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Abstract Blinatumomab has emerged as a promising component of first-line therapy for acute B-cell precursor lymphoblastic leukemia (BCP-ALL), bolstering treatment efficacy. To mitigate CD19 selection pressure and reduce the incidence of blinatumomab-associated toxicities, pre-treatment chemotherapy is recommended before administering blinatumomab. From September 2022 to December 2023, we conducted a single-arm, multicenter, phase 2 trial (NCT05557110) in newly diagnosed Philadelphia chromosome-negative BCP-ALL (Ph-negative BCP-ALL) patients. Participants received induction treatment with reduced-dose chemotherapy (RDC), comprising idarubicin, vindesine, and dexamethasone over 7 days, followed by 2 weeks of blinatumomab. Those failing to achieve composite complete remission (CRc) received an additional 2 weeks of blinatumomab. The primary endpoint was the CRc rate post initial induction treatment. Of the 35 enrolled patients, 33 (94%) achieved CRc after 2 weeks of blinatumomab, with 30 (86%) achieving measurable residual disease (MRD) negativity. Two patients extended blinatumomab to 4 weeks. With either 2 or 4 weeks of blinatumomab treatment, all patients achieved CR (35/35) and 89% (31/35) were MRD negativity. The median time to CR was 22 days. Immune effector cell-associated neurotoxicity syndrome was limited (14%, all grade 1). Non-hematological adverse events of grade 3 or higher included pneumonia (17%), sepsis (6%), and cytokine release syndrome (9%). With a median follow-up of 11.5 months, estimated 1-year overall survival and 1-year progression-free survival rates were 97.1% and 82.2%, respectively. These findings affirm that RDC followed by blinatumomab is an effective and well-tolerated induction regimen for newly diagnosed Ph-negative BCP-ALL, supporting a shift towards less intensive and more targeted therapeutic approaches. Trial registration: https://www.clinicaltrials.Gov . Identifier NCT05557110.

This study presents the identification of four novel Xylaria species, discovered in the karst region of China. The discovery was facilitated by a rigorous analysis that encompassed both morpho-anatomical features and multi-locus phylogenetics utilizing sequences from the ITS, rpb2, and TUB2 loci. The newly identified species are designated as Xylaria jichuanii sp. nov., X. nanningensis sp. nov., X. orientalis sp. nov., and X. taiyangheensis sp. nov. The distinction of these species from their known counterparts was verified through comparison of morphological features and phylogenetic analysis. The study further provides detailed morphological descriptions, illustrative representations, and a phylogenetic tree, all of which contribute to the taxonomic positioning of these novel species.

Molecular phylogeny and morphological characteristics of collections of diatrypaceous fungi from Guizhou Province, China, lead to the establishment of a new genus, Stromatolinea, and the identification of four new species and two new combinations. The taxa were found growing on the dead culms of Phyllostachys bamboo. The new genus is distinguished by its well-developed, discrete linear stromata with yellow interior tissue and allantoid subhyaline ascospores. The newly described species are Stromatolinea grisea, S. guizhouensis, S. hydei, and S. xishuiensis. Additionally, two new combinations, Stromatolinea linearis and S. phaselina, are proposed based on comparative analysis and morphology. Phylogenetic analyses were conducted using ITS and TUB2 sequences. The study includes comprehensive morphological descriptions, illustrations, and a phylogenetic tree depicting the placement of the new taxa.

Abstract Objective The current research aims to evaluate the efficacy and safety of anlotinib, an orally administered small-molecular tyrosine kinase inhibitor (TKI), in the treatment of recurrent epithelial ovarian cancer (EOC). Methods Patients with recurrent EOC subjected to treatment with anlotinib in Fourth Hospital of Hebei Medical University from 2020 to 2022 were included. The evaluation involved a thorough review of medical records, focusing on parameters such as the objective response rate (ORR), disease control rate (DCR), survival outcomes, and safety profile. Results This study recorded 51 patients, with 26 patients undergoing anlotinib monotherapy. The median progression-free survival (PFS) was 4.0 months, whereas the median overall survival (OS) was not reached. Seven cases underwent a combined treatment of anlotinib with chemotherapy. Among them, two patients achieved partial response (PR), two were categorized as stable disease (SD), and three were identified as having progressive disease (PD). The ORR and DCR were 28.5% (2/7) and 57.1% (4/7), respectively. Additionally, 18 cases received anlotinib maintenance therapy, and the median PFS and the median OS were 7.0 months and 25.5 months, respectively. The most prevalent adverse effects included fatigue (38.6%), hypertension (27.3%), nausea and vomiting (25.0%) and hand-foot syndrome (25.0%). Conclusion Anlotinib demonstrated mild efficacy in the treatment of recurrent EOC, whether employed as monotherapy, chemotherapy-combined therapy, or maintenance therapy. The safety profile was proven manageable and well-tolerated, suggesting that anlotinib may emerge as a viable and novel treatment option for recurrent EOC.

Abstract Background Treatment strategy against immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) frequently requires other immunosuppressive agents. Tofacitinib is a rapidly acting JAK-STAT inhibitor with proven efficacy in multiple autoimmune diseases. We aimed to evaluate the efficacy and safety of tofacitinib in the management of irAEs in cancer patients. Methods Cancer patients who received ICIs and were treated with tofacitinib for the management of irAEs at 6 institutions were retrospectively included in this study. Demographic and clinical characteristics were obtained from electronic medical records. Longitudinal assessment of cardiac troponin T (cTnT) with clinical assessment was utilized to evaluate the benefit of tofacitinib treatment in patients with ICI myocarditis. Overall survival (OS) was also assessed. Results Fifty-three patients were included in this study. The median time from irAE onset to tofacitinib therapy was 17 (range, 2–186) days and the median duration of tofacitinib treatment was 52.5 (range, 3–277) days. Enrolled patients were subdivided into 3 groups based on clinical severity and steroid responsiveness including 11 life-threatening cases, 30 steroid-resistant cases, and 12 cases with steroid taper failure. Clinical remission rate in each group was 54.5%, 96.7%, and 100%, respectively (P

Abstract Objective In the surgery-focused field of obstetrics and gynecology (OB-GYN), the development of residents’ skills is paramount. This study aims to evaluate the impact of an enhanced Peyton Four-Step Teaching Model on the foundational skill training of first-year OB-GYN residents. Methods Utilizing a cohort study design, we assessed 116 first-year residents from the OB-GYN residency program at Shengjing Hospital of China Medical University from June 2021 to June 2023. The 57 residents beginning their training in 2022 were part of the Refined Peyton (RP) group, introduced to the RP method; the 59 residents from 2021 served as the Traditional Teaching-mode (TTM) group, receiving conventional simulation-based instruction. Teaching effectiveness was assessed by comparing theoretical knowledge and skill performance assessments, National Medical Licensing Examination (NMLE) pass rates, direct observation of procedural skills (DOPS) one year post-training, and survey feedback. Results The theoretical knowledge scores for both groups were comparable at 78.78 ± 4.08 and 78.70 ± 3.83, with no significant difference (P = 0.76). However, the experimental group demonstrated superior performance in skill operation assessments, first-time NMLE pass rates, and DOPS evaluations one year after training [(77.05 ± 5.39) vs. (84.60 ± 5.65), 100.0% (57/57) vs. 86.4% (51/59), and (75.22 ± 3.56) vs. (82.54 ± 3.43)], as well as higher teaching satisfaction scores [(4.63 ± 0.46) vs. (3.92 ± 0.62)], with all differences being statistically significant (P

Abstract The honeybee gut microbiome is crucial for degrading diverse pollen glycans. Yet it is unclear how this process shapes the interactions among bacteria. Here, we demonstrate a conditional mutualistic interaction between strains of two honeybee gut bacteria Bifidobacterium asteroides and Gilliamella apicola. When co-occurring in vitro and in vivo, Bifidobacterium provides complementary demethylation service to promote Gilliamella growth on methylated homogalacturonan, an enriched polysaccharide of pectin. In exchange, Gilliamella shares digestive products with Bifidobacterium, through which a positive interaction is established. This positive interaction vanishes when Bifidobacterium is not required on a non-methylated diet. Results from biochemical and gene expression analyses combined with model simulation further suggest that the ratio change of the two major homogalacturonan breakdown products, galacturonic acid (GalA) and di-GalA, determines the bacterial interaction. This study unravels how glycan metabolism may shape the interactions between honeybee gut bacteria.

