Antibody Lineages with Vaccine-Induced Antigen-Binding Hotspots Develop Broad HIV Neutralization.

The vaccine-mediated elicitation of antibodies (Abs) capable of neutralizing diverse HIV-1 strains has been a long-standing goal. To understand how broadly neutralizing antibodies (bNAbs) can be elicited, we identified, characterized, and tracked five neutralizing Ab lineages targeting the HIV-1-fusion peptide (FP) in vaccinated macaques over time. Genetic and structural analyses revealed two of these lineages to belong to a reproducible class capable of neutralizing up to 59% of 208 diverse viral strains. B cell analysis indicated each of the five lineages to have been initiated and expanded by FP-carrier priming, with envelope (Env)-trimer boosts inducing cross-reactive neutralization. These Abs had binding-energy hotspots focused on FP, whereas several FP-directed Abs induced by immunization with Env trimer-only were less FP-focused and less broadly neutralizing. Priming with a conserved subregion, such as FP, can thus induce Abs with binding-energy hotspots coincident with the target subregion and capable of broad neutralization.

SUMOylation Fine-Tunes Endothelial HEY1 in the Regulation of Angiogenesis.

BACKGROUND: Angiogenesis, which plays a critical role in embryonic development and tissue repair, is controlled by a set of angiogenic signaling pathways. As a TF (transcription factor) belonging to the basic helix-loop-helix family, HEY (hairy/enhancer of split related with YRPW motif)-1 (YRPW motif, abbreviation of 4 highly conserved amino acids in the motif) has been identified as a key player in developmental angiogenesis. However, the precise mechanisms underlying HEY1's actions in angiogenesis remain largely unknown. Our previous studies have suggested a potential role for posttranslational SUMOylation in the dynamic regulation of vascular development and organization. METHODS: Immunoprecipitation, mass spectrometry, and bioinformatics analysis were used to determine the biochemical characteristics of HEY1 SUMOylation. The promoter-binding capability of HEY1 was determined by chromatin immunoprecipitation, dual luciferase, and electrophoretic mobility shift assays. The dimerization pattern of HEY1 was determined by coimmunoprecipitation. The angiogenic capabilities of endothelial cells were assessed by CCK-8 (cell counting kit-8), 5-ethynyl-2-deoxyuridine staining, wound healing, transwell, and sprouting assays. Embryonic and postnatal vascular growth in mouse tissues, matrigel plug assay, cutaneous wound healing model, oxygen-induced retinopathy model, and tumor angiogenesis model were used to investigate the angiogenesis in vivo. RESULTS: We identified intrinsic endothelial HEY1 SUMOylation at conserved lysines by TRIM28 (tripartite motif containing 28) as the unique E3 ligase. Functionally, SUMOylation facilitated HEY1-mediated suppression of angiogenic RTK (receptor tyrosine kinase) signaling and angiogenesis in primary human endothelial cells and mice with endothelial cell-specific expression of wild-type HEY1 or a SUMOylation-deficient HEY1 mutant. Mechanistically, SUMOylation facilitates HEY1 homodimer formation, which in turn preserves HEY1's DNA-binding capability via recognition of E-box promoter elements. Therefore, SUMOylation maintains HEY1's function as a repressive TF controlling numerous angiogenic genes, including RTKs and Notch pathway components. Proangiogenic stimuli induce HEY1 deSUMOylation, leading to heterodimerization of HEY1 with HES (hairy and enhancer of split)-1, which results in ineffective DNA binding and loss of HEY1's angiogenesis-suppressive activity. CONCLUSIONS: Our findings demonstrate that reversible HEY1 SUMOylation is a molecular mechanism that coordinates endothelial angiogenic signaling and angiogenesis, both in physiological and pathological milieus, by fine-tuning the transcriptional activity of HEY1. Specifically, SUMOylation facilitates the formation of the HEY1 transcriptional complex and enhances its DNA-binding capability in endothelial cells.

Scbean: a python library for single-cell multi-omics data analysis.

SUMMARY: Single-cell multi-omics technologies provide a unique platform for characterizing cell states and reconstructing developmental process by simultaneously quantifying and integrating molecular signatures across various modalities, including genome, transcriptome, epigenome, and other omics layers. However, there is still an urgent unmet need for novel computational tools in this nascent field, which are critical for both effective and efficient interrogation of functionality across different omics modalities. Scbean represents a user-friendly Python library, designed to seamlessly incorporate a diverse array of models for the examination of single-cell data, encompassing both paired and unpaired multi-omics data. The library offers uniform and straightforward interfaces for tasks, such as dimensionality reduction, batch effect elimination, cell label transfer from well-annotated scRNA-seq data to scATAC-seq data, and the identification of spatially variable genes. Moreover, Scbean's models are engineered to harness the computational power of GPU acceleration through Tensorflow, rendering them capable of effortlessly handling datasets comprising millions of cells. AVAILABILITY AND IMPLEMENTATION: Scbean is released on the Python Package Index (PyPI) (https://pypi.org/project/scbean/) and GitHub (https://github.com/jhu99/scbean) under the MIT license. The documentation and example code can be found at https://scbean.readthedocs.io/en/latest/.

Endothelial FIS1 DeSUMOylation Protects Against Hypoxic Pulmonary Hypertension.

BACKGROUND: Hypoxia is a major cause and promoter of pulmonary hypertension (PH), a representative vascular remodeling disease with poor prognosis and high mortality. However, the mechanism underlying how pulmonary arterial system responds to hypoxic stress during PH remains unclear. Endothelial mitochondria are considered signaling organelles on oxygen tension. Results from previous clinical research and our studies suggested a potential role of posttranslational SUMOylation (small ubiquitin-like modifier modification) in endothelial mitochondria in hypoxia-related vasculopathy. METHODS: Chronic hypoxia mouse model and Sugen/hypoxia rat model were employed as PH animal models. Mitochondrial morphology and subcellular structure were determined by transmission electron and immunofluorescent microscopies. Mitochondrial metabolism was determined by mitochondrial oxygen consumption rate and extracellular acidification rate. SUMOylation and protein interaction were determined by immunoprecipitation. RESULTS: The involvement of SENP1 (sentrin-specific protease 1)-mediated SUMOylation in mitochondrial remodeling in the pulmonary endothelium was identified in clinical specimens of hypoxia-related PH and was verified in human pulmonary artery endothelial cells under hypoxia. Further analyses in clinical specimens, hypoxic rat and mouse PH models, and human pulmonary