contradictions between electric polarization and breakdown strength. Here, we proposed a novel facile strategy that simultaneously achieves the construction of in-plane oriented BaTiO3 nanowires and crystallization modulation of PVDF matrix via an in-situ uniaxial stretch process. The polar phase transition and enhanced Young's modulus facilitate the synergetic improvement of electric polarization and voltage endurance capability for PVDF matrix. Additionally, the aligned distribution of nanowires could reduce the contact probability of nanowire tips, thus alleviating electric field concentration and hindering the conductive path. Finally, a record high energy density of 38.3 ​J/cm3 and 40.9 ​J/cm3 are achieved for single layer and optimized sandwich-structured nanocomposite, respectively. This work provides a unique structural design and universal method for dielectric nanocomposites with ultrahigh energy density, which presents a promising prospect of practical application for modern energy storage systems.

Quantum non-demolition measurement with an off-resonance polarized probe is a widely utilized technique for atomic sensors. We observe previously unexplored spin-alignment polarization induced by the far-detuned off-resonance linear probe in an ultrasensitive optical polarimetry. The evolution of probe-generated multipole moments exacerbates probe noise due to strong magnetic couplings. We demonstrate a method to decouple spin-alignment from magnetic fields by manipulating the multipole moments in zero-fields. The probe noise is suppressed by 10 dB with the proposed method, achieving a noise floor at the standard quantum limit. The realized shot-noise-limited optical polarimetry holds significant promise for atomic sensors aimed at ultra-sensitivity.

Abstract Gene‐editing technology has become a transformative tool for the precise manipulation of biological genomes and holds great significance in the field of animal disease‐resistant breeding. Mastitis, a prevalent disease in animal husbandry, imposes a substantial economic burden on the global dairy industry. In this study, a regulatory sequence gene editing breeding strategy for the successful creation of a gene‐edited dairy (GED) goats with enhanced mastitis resistance using the ISDra2‐TnpB system and dairy goats as the model animal is proposed. This included the targeted integration of an innate inflammatory regulatory sequence (IRS) into the promoter region of the lysozyme (LYZ) gene. Upon Escherichia Coli (E. coli) mammary gland infection, GED goats exhibited increased LYZ expression, showing robust anti‐mastitis capabilities, mitigating PANoptosis activation, and alleviating blood‐milk‐barrier (BMB) damage. Notably, LYZ is highly expressed only in E. coli infection. This study marks the advent of anti‐mastitis gene‐edited animals with exogenous‐free gene expression and demonstrates the feasibility of the gene‐editing strategy proposed in this study. In addition, it provides a novel gene‐editing blueprint for developing disease‐resistant strains, focusing on disease specificity and biosafety while providing a research basis for the widespread application of the ISDra2‐TnpB system.

As the prevalence of obesity continues to rise globally, the research on adipocytes has attracted more and more attention. In the presence of nutrient overload, adipocytes are exposed to pressures such as hypoxia, inflammation, mechanical stress, metabolite, and oxidative stress that can lead to organelle dysfunction. Endoplasmic reticulum (ER) is a vital organelle for sensing cellular pressure, and its homeostasis is essential for maintaining adipocyte function. Under conditions of excess nutrition, ER stress (ERS) will be triggered by the gathering of abnormally folded proteins in the ER lumen, resulting in the activation of a signaling response known as the unfolded protein responses (UPRs), which is a response system to relieve ERS and restore ER homeostasis. However, if the UPRs fail to rescue ER homeostasis, ERS will activate pathways to damage cells. Studies have shown a role for disturbed activation of adipocyte ERS in the pathophysiology of obesity and its complications. Prolonged or excessive ERS in adipocytes can aggravate lipolysis, insulin resistance, and apoptosis and affect the bioactive molecule production. In addition, ERS also impacts the expression of some important genes. In view of the fact that ERS influences adipocyte function through various mechanisms, targeting ERS may be a viable strategy to treat obesity. This article summarizes the effects of ERS on adipocytes during obesity.

IntroductionSampling for describing plant–pollinator interaction networks has been performed using techniques that either focus on the plants (with flower-visit data) or the animals (with analyzing pollen on the body surface of flower visitors). The differences in the structure of the networks obtained using these methods likely influences our understanding of the contribution of nocturnal pollinators, yet this key finding has yet to be the focus of study.MethodsIn this study, we conducted an intensive diurnal field survey in the subalpine meadows of the Dajiuhu Wetland and supplemented the data with an analysis of diurnal and nocturnal pollen data to examine the changes in pollination networks.ResultsWe observed 41 plant and 154 pollinator species, corresponding to 665 specific interactions. Visitation and pollen analyses showed significant differences in the composition and interaction between network plants and pollinators, resulting in important structural changes in the network. Given that the diurnal pollen data showed new links that were preferentially attached to highly connected nodes, the level of asymmetric specialization did not decrease; however, nestedness increased 1.3-fold, and mean pollinator connectivity from 3.1 to 5.1. As the behaviors of nocturnal pollinators tended to be more specialized, the inclusion of nocturnal pollen data led to an increase in the number of extreme-specialist pollinator species. Consequently, nestedness decreased 0.8-fold, but mean plant connectivity went from 14.2 to 16.2.DiscussionThese findings suggest that the structure of pollination networks is influenced by the sampling methods and the level of detail of the investigation. Our study has strong implications for the development of monitoring schemes for plant–pollinator interactions. Due to the practical difficulties of nocturnal field visitation, when conducting research, combining diurnal field visitation with both diurnal and nocturnal pollen analyses is the most convenient and realistic method to capture the full complexity of these networks.