Abstract Nanocrystalline metallic materials have the merit of high strength but usually suffer from poor ductility and rapid grain coarsening, limiting their practical application. Here, we introduce a core-shell nanostructure in a multicomponent alloy to address these challenges simultaneously, achieving a high tensile strength of 2.65 GPa, a large uniform elongation of 17%, and a high thermal stability of 1173 K. Our strategy relies on an ordered superlattice structure that excels in dislocation accumulation, encased by a ≈3 nm disordered face-centered-cubic nanolayer acting as dislocation sources. The ordered superlattice with high anti-phase boundary energy retards dislocation motions, promoting their interaction and storage within the nanograins. The disordered interfacial nanolayer promotes dislocation emission and effectively accommodates the plastic strain at grain boundaries, preventing intergranular cracking. Consequently, the order-disorder core-shell nanostructure exhibits enhanced work-hardening capability and large ductility. Moreover, such core-shell nanostructure exhibits high coarsening resistance at elevated temperatures, enabling it high thermal stability. Such a design strategy holds promise for developing high-performance materials.

Abstract There is no effective and noninvasive solution for thrombolysis because the mechanism by which certain thrombi become tissue plasminogen activator (tPA)-resistant remains obscure. Endovascular thrombectomy is the last option for these tPA-resistant thrombi, thus a new noninvasive strategy is urgently needed. Through an examination of thrombi retrieved from stroke patients, we found that neutrophil extracellular traps (NETs), ε-(γ-glutamyl) lysine isopeptide bonds and fibrin scaffolds jointly comprise the key chain in tPA resistance. A theranostic platform is designed to combine sonodynamic and mechanical thrombolysis under the guidance of ultrasonic imaging. Breakdown of the key chain leads to a recanalization rate of more than 90% in male rat tPA-resistant occlusion model. Vascular reconstruction is observed one month after recanalization, during which there was no thrombosis recurrence. The system also demonstrates noninvasive theranostic capabilities in managing pigs’ long thrombi (>8 mm) and in revascularizing thrombosis-susceptible tissue-engineered vascular grafts, indicating its potential for clinical application. Overall, this noninvasive theranostic platform provides a new strategy for treating tPA-resistant thrombi.

To examine how different harvesting periods affect the storage quality of 'Satsuma' plum fruits, this study analyzed 13 quality and physiological metrics post-harvest and utilized principal component analysis (PCA) and mathematical models to assess (0±0.5)℃ low temperature storage quality across three different harvesting periods (100 d after flowering, 103 d after flowering, 106 d after flowering). The results showed that harvesting at 103 days after full bloom led to the best preservation effect. Additionally, the hardness and total acidity of plum fruit decreased by 37.37% and 27.06% respectively until the end of the storage period, which was the slowest. Furthermore, changes in relative conductivity, anthocyanins, total soluble solids, malondialdehyde, total phenols, and flavonoids were relatively smooth. The activity of polyphenol oxidase was low, while peroxidase, superoxide dismutase, and catalase activities were high, specifically catalase activities. After conducting PCA analysis, it was determined that PC1, PC2, and PC3 accurately capture 87.472% of the relevant information. These results suggested that varying harvesting periods would have significant impacts on all indicators. The mathematical model analysis revealed that the plum fruits harvested at 100, 103, and 106 days after bloom, and stored for 56 days, had comprehensive scores of 1.06, 0.99, and 2.69, respectively. Lower comprehensive scores indicated better quality, so the order of preservation effect was as follows: 103 days after bloom>100 days after bloom>106 days after bloom. The study provides a theoretical framework for evaluating postharvest preservation and quality of plum fruits, along with technical parameters to enable timely harvesting.

ABSTRACT Aims Very few cohort studies are available about the relation between remnant cholesterol (RC) and diabetes. Based on a prospective cohort survey, this research aimed at investigating if high RC was related to a future diabetes risk in the Chinese population, as well as to compare the association between RC, high‐density lipoprotein cholesterol (HDL‐C), low‐density lipoprotein cholesterol (LDL‐C), total cholesterol (TC), triglycerides (TG), TG/HDL‐C, LDL‐C/HDL‐C, TC/HDL‐C, and non‐high‐density lipoprotein cholesterol (non‐HDL‐C), and future diabetes risk. Materials and Methods 6,700 baseline normoglycemic participants of the REACTION study's Beijing center were recruited in 2011–2012 and followed up in 2015. Multivariate Cox regression analyses were performed to explore the relationship of RC, HDL‐C, LDL‐C, TC, TG, LDL‐C/HDL‐C, TG/HDL‐C, TC/HDL‐C, and non‐HDL‐C and a future diabetes risk. Results After potential confounders were adjusted for, only RC (HR 1.134, 95% CI 1.016–1.267, P = 0.025) was positively related to a future diabetes risk, and only HDL‐C (HR 0.728, 95% CI 0.578–0.918, P = 0.007) was negatively related to a future diabetes risk. The rest of the lipid parameters were not related to a future risk of diabetes. Sensitivity and stratification analyses revealed that the relation between RC and future diabetes risk was stable. RC and future diabetes risk were still positively correlated even when the HDL‐C was ≥1.04 mmol/L (HR 1.167, 95% CI 1.050–1.297, P = 0.004). Conclusions It was RC, but not other lipid parameters, that was independently and positively related to a future risk of diabetes among the Chinese general population. Moreover, the relationship between RC and diabetes risk was stable, even with appropriate levels of HDL‐C.

The confined aquifer dewatering for long-deep excavations usually encounters challenges due to complicated geotechnical conditions, large excavation sizes, and high hydraulic pressures. To propose the most efficient scheme of confined aquifer dewatering for long-deep excavations, dewatering optimizations were performed using the simulation–optimization method. An open cut tunnel of the Jiangyin-Jingjiang Yangtze River Tunnel Project was taken as an example. The methods of finite element and linear programming (LP) were combined to optimize the dewatering process. A three-dimensional finite element model was developed. After simulating the pumping tests, hydraulic conductivity was inverted. Then, necessary parameters in the LP method were determined by simulating dewatering with each pumping well, and various LP models were developed based on some important influence factors such as dewatering sequence, considered pumping wells, and pumping rate limitation. Finally, the optimal pumping rates were solved and applied to the numerical model, with induced drawdown and ground settlement computed for comparison. The results indicate that the optimization can significantly reduce the required wells in the original design. Dewatering in the deepest zone exhibits the highest efficiency for long-deep excavations with gradually varying depths. For the dewatering sequence from the shallowest to the deepest zone, more pumping wells are required but less energy is consumed. Higher quantity and more advantageous locations of pumping wells in the LP model usually result in lower total pumping rate, drawdown, and ground settlement. If more pumping wells are considered in the deepest zone, pumping rate limitation of single well will only slightly increase the total pumping rate, number of required pumping wells, drawdown, and ground settlement.

Abstract During the drilling process, the issue of drilling fluid loss can lead to changes in the mechanical properties of the formation, thereby altering the stress environment of nearby faults. In order to assess the risk of fault activation during drilling operations, the Ordos M area shale was selected as the research object. Mechanical experiments were conducted on rock samples immersed in water-based drilling fluid with a pressure differential of 2 MPa and a temperature of 50 °C. The changes in the mechanical properties of the shale before and after immersion in drilling fluid were determined. Based on the experimental results, combined with the spring combination model and fault activation theory, a quantitative evaluation of fault activation risk was conducted. The findings revealed that the shale in this region has a high clay content, demonstrating a certain level of water sensitivity. The presence of micro-pores and micro-fractures is well-developed, increasing the interaction probability between drilling fluids and clay minerals. After immersion in drilling fluid, there was a varied decline in all mechanical strengths of the shale. The elastic modulus is positively correlated with the shear strength and Coulomb stress of the fault plane. The Poisson’s ratio is positively correlated with the shear strength and negatively correlated with the Coulomb stress. The greater the internal friction and cohesion, the higher the shear strength of the fault plane, and the larger the friction coefficient, the smaller the Coulomb stress, resulting in a more stable fault.

Abstract Background Evidence on the association between serum vitamin C (sVC) levels and obesity is limited. This study aimed to explore the relationship between sVC and body mass index (BMI) in adolescents aged 12 to 19 years. Methods We analyzed data from the National Health and Nutrition Examination Survey (NHANES) 2003–2006, with 3952 participants. sVC and BMI were independent variables and dependent variables, respectively. The associations of sVC with BMI were examined using multivariable linear regression models. Age, sex, and race/ethnicity were analyzed as subgroups. Then, we devised smooth curve fittings and saturation threshold analysis to address the nonlinear relationship. Results sVC had a negative correlation with BMI after adjusting for all covariates (β: -1.020, 95% CI: -1.359, -0.680). In the subgroup analysis by age, sex, and race/ethnicity, there was still a negative correlation between sVC and BMI (p

Abstract Chronic heart failure is one of the most common reasons for hospitalization. Current risk stratification is based on ejection fraction, whereas many arrhythmic events occur in patients with relatively preserved ejection fraction. We aim to investigate the mechanistic link between proarrhythmic abnormalities, reduced contractility and diastolic dysfunction in heart failure, using electromechanical modelling and simulations of human failing cardiomyocytes. We constructed, calibrated and validated populations of human electromechanical models of failing cardiomyocytes, that were able to reproduce the prolonged action potential, reduced contractility and diastolic dysfunction as observed in human data, as well as increased propensity to proarrhythmic incidents such as early afterdepolarization and beat-to-beat alternans. Our simulation data reveal that proarrhythmic incidents tend to occur in failing myocytes with lower diastolic tension, rather than with lower contractility, due to the relative preserved SERCA and sodium calcium exchanger current. These results support the inclusion of end-diastolic volume to be potentially beneficial in the risk stratifications of heart failure patients.

Three mole percent yttria-stabilized tetragonal zirconia polycrystal (3Y-TZP) ceramics are exemplary materials for dental restoration due to their high mechanical strength, fracture toughness, chemical endurance, and biocompatibility. Nevertheless, 3Y-TZP ceramics are opaque and their CAD/CAM manufacturing process may cause micro-cracks in conventional clinical practice. In this study, 3Y-TZP ceramic samples were prepared using vat photopolymerization, pre-sintering, external staining, and final high-temperature sintering. The microstructures, mechanical properties, optical properties, and cytotoxicity of the 3Y-TZP ceramic samples were investigated. The results indicate that with increasing Fe3+ concentration of staining solution from 0.1 mol/L to 0.3 mol/L and increasing staining time from 5 s to 30 min, the 3Y-TZP ceramic samples showed a tetragonal crystal structure of zirconia with densely packed grains and a slight increase in grain size. The flexural strength, Vickers hardness, and fracture toughness of 3Y-TZP ceramic samples stained in 0.1–0.3 mol/L Fe3+ solution for 5 s to 3 min were all greater than 665 MPa, 11.9 GPa, and 5 MPa m1/2, respectively, meeting the mechanical requirements for clinical application. Colorimetric analysis revealed a decrease in L* (black-white index) from 90.4 to 81.3, an increase in a* (green-red index) from −1.5 to 3.2, and an increase in b* (blue-yellow index) from 11.6 to 20.3, approximating the commercial VITA 3D-Master Shade Guide chromaticity. Furthermore, the 3Y-TZP ceramic samples exhibited a cell viability of 90% or higher toward L929 cells.

Abstract Background Selenium nanoparticles (SeNPs) are increasingly gaining attention due to its characteristics of low toxicity, high activity, and stability. Additionally, Bacillus licheniformis, as a probiotic, has achieved remarkable research outcomes in diverse fields such as medicine, feed processing, and pesticides, attracting widespread attention. Consequently, evaluating the activity of probiotics and SeNPs is paramount. The utilization of probiotics to synthesize SeNPs, achieving large-scale industrialization, is a current hotspot in the field of SeNPs synthesis and is currently the most promising synthetic method. To minimize production costs and maximize yield of SeNPs, this study selected agricultural by-products that are nutrient-rich, cost-effective, and readily available as culture medium components. This approach not only fulfills industrial production requirements but also mitigates the impact on downstream processes. Results The experimental findings revealed that SeNPs synthesized by B. licheniformis F1 exhibited a spherical morphology with diameters ranging from 110 to 170 nm and demonstrating high stability. Both the secondary metabolites of B. licheniformis F1 and the synthesized SeNPs possessed significant free radical scavenging ability. To provide a more robust foundation for acquiring large quantities of SeNPs via fermentation with B. licheniformis F1, key factors were identified through single-factor experiments and response surface methodology (RSM) include a 2% seed liquid inoculum, a temperature of 37 ℃, and agitation at 180 rpm. Additionally, critical factors during the optimization process were corn powder (11.18 g/L), soybean meal (10.34 g/L), and NaCl (10.68 g/L). Upon validating the optimized conditions and culture medium, B. licheniformis F1 can synthesize nearly 100.00% SeNPs from 5 mmol/L sodium selenite. Subsequently, pilot-scale verification in a 5 L fermentor using the optimized medium resulted in a shortened fermentation time, significantly reducing production costs. Conclusion In this study, the efficient production of SeNPs by the probiotic B. licheniformis F1 was successfully achieved, leading to a significant reduction in fermentation costs. The exploration of the practical applications of this strain holds significant potential and provides valuable guidance for facilitating the industrial-scale implementation of microbial synthesis of SeNPs.

Abstract Background Human umbilical cord mesenchymal stem cells-derived extracellular vesicles (hUCMSC-EVs) have potent immunomodulatory properties similar to parent cells. This study investigated the therapeutic effects and immunomodulatory mechanisms of hUCMSC-EVs in an experimental lupus nephritis model. Methods The hUCMSC-EVs were isolated by using differential ultracentrifugation. In vivo, the therapeutic effects of hUCMSC-EVs in lupus-prone MRL/lpr mice were investigated, and the mechanisms of treatment were explored according to the abnormal T and B cell responses among both the spleen and kidney. Results MRL/lpr mice treated with hUCMSC-EVs reduced proteinuria extent, serum creatinine and renal pathological damage; decreased splenic index and serum anti-dsDNA IgG level; and improved survival rate. hUCMSC-EVs lowered the percentage of T helper (Th)1 cells, double-negative T (DNT) cells, and plasma cells among splenocytes; inhibited the infiltration of Th17 cells but promoted regulatory T (Treg) cells in the kidney, followed by a reduction in pro-inflammatory cytokine levels(IFN-γ, IL-2, IL-6, IL-21, and IL-17 A). In addition, hUCMSC-EVs inhibited the activation of STAT3 and down-regulated IL-17 A protein levels in the kidney. Conclusion The results of this study demonstrated that hUCMSC-EVs had therapeutic effects on experimental lupus nephritis (LN) by regulating Th1/Th17/Treg imbalance and inhibiting DNT and plasma cells. Additionally, hUCMSC-EVs inhibited Th17 cell differentiation in kidney by regulating the IL-6/STAT3/IL-17 signal pathway, which might be an important mechanism for alleviating renal injury. Taken together, we demonstrated that hUCMSC-EVs regulating T and B cell immune responses might represent a novel mechanism of hUCMSCs in treating LN, thus providing a new strategy for treating LN.

Abstract Genetically-encoded dopamine (DA) sensors enable high-resolution imaging of DA release, but their ability to detect a wide range of extracellular DA levels, especially tonic versus phasic DA release, is limited by their intrinsic affinity. Here we show that a human-selective dopamine receptor positive allosteric modulator (PAM) can be used to boost sensor affinity on-demand. The PAM enhances DA detection sensitivity across experimental preparations (in vitro, ex vivo and in vivo) via one-photon or two-photon imaging. In vivo photometry-based detection of optogenetically-evoked DA release revealed that DETQ administration produces a stable 31 minutes window of potentiation without effects on animal behavior. The use of the PAM revealed region-specific and metabolic state-dependent differences in tonic DA levels and enhanced single-trial detection of behavior-evoked phasic DA release in cortex and striatum. Our chemogenetic strategy can potently and flexibly tune DA imaging sensitivity and reveal multi-modal (tonic/phasic) DA signaling across preparations and imaging approaches.

Abstract Phage therapy holds promise as an alternative to antibiotics for combating multidrug-resistant bacteria. However, host bacteria can quickly produce progeny that are resistant to phage infection. In this study, we investigated the mechanisms of bacterial resistance to phage infection. We found that Rsm1, a mutant strain of Salmonella enteritidis (S. enteritidis) sm140, exhibited resistance to phage Psm140, which was originally capable of lysing its host at sm140. Whole genome sequencing analysis revealed a single nucleotide mutation at position 520 (C → T) in the rfbD gene of Rsm1, resulting in broken lipopolysaccharides (LPS), which is caused by the replacement of CAG coding glutamine with a stop codon TAG. The knockout of rfbD in the sm140ΔrfbD strain caused a subsequent loss of sensitivity toward phages. Furthermore, the reintroduction of rfbD in Rsm1 restored phage sensitivity. Moreover, polymerase chain reaction (PCR) amplification of rfbD in 25 resistant strains revealed a high percentage mutation rate of 64% within the rfbD locus. We assessed the fitness of four bacteria strains and found that the acquisition of phage resistance resulted in slower bacterial growth, faster sedimentation velocity, and increased environmental sensitivity (pH, temperature, and antibiotic sensitivity). In short, bacteria mutants lose some of their abilities while gaining resistance to phage infection, which may be a general survival strategy of bacteria against phages. This study is the first to report phage resistance caused by rfbD mutation, providing a new perspective for the research on phage therapy and drug-resistant mechanisms.

Abstract Traditional herbs have a history of clinical use in anti-fatigue. However, several adverse effects of herbs have been identified. Pityriasis rosea-like eruption (PR-LE) is a rare cutaneous complication of herbs. To the best of our knowledge, there have been few reports of PR-LE following herbs. Here, we described a case of PR-LE that developed 6 days after taking anti-fatigue herbs. After the 17 days of stopping Aconitum carmichaelii Debx and Panax Ginseng, it notably faded. So, when anti-fatigue herbs being authorized for fatigue use, monitoring for potential adverse effects is necessary.

Abstract In recent years, deep learning has been widely used in vulnerability detection with remarkable results. These studies often apply natural language processing (NLP) technologies due to the natural similarity between code and language. Since NLP usually consumes a lot of computing resources, its combination with quantum computing is becoming a valuable research direction. In this paper, we present a Recurrent Quantum Embedding Neural Network (RQENN) for vulnerability detection. It aims to reduce the memory consumption of classical models for vulnerability detection tasks and improve the performance of quantum natural language processing (QNLP) methods. We show that the performance of RQENN achieves the above goals. Compared with the classic model, the space complexity of each stage of its execution is exponentially reduced, and the number of parameters used and the number of bits consumed are significantly reduced. Compared with other QNLP methods, RQENN uses fewer qubit resources and achieves a 15.7% higher accuracy in vulnerability detection.

Abstract Abnormalities in the extracellular matrix (ECM) play important roles in the regulation and progression of clear cell renal cell carcinoma (ccRCC). The cysteine cathepsin is one of the major proteases involved in ECM remodeling and has been shown to be aberrantly expressed in multiple cancer types. However, the clinical significance and biological function of distinct cysteine cathepsins in ccRCC remain poorly understood. In this study, several bioinformatics databases, including UALCAN, TIMER, GEPIA and the Human Protein Atlas datasets, were used to analyze the expression and prognostic value of different cysteine cathepsin family members in ccRCC. We found that the expression level of CTSF was downregulated in tumor tissues and closely related to the poor survival of ccRCC patients. Further in vitro experiments suggested that CTSF overexpression suppressed the proliferation and migration of ccRCC cells. Moreover, the expression of CTSF was shown to be associated with several immune-infiltrating cells and immunomodulators in ccRCC. These results indicated that CTSF might be a promising diagnostic and prognostic marker in ccRCC.

Abstract Background Chronic inflammation may contribute to increased mortality risk in individuals with osteoarthritis (OA), but research on the prognostic value of inflammatory biomarkers is limited. We aimed to evaluate the associations of the systemic immune–inflammation index (SII) and systemic inflammation response index (SIRI) with all-cause and cardiovascular mortality among US adults with OA. Methods This cohort study included 3545 adults with OA aged ≥ 20 years from the National Health and Nutrition Examination Survey 1999–2020. The SII and SIRI were calculated using complete blood cell count data. Participants were categorized as having a higher or lower SII and SIRI using cutoff points derived by the maximally selected rank statistics method. Cox proportional hazards models, Fine–Gray competing risk regression models and time-dependent receiver operating characteristic (ROC) analysis were used to evaluate the associations between the SII/SIRI and mortality in OA patients. Results Over a median follow-up of 5.08 (3.42–9.92) years, 636 (17.94%) deaths occurred, including 149 (4.20%) cardiovascular deaths. According to multivariable-adjusted models involving demographic, socioeconomic, and health factors, OA patients with a higher SII had a twofold greater risk of all-cause mortality than patients with a lower SII (HR 2.01; 95% CI: 1.50–2.68). Similarly, a higher SIRI was associated with an 86% increased risk of all-cause mortality relative to a lower SIRI (HR 1.86; 95% CI: 1.46–2.38). Similar to the trend found with all-cause mortality, patients with an elevated SII and SIRI had a 88% and 67% increased risk of cardiovascular mortality, respectively, compared to patients with a lower SII (HR 1.88; 95% CI: 1.16–3.03) and SIRI (HR 1.67; 95% CI: 1.14–2.44). Time-dependent ROC curves showed that both the SII and SIRI have moderate and valid performance in predicting short- and long-term mortality in patients with OA. Conclusions Higher SII and SIRI values were associated with greater all-cause and cardiovascular mortality among US adults with OA.

Objective The most common causes of plantar and heel pain are plantar fasciitis and calcaneal spurs, and they often co‐exist. Surgery is a recognized treatment for refractory plantar fasciitis. However, few studies have proposed treatment options for patients with metatarsophalangeal fasciitis with bone spurs. Accordingly, this study's purpose was to propose a four‐step surgical regimen, and to improve the surgical outcome of plantar fasciitis with osteophytes and to establish a procedure for surgical treatment. Methods Retrospective analysis of 45 patients suffering from plantar fasciitis with bone spurs from 2020 to 2023. All patients underwent a four‐step procedure, including plantar fascia release, calcaneal spur grinding, inflammatory tissue removal, and calcaneal burr decompression. The imaging parameters and functional scores were recorded before and after the operation. The objective evaluation included the measurement of calcaneal spur length on radiographs. Clinical evaluation included the American Orthopaedic Foot and Ankle Society (AOFAS), the Visual Analog Scale (VAS), and the Foot and Ankle Outcome Scale (FAOS). Measurement data that conformed to normal distribution were expressed as (x2 ± s), and pre‐and postoperative AOFAS, FAOS, and VAS scores were compared using repeated‐measures ANOVA, and preoperative and postoperative spur lengths were compared using paired t‐tests. Results The 45 patients were followed up for 3 to 30 months, (17.72 ± 8.53) months, at final follow‐up, the patient's AOFAS score improved from preoperative (74.93 ± 5.56) to (94.78 ± 3.98), FAOS score increased from preoperative (76.42 ± 3.37) to (96.16 ± 2.74), the VAS score decreased from (3.18 ± 0.54) to (1.07 ± 1.20) (p