Lung auscultation is essential for early lung condition detection. Categorizing adventitious lung sounds requires expert discrimination by medical specialists. This paper details the features of LungNeXt, a novel classification model specifically designed for lung sound analysis. Furthermore, we propose two auxiliary methods: RandClipMix (RCM) for data augmentation and Enhanced Mel-Spectrogram for Feature Extraction (EMFE). RCM addresses the issue of data imbalance by randomly mixing clips within the same category to create new adventitious lung sounds. EMFE augments specific frequency bands in spectrograms to highlight adventitious features. These contributions enable LungNeXt to achieve outstanding performance. LungNeXt optimally integrates an appropriate number of NeXtblocks, ensuring superior performance and a lightweight model architecture. The proposed RCM and EMFE methods, along with the LungNeXt classification network, have been evaluated on the SPRSound dataset. Experimental results revealed a commendable score of 0.5699 for the lung sound five-category task on SPRSound. Specifically, the LungNeXt model is characterized by its efficiency, with only 3.804M parameters and a computational complexity of 0.659G FLOPS. This lightweight and efficient model is particularly well-suited for applications in electronic stethoscope back-end processing equipment, providing efficient diagnostic advice to physicians and patients.

BackgroundWWOX-related epileptic encephalopathy is an autosomal recessive disorder caused by mutations in the WW-containing oxidoreductase gene, characterized by the onset of refractory seizures in infants. Early-onset epilepsy, electroencephalography abnormalities, and developmental delay or degeneration are the main clinical manifestations. Early death can occur in severe cases. In the present study, a novel variant in WWOX was detected in a patient with epilepsy and his healthy parents.Case presentationA 5-month-old boy presented with epilepsy. The main manifestations were intractable seizures, mental and motor retardation and hearing impairment. Subsequent genetic testing revealed the presence of an epilepsy-associated novel mutation: c.991C>A (amino acid change: p.Ser304Tyr) in the WWOX gene. Variants were inherited from parents with healthy phenotypes. Finally, a patient died at 6 months of age.ConclusionThe discovery of novel variants has enriched the existing database of WWOX gene variants and may expand the range of clinical options for treating WWOX-related disorders.

For the first time, we used laccase (LA) and hydrogen peroxide (H2O2) in supercritical fluid of carbon dioxide (SCF-CO2) to develop a method of bleaching cashmere fiber production in an ecofriendly way. The obtained results found that the whiteness of the cashmere was improved significantly involving a high bleaching efficient with this method, as well as influenced notably by the dosages of H2O2 and LA, bleaching temperature, pressure and duration. Various natural colorants on the cashmere sample were effectively decomposed and removed by the bleaching ingredients from the H2O2 and biologic catalyst of LA via an efficient transfer of those species onto cashmere surfaces from (H2O2 + LA+PEG1000 + H2O)/SCF-CO2 system. Particularly, this supercritical bleaching method with LA and H2O2 in SCF-CO2 reduced the number of damages to the cashmere fibers. Furthermore, we also successfully validated the supercritical removal of colorants by using X-ray energy spectroscopy (EDS) and scanning electron microscopy (SEM) analysis. Strength measurements and thermogravimetric (TG) and differential thermogravimetric (DTG) analysis demonstrate that supercritical bleaching had a reduced impact on the thermal and mechanical properties of the cashmere fiber. An optimized enzymatic-oxygen bleaching process in SCF-CO2 was further recommended by accompanying with a high whiteness value at 83.36 and an acceptable alkali solubility at 15.55 %. This developed supercritical bleaching method is prospective to be utilized for clear production of cashmere fibers by avoiding an extensive use of chemicals and the generation of heavy wastewater, as well as with less or non-effluent discharge.

BackgroundThe skin fungal communities of animals play a crucial role in maintaining host health and defending against pathogens. Because fungal infections can affect the skin microbiota of bats, gaining a comprehensive understanding of the characteristics of healthy bat skin fungal communities and the ecological processes driving them provides valuable insights into the interactions between pathogens and fungi.MethodsWe used Kruskal–Wallis tests and Permutational Multivariate Analysis of Variance (PERMANOVA) to clarify differences in skin fungal community structure among bat species. A Generalized Linear Model (GLM) based on a quasi-Poisson distribution and partial distance-based redundancy analysis (db-RDA) was performed to assess the influence of variables on skin fungal communities. Using community construction models to explore the ecological processes driving fungal community changes, t-tests and Wilcoxon tests were used to compare the alpha diversity and species abundance differences between the fungal structure on bat species’ skin and the environmental fungal pool.ResultsWe found significant differences in the composition and diversity of skin fungal communities among bat species influenced by temperature, sampling site, and body mass index. Trophic modes and skin fungal community complexity also varied among bat species. Null model and neutral model analysis demonstrated that deterministic processes dominated the assembly of skin fungal communities, with homogeneous selection as the predominant process. Skin fungal communities on bat species were impacted by the environmental fungal reservoir, and actively selected certain amplicon sequence variants (ASVs) from the environmental reservoir to adhere to the skin.ConclusionIn this study, we revealed the structure and the ecological process driving the skin fungal community across bat species in northern China. Overall, these results broaden our knowledge of skin fungal communities among bat species, which may be beneficial to potential strategies for the protection of bats in China.