The handling safety of high explosives, as routinely characterized by the drop-weight impact sensitivity (IS), has important repercussions on the development of explosives. Herein, the impressive low IS of β-HMX (1,3,5,7-tetranitro-1,3,5,7-tetraazacyclooctane) spherulite and the corresponding desensitization mechanism are elaborated with the influential role of the grain boundary. The sensitivity was evaluated by a substantial number of IS tests using “X out of 25”, Bruceton “up and down” and high-speed photography technology. The collected data, comprising over 12 batches of samples for a total of about 400 impact tests, were analyzed as a function of the particle structure parameters. The IS was found to positively relate to the porosity calculated from Small-Angle X-ray Scattering data which semi-quantitatively reflected the grain boundary in spherulite. The investigation into the influence of shape suggests that while particle shape did contribute to desensitization, the primary factor affecting the reduction in HMX sensitivity was the presence of grain boundaries. The grain boundary strengthening and spherical envelope were found to be influential as they may be beneficial for energy de-localization, thereby mitigating localized heating. The polycrystalline spherulite with purity (>98.5%), sphericity (>80.0%) and porosity (>0.4%) carefully controlled exhibited the ignition probability of 0% and H50 of c.a. 99.0 cm, outperforming any other monocrystalline β-HMX particles. This work introduces the grain boundary as a new consideration for desensitization in energetic crystals, which has been previously underestimated but holds promise for the design of high explosives with improved handling safety.

Isothermal heat treatment experiments were used to studied the dissolution behavior and kinetics of the γ′ precipitates within the hot-extruded novel powder metallurgy Ni-based superalloy A1. The characteristics of the γ′ precipitates were accurately and rapidly extracted by deep learning methods. The JMAK models were established to predict the change of the area fraction of γ′ precipitates during heat treatment. The determination coefficient R2 of model is 0.99. The results indicate that the dissolution sequence, morphological evolution, and dissolution mechanisms of the three types of γ′ precipitates are different. The small-sized tertiary γ′ precipitates (γ′t) dissolve first, while the larger-sized primary γ′ precipitates (γ′p) dissolve last. After 15 min at 1120 °C, there were only a small amount of γ′ precipitates with 0.19 ± 0.03 % area fraction. And there was not significant changed over time. After 1 min at 1150 °C, the γ′ precipitates completely dissolved. During the process of low temperature subsolvus heat treatment (1060 °C, 1090 °C), the large-sized γ′s grown at the expense of consuming the small-sized γ′ precipitates, and the γ′s tend towards directional arrangement due to elastic interaction energy. During the subsolvus heat treatment process, the γ′p spilt due to elastic strain energy and the uneven diffusion of alloying elements, while neck-connected coalescence coarsening occurs due to the overlapping diffusion fields.

Abstract Nonlinear optical activities, especially second harmonic generation (SHG), are key phenomena in inversion-symmetry-broken two-dimensional (2D) transition metal dichalcogenides (TMDCs). On the other hand, anisotropic nonlinear optical processes are important for unique applications in nano-nonlinear photonic devices with polarization functions, having become one of focused research topics in the field of nonlinear photonics. However, the strong nonlinearity and strong optical anisotropy do not exist simultaneously in common 2D materials. Here, we demonstrate strong second-order and third-order susceptibilities of 64 pm/V and 6.2×10−19 m2/V2, respectively, in the even-layer PdPSe, which has not been discovered in other common TMDCs (e.g., MoS2). Strikingly, it also simultaneously exhibited strong SHG anisotropy with an anisotropic ratio of ~45, which is the largest reported among all 2D materials to date, to the best of our knowledge. In addition, the SHG anisotropy ratio can be harnessed from 0.12 to 45 (375 times) by varying the excitation wavelength due to the dispersion of $${\chi }^{(2)}$$ χ ( 2 ) values. As an illustrative example, we further demonstrate polarized SHG imaging for potential applications in crystal orientation identification and polarization-dependent spatial encoding. These findings in 2D PdPSe are promising for nonlinear nanophotonic and optoelectronic applications.

In the Jiepailing mining area, during the exploration and mining of deep polymetallic ores, the water filling in the pits and extensive karst ground collapses in the Yujia area occurred.Although previous studies have investigated the hydrogeological conditions in the mining area, the potential sources and pathways of water filling that threaten mine safety and damage the surrounding geological environment, are not clear. This study investigated the hydrogeological conditions and analyzed the pathways of water filling in the Jiepailing mining area by using systematical analysis of hydrogeological data from various stages,ground surface investigation, geophysical exploration, drilling, and pumping tests. The results show that: (1) the northeastern fault F303 is found,loocated in the southwestern part of the study area. (2) In the western part of the mining area the absence of the aquifuge between F201 and F32 leads to Shidengzi Formation directly contacting the Hutian Group and Zimenqiao Formation.It constitutes the main pathway of water filling in the mine pits, affected by F201, F303, and F32. In the northwestern part of the mining area, the contact zone between the granodiorite porphyry and the surrounding rock has good water-richness, forming the other pathway for water filling in the mine pits. The main sources of water filling are the groundwater in the western Hutian Group and Tianweixi river water. This study suggests executing curtain grouting on the west side of F1 by the lower impermeable layer group to block water pathways within the Hutian Group of the Zimenqiao Formation, thereby interrupting the hydraulic connection between the mining area and the river water, as well as groundwater in the Hutian Group. The results can provide basic information for the implementation of water prevention and control in the mine area.

Abstract Vitamin A plays a pivotal role in health, particularly in regulating fat metabolism. Despite its significance, research into the direct relationship between vitamin A levels and obesity, especially among adolescents, is sparse. This study aims to explore this association within the adolescent population in the United States. This cross-sectional study analyzed the National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2006, with 8218 participants. The levels of vitamin A in the serum were determined based on utilizing high-performance liquid chromatography with photodiode array detection. The relationship between serum vitamin A concentrations and body mass index (BMI) was evaluated using weighted multiple linear regression models, incorporating subgroup analyses by sex and race/ethnicity to provide nuanced insights. A positive correlation was observed between serum vitamin A levels and BMI, with BMI increasing progressively across vitamin A quartiles (P

Abstract Immunotherapy with chimeric antigen receptor T cells for pediatric solid and brain tumors is constrained by available targetable antigens. Cancer-specific exons present a promising reservoir of targets; however, these have not been explored and validated systematically in a pan-cancer fashion. To identify cancer specific exon targets, here we analyze 1532 RNA-seq datasets from 16 types of pediatric solid and brain tumors for comparison with normal tissues using a newly developed workflow. We find 2933 exons in 157 genes encoding proteins of the surfaceome or matrisome with high cancer specificity either at the gene (n = 148) or the alternatively spliced isoform (n = 9) level. Expression of selected alternatively spliced targets, including the EDB domain of fibronectin 1, and gene targets, such as COL11A1, are validated in pediatric patient derived xenograft tumors. We generate T cells expressing chimeric antigen receptors specific for the EDB domain or COL11A1 and demonstrate that these have antitumor activity. The full target list, explorable via an interactive web portal ( https://cseminer.stjude.org/ ), provides a rich resource for developing immunotherapy of pediatric solid and brain tumors using gene or AS targets with high expression specificity in cancer.

Anti-thyroglobulin antibodies (TgAb) and/or anti-thyroid peroxidase antibodies (TPOAb) positivity at baseline is a risk marker for thyroid immune-related adverse events (thyroid-irAEs) in anti-programmed cell death-1 antibody (PD-1-Ab) treatment; however, it is unknown if TgAb and TPOAb titers are associated with clinical characteristics of thyroid-irAEs. Among 586 patients treated with PD-1-Ab at Nagoya University Hospital between 2 November 2015 and 30 September 2021, 57 patients developed thyroid-irAEs (thyrotoxicosis [n = 38]; hypothyroidism without prior thyrotoxicosis {isolated hypothyroidism} [n = 19]) in whom thyroid function, and TgAb and TPOAb titers were determined at baseline and at the onset. The changes in TgAb (median, 54.8 vs. 0.2 IU/mL; p = 0.002) and TPOAb titers (31.6 vs. 0 IU/mL; p = 0.032) from baseline to onset of developing thyroid-irAEs were greater in patients with thyrotoxicosis than patients with isolated hypothyroidism. Higher TgAb and TPOAb titers, and the TgAb titer at baseline were associated with an earlier onset of thyrotoxicosis and higher peak free thyroxine levels, respectively. Twenty-eight patients who developed hypothyroidism after thyrotoxicosis had higher TgAb (54.5 vs. 10.7 IU/mL; p = 0.011) and TPOAb titers at baseline (46.1 vs. 9.0 IU/mL; p < 0.001) and greater changes in TgAb (61.7 vs. 7.8 IU/mL; p = 0.025) and TPOAb titers (52.8 vs. –0.8 IU/mL; p < 0.001) than patients who did not develop hypothyroidism. The TgAb titer at baseline and changes in the TgAb and TPOAb titers were greater in patients with thyrotoxicosis than patients with isolated hypothyroidism, suggesting that the magnitude of the thyroid autoimmune response reflects the clinical types of thyroid-irAEs.

Abstract Objectives To investigate the factors associated with voluntary HIV counseling and testing (VCT) among young students engaging in casual sexual activity and to establish a scientific rationale for developing targeted intervention strategies for preventing HIV/AIDS in this population. Methods Stratified cluster sampling was used to conduct a survey using questionnaires to collect demographic and behavioral information for statistical analysis. Results Data from 611 young students, who reported engaging in casual sexual activity, were included in the statistical analysis. Among these, 68 (11.13%) students underwent the VCT. Among young students who engaged in casual sexual activity, those who were non-Zhejiang residents (adjusted odds ratio [aOR]: 2.11; 95% Confidence Interval [CI]: 1.17–3.80), those who had received AIDS-themed lectures or health education courses from the school in the past year (aOR = 3.96, 95% CI = 1.49–10.50), those who had received HIV risk self-assessment conducted by the school in the past year (aOR = 2.31, 95% CI = 1.17–4.59), and those who had engaged in commercial sex activity in the past year (aOR = 1.98, 95% CI = 1.07–3.66) were more inclined to have undergone VCT. Male students (aOR = 0.37, 95% CI = 0.18–0.77) and those who used condoms consistently during casual sexual activity (aOR = 0.45, 95% CI = 0.21–0.97) were less likely to undergo VCT. Conclusion Casual sexual activity was relatively prevalent among young students, posing a potential risk for HIV transmission. These findings will be instrumental in the development more effective HIV prevention and control strategies for young students. Additionally, it highlights the necessity of promoting and popularizing VCT among young students without Zhejiang province residency, who are involved in commercial sexual activity, and/or those who lacking HIV education. Moreover, additional research and implementation of refined HIV behavioral interventions specifically tailored to young students are necessary to enhance their awareness and knowledge of HIV prevention.

Increasing the soybean-planting area and increasing the soybean yield per unit area are two effective solutions to improve the overall soybean yield. Northeast China has a large saline soil area, and if soybeans could be grown there with the help of isolated saline-tolerant rhizobia, the soybean cultivation area in China could be effectively expanded. In this study, soybeans were planted in soils at different latitudes in China, and four strains of rhizobia were isolated and identified from the soybean nodules. According to the latitudes of the soil-sampling sites from high to low, the four isolated strains were identified as HLNEAU1, HLNEAU2, HLNEAU3, and HLNEAU4. In this study, the isolated strains were identified for their resistances, and their acid and saline tolerances and nitrogen fixation capacities were preliminarily identified. Ten representative soybean germplasm resources in Northeast China were inoculated with these four strains, and the compatibilities of these four rhizobium strains with the soybean germplasm resources were analyzed. All four isolates were able to establish different extents of compatibility with 10 soybean resources. Hefeng 50 had good compatibility with the four isolated strains, while Suinong 14 showed the best compatibility with HLNEAU2. The isolated rhizobacteria could successfully establish symbiosis with the soybeans, but host specificity was also present. This study was a preliminary exploration of the use of salinity-tolerant rhizobacteria to help the soybean nitrogen fixation in saline soils in order to increase the soybean acreage, and it provides a valuable theoretical basis for the application of saline-tolerant rhizobia.

ABSTRACTThe combination of low temperatures, oligotrophic conditions, high altitude, and varying salinity in Tibetan Plateau lakes endows them with a wealth of distinctive fungal resources. This study aimed to investigate the diversity of culturable fungi in sediment and water samples collected from six lakes located on the Tibetan Plateau at elevations above 4,500 m. A total of 843 fungal strains were isolated by dilution plate method using four different media. Initial ITS analyses revealed that they belong to 156 species across 83 genera, spanning 50 families, 26 orders, 12 classes, and 6 phyla. Further morphological and multi-locus phylogenetic analyses were conducted, resulting in the formal descriptions of a new genus, Xizangia, and seven new species, including Alternaria xizangensis, Emericellopsis ovoidea, Myceliophthora xizangica, Preussia cylindricalis, Preussia sedimenticola, Pseudeurotium sedimenticola, and Xizangia sedimenticola. This research provides insights into the biodiversity of culturable fungi in the unique and extreme ecosystem, shedding light on the potential discovery of novel species and genera.

Abstract Six-dimensional pose estimation task predicts its 3D rotation matrix and 3D translation matrix in the world coordinate system by inputting the color image or depth image of the target object. Existing methods usually use deep neural networks to directly predict or regress object poses based on keypoint methods. The prediction results usually have deviations depending on whether the surface shape of the object is prominent or not and the size of the object. To solve this problem, we propose the six-dimensional pose estimation based on multi-task parameter sharing (PMP) framework to incorporate object category information into the pose estimation network through the form of an object classification auxiliary task. First, we extract the image features and point cloud features of the target object separately, and fuse them point by point; then, we share the confidence of each keypoint in pose estimation task and the knowledge of the classification task, get the key points with higher confidence, and predict the object pose; finally, the obtained object pose is passed through an iterative optimization network to obtain the final pose. The experimental results on the LineMOD dataset show that the proposed method can improve the accuracy of pose estimation and narrow the gap in the prediction accuracy of objects with different shapes. We also tested on a new dataset of small-scale objects, which contains object RGBD images and accurate 3D point cloud information. The proposed method is applied to the grasping experiment on the UR5 robotic arm, which satisfies the real-time pose estimation results during the grasping process.

Citrus aurantium L., sometimes known as “sour orange,” is an important Chinese herb with young, immature fruits, or “zhishi,” that are high in synephrine. Synephrine is a commonly utilized natural chemical with promising applications in effectively increasing metabolism, heat expenditure, energy level, oxidative fat, and weight loss. However, little is known about the genes and pathways involved in synephrine production during the critical developmental stages of C. aurantium L., which limits the development of the industry. According to this study, the concentration of synephrine gradually decreased as the fruit developed. Transcriptome sequencing was used to examine the DEGs associated with synephrine connections and served as the foundation for creating synephrine-rich C. aurantium L. Comparisons conducted between different developmental stages to obtain DEGs, and the number of DEGs varied from 690 to 3,019. Tyrosine and tryptophan biosynthesis, glycolysis/gluconeogenesis, pentose phosphate pathway, phenylalanine, and tyrosine metabolism were the main KEGG pathways that were substantially enriched. The results showed that 25 genes among these KEGG pathways may be related to synephrine synthesis. The WGCNA and one-way ANOVA analysis adoption variance across the groups suggested that 11 genes might play a crucial role in synephrine synthesis and should therefore be further analyzed. We also selected six DEGs at random and analyzed their expression levels by RT-qPCR, and high repeatability and reliability were demonstrated by our finished RNA-seq study results. These results may be useful in selecting or modifying genes to increase the quantity of synephrine in sour oranges.

BackgroundHIV notification and testing integrated into partner service (PS) practices among HIV-positive individuals have been proven to be an efficient approach for case finding, although it remains a weak link in China. Although nonmarital sexual activities accounted for a large proportion of newly diagnosed HIV-positive cases in China, little is known about PS uptake and associated factors within nonmarital partnerships. ObjectiveThis study aimed to describe HIV PS utilization and its associated factors among HIV-positive individuals with nonmarital sexual partners. MethodsWe recruited newly diagnosed HIV-positive individuals who had nonmarital sexual partners in 2022 in Zhejiang Province and offered them PS. We described the PS uptake cascade within sexual partner categories and analyzed the associated factors with 3 primary outcomes from the participants’ perspective: nonmarital partner enumeration, HIV testing, and HIV positivity. ResultsIn this study, 3509 HIV-positive individuals were recruited as participants, and they enumerated 2507 nonmarital sex partners (2507/14,556, 17.2% of all nonmarital sex partners) with contact information. Among these, 43.1% (1090/2507) underwent an HIV test, with an HIV-positive rate of 28.3% (309/1090). Heterosexual commercial partners were the least likely of being enumerated (441/4292, 10.3%) and had the highest HIV-positive rate (40/107, 37.4%). At the participant level, 48.1% (1688/3509) of the participants enumerated at least one nonmarital sex partner with contact information, 52.7% (890/1688) had a sex partner tested for HIV, and 31% (276/890) had at least one nonmarital sex partner who tested positive. Multivariate analysis indicated that gender and transmission route were associated with both nonmarital sex partner enumeration and HIV testing. Age and occupation were associated with nonmarital sex partner enumeration and HIV positivity. Compared with participants who had no regular nonmarital sex partner, those who had a regular nonmarital sex partner were more likely to enumerate nonmarital sex partners (adjusted odds ratio [aOR] 3.017, 95% CI 2.560-3.554), have them get tested for HIV (aOR 1.725, 95% CI 1.403-2.122), and have an HIV-positive nonmarital sex partner (aOR 1.962, 95% CI 1.454-2.647). ConclusionsThe percentage of partner enumeration was low, and HIV testing rate was moderate among nonmarital partnerships of HIV-positive individuals. More efforts should be made to improve PS practices among HIV-positive individuals and address the gap in partner enumeration, especially for heterosexual commercial nonmarital partnerships. Additionally, enhancing PS operational skills among health care personnel could increase the overall efficiency of PS uptake in China.

Background: Early childhood obesity poses a significant global public health challenge, necessitating the identification of treatable causes, particularly congenital leptin deficiencies. Serum leptin level measurement aids in diagnosing these rare contributors, guiding effective management. Methods: A Chinese family with early-onset obesity underwent LEP mutational screening via direct sequencing. mRNA expression and protein stability patterns of LEP were separately analyzed using qPCR and bioinformatics. Results: We present a case of a 12.5-year-old girl born to non-obese, non-consanguineous Chinese parents, exhibiting low leptin levels. Leptin gene sequencing revealed novel compound heterozygous mutations in exon 3. RT-PCR analysis showed the mutation didn't affect leptin production. Bioinformatics analysis indicated the variant rendered the leptin protein unstable. Conclusion: Loss-of-function mutations in LEP underlies early-onset obesity in the patient.

A Ti–48Al–2Cr–2Nb alloy was produced by electron beam powder bed fusion. The effect of the volume energy density parameter on the forming quality was investigated, and the tissue characteristics, hardness distribution, and mechanical properties of the alloy were analyzed. The results showed that the quality was better when the volume energy density parameter was 21.5–22.5 J/mm3. The microstructure of the alloy has the phenomenon of changing with the forming height: with an increase in the forming height, the forming part produces the phenomenon of strip microstructure along the construction direction, and the regional microstructure variability occurs under the cross section of the same height. The average hardness of the alloy reached 375.2 HV at the bottom, 381.8 HV in the middle, and 389.6 HV at the top, and the standard errors of the hardness values were 12.40, 10.49, and 7.12 HV, respectively, with the microhardness showing a gradual increase along the molding direction, and the homogeneity was gradually better. The transverse tensile strength at room temperature reached 526 MPa, the yield strength reached 461 MPa, and the elongation at break reached 1.24%, while the longitudinal tensile strength reached 486 MPa, the yield strength reached 414 MPa, and the elongation at break reached 1.02%.

IntroductionThe incidence of knee osteoarthritis (KOA) is moderately correlated with age and body weight and increases with life span and weight gain, associated with tearing and wearing the knee joints. KOA can adjust the force through the human lower limbs, redistribute the load of the knee joint, reduce the pain, and restore mobility when the arthritis changes are mild. However, most of the existing knee orthosis cannot be adjusted adaptively according to the needs of patients.MethodologyThis study establishes a biomechanical model of the knee joint to analyze the medial and lateral forces acting on the joint. The new adjustable knee orthosis is designed. It applies the principle of four-point bending to apply pressure to both sides of the knee joint, thereby adjusting the varus angle and modifying the medial and lateral forces on the knee joint. Through structural optimization, the prototype of the knee orthosis weighs only 324 g. Utilizing three-dimensional scanning technology, discrete point cloud data of the leg surface is obtained, reconstructed, and processed to create a 3D model of the human leg surface. The design ensures a close fit to the human leg surface, offering comfortable wear. A pressure sensing film system is employed to build a pressure sensing test system, where the knee orthosis is worn on a prosthesis for pressure testing to evaluate its ability to adjust knee joint forces.ResultsThe pressure test results demonstrate that the knee orthosis can stably provide an adjustment angle of 0–7° and sustain a maximum force of 10N on both sides of the knee joint over extended periods. A self-developed 8-channel plantar pressure sensing insole is calibrated against commercial plantar pressure sensors. Human wear tests on 15 subjects show that during the operation of the knee orthosis, it significantly adjusts plantar pressures, reducing lateral foot pressures by 22% overall, with more pronounced corrective effects observed in lighter participants.DiscussionIn this study, a wedge-shaped adaptive knee orthosis was provided for KOA patients. The four-point force principle was used to balance the force between femurs and tibia and adjust the meniscus contact gap. The orthotic appliance has the advantages of simple mechanical structure, adjustable correction Angle and good wearing comfort.

Abstract Platelets play a key role in physiological hemostasis and pathological thrombosis. Based on the limitations of current antiplatelet drugs, it's important to elucidate the mechanisms of regulating platelet activation. In addition to dissolving lipid nutrients, bile acids (BAs) can regulate platelet function. However, the specific mechanisms underlying BAs‐mediated effects on platelet activation and thrombotic diseases remain unknown. Therefore, the effects of BAs on platelets and intracellular regulatory mechanisms are explored. It is showed that the inhibitory effect of secondary BAs is more significant than that of primary BAs; lithocholic acid (LCA) shows the highest inhibitory effect. In the process of platelet activation, BAs suppress platelet activation via the spleen tyrosine kinase (SYK), protein kinase B (Akt), and extracellular signal‐regulated kinase1/2 (Erk1/2) pathways. Nck adaptor proteins (NCK1) deficiency significantly suppress the activity of platelets and arterial thrombosis. Phosphorylated proteomics reveal that LCA inhibited phosphorylation of syntaxin‐11 at S80/81 in platelets. Additional LCA supplementation attenuated atherosclerotic plaque development and reduced the inflammation in mice. In conclusion, BAs play key roles in platelet activation via Syk, Akt, ERK1/2, and syntaxin‐11 pathways, which are associated with NCK1. The anti‐platelet effects of BAs provide a theoretical basis for the prevention and therapy of thrombotic diseases.

Abstract Background Not many large‐sample investigations are available that compare the potency of the relationship of remnant cholesterol (RC) and other lipid parameters with diabetes and prediabetes. The goals of our study are to discover the relationship between RC and prediabetes, diabetes, and insulin resistance (IR) and to investigate RC, high‐density lipoprotein cholesterol (HDL‐C), non‐HDL‐C, triglycerides (TG), low‐density lipoprotein cholesterol (LDL‐C), total cholesterol (TC), TC/HDL‐C, LDL‐C/HDL‐C, and TG/HDL‐C, which are the lipid parameters that are most positively related to diabetes, prediabetes, and IR. Methods This research enrolled 36 684 subjects from China's eight provinces. We employed multiple logistic regression analysis for testing the relationship between lipid parameters and diabetes, prediabetes, and IR. Results After adjusting for potential confounders, and comparing the results with other lipid parameters, the positive relationship between RC and diabetes (odds ratio [OR] 1.417, 95% confidence interval [CI]: 1.345–1.492), prediabetes (OR 1.555, 95% CI: 1.438–1.628), and IR (OR 1.488, 95% CI: 1.404–1.577) was highest. RC was still related to diabetes, prediabetes, and IR even when TG

Abstract Background Novel diabetes phenotypes were proposed by the Europeans through cluster analysis, but Chinese community diabetes populations might exhibit different characteristics. This study aims to explore the clinical characteristics of novel diabetes subgroups under data‐driven analysis in Chinese community diabetes populations. Methods We used K‐means cluster analysis in 6369 newly diagnosed diabetic patients from eight centers of the REACTION (Risk Evaluation of cAncers in Chinese diabeTic Individuals) study. The cluster analysis was performed based on age, body mass index, glycosylated hemoglobin, homeostatic modeled insulin resistance index, and homeostatic modeled pancreatic β‐cell functionality index. The clinical features were evaluated with the analysis of variance (ANOVA) and chi‐square test. Logistic regression analysis was done to compare chronic kidney disease and cardiovascular disease risks between subgroups. Results Overall, 2063 (32.39%), 658 (10.33%), 1769 (27.78%), and 1879 (29.50%) populations were assigned to severe obesity‐related and insulin‐resistant diabetes (SOIRD), severe insulin‐deficient diabetes (SIDD), mild age‐associated diabetes mellitus (MARD), and mild insulin‐deficient diabetes (MIDD) subgroups, respectively. Individuals in the MIDD subgroup had a low risk burden equivalent to prediabetes, but with reduced insulin secretion. Individuals in the SOIRD subgroup were obese, had insulin resistance, and a high prevalence of fatty liver, tumors, family history of diabetes, and tumors. Individuals in the SIDD subgroup had severe insulin deficiency, the poorest glycemic control, and the highest prevalence of dyslipidemia and diabetic nephropathy. Individuals in MARD subgroup were the oldest, had moderate metabolic dysregulation and the highest risk of cardiovascular disease. Conclusion The data‐driven approach to differentiating the status of new‐onset diabetes in the Chinese community was feasible. Patients in different clusters presented different characteristics and risks of complications.

ObjectiveThis study aimed to investigate the factors associated with online dating among college students engaging in casual sexual behavior, by understanding these factors, targeted intervention measures can be formulated for relevant departments to help college students better manage their sexual health and offer useful reference for the development of sexual health education.MethodsA cross-sectional survey was conducted using a stratified cluster sampling method. Demographic and behavioral information was gathered through questionnaires for univariable and multivariable logistic regression analysis.ResultsA total of 595 college students engaging in casual sexual behavior were included in the study, of whom 345 (57.98%) had found casual sexual partners through the internet. Multiple regression analysis indicated that male participants, those aged 20–21 years, those who had recently attended AIDS-themed lectures or health education classes at school, participants who were willing to engage in commercial sexual activities during online dating, participants who accepted sexual activities among men who have sex with men (MSM), those who reported having sexual intercourse with regular partners in the past year, participants who wanted to know if their online dating partners were HIV-diagnosed, those who had engaged in commercial sexual behavior in the past year and those who perceived themselves to be at risk of HIV infection were more likely to engage in online dating. Participants with general/disharmonious family relationships, those who consistently used condoms during casual sexual behavior and those who occasionally used condoms were less likely to engage in online dating.ConclusionThere were a certain extent proportion of casual partners among college students were sourced from the internet, indicating the profound influence of online dating on casual sexual behavior. Therefore, future research and intervention measures should focus on sexual health education and promotion on online dating platforms, strengthen regulations and guidance on college students’ online dating behavior, and raise awareness of HIV prevention in this group.

BackgroundMicrobial community dynamics have been involved in numerous diseases, including cancer. The diversity of intertumoral microbiota in human papillomavirus independent endocervical adenocarcinoma (HPVI ECA) is not well-characterized.ObjectiveOur objective is to delineate the intratumoral microbiota profile in HPVI ECA and investigate its potential influence on oncogenesis.MethodsWe analyzed 45 HPVI ECA cases, comprising 36 gastric-type ECA (GEA) and 9 clear cell carcinomas (CCC). We compared the microbial composition within cancerous and adjacent noncancerous tissue samples using 5R-16S ribosomal DNA sequencing. Further, we investigated the correlation between specific microbes and clinical-pathological metrics as well as patient outcomes.ResultsOur findings demonstrate notable differences in the microbial spectra between cancerous and adjacent noncancerous tissues. Amongst HPVI ECA subtypes, GEAs exhibit more microbial variations compared to CCCs. Using the Random Forest algorithm, we identified two distinct microbial signatures that could act as predictive biomarkers for HPVI ECA and differentiate between GEA and CCC. Varied microbial abundances was related to clinical characteristics of HPVI ECA patients. In addition, high levels of Micrococcus and low levels of unknown genus75 from the Comamonadaceae family were associated with poorer outcomes in HPVI ECA patients. Similarly, an abundance of Microbacterium correlated with reduced overall survival (OS), and a high presence of Streptococcaceae family microbes was linked to reduced recurrence-free survival (RFS) in GEA patients. Intriguingly, a high abundance of Micrococcus was also associated with a worse OS in GEA patients.ConclusionThe study reveals distinct microbial signatures in HPVI ECA, which have potential as biomarkers for disease prognosis. The correlation between these tumor-associated microbiota features and clinicopathological characteristics underscores the possibility of microbiome-based interventions. Our research provides a foundation for more in-depth studies into the cervical microbiome’s role in HPVI ECA.

Background Intracranial haemorrhage (ICH) poses a significant threat to patients on Direct Oral Anticoagulants (DOACs), with existing risk scores inadequately predicting ICH risk in these patients. We aim to develop and validate a predictive model for ICH risk in DOAC-treated patients. Methods 24,794 patients treated with a DOAC were identified in a province-wide electronic medical and health data platform in Tianjin, China. The cohort was randomly split into a 4:1 ratio for model development and validation. We utilized forward stepwise selection, Least Absolute Shrinkage and Selection Operator (LASSO), and eXtreme Gradient Boosting (XGBoost) to select predictors. Model performance was compared using the area under the curve (AUC) and net reclassification index (NRI). The optimal model was stratified and compared with the DOAC model. Results The median age is 68.0 years, and 50.4% of participants are male. The XGBoost model, incorporating six independent factors (history of hemorrhagic stroke, peripheral artery disease, venous thromboembolism, hypertension, age, low-density lipoprotein cholesterol levels), demonstrated superior performance in the development dateset. It showed moderate discrimination (AUC: 0.68, 95% CI: 0.64–0.73), outperforming existing DOAC scores (ΔAUC = 0.063, P = 0.003; NRI = 0.374, P

In this work, the effect of temperature on interfaces with viscoelastic behavior was investigated using experimental and theoretical means. In particular, rubber/woven fabrics with thickness of 0.5 mm were subjected to self-designed shear tests at temperatures ranging from 263.15 to 383.15 K. Derived interface cyclic regeneration was observed through shear tests. Subsequently, a bi-linear cohesive zone model (CZM) was used to describe the shear test data. A novel image processing algorithm was developed to analyze the damaged morphology of the rubber/weave interface. It was found that hairniness amount decreased by 68.4 % when the temperature increased from 263.15 to 383.15 K. In addition, by combining the bi-linear CZM with the Kohlrausch–William–Watts law, Wiliams-Landel-Ferry equation and BK criterion, a 3D temperature-dependent constitutive model (KBW) was developed. The model successfully simulated the viscoelasticity of interfaces at different temperatures with margin of error less than 9 %. Thus, this study provides a strategy for elucidating the temperature dependence of interfaces with viscoelastic behavior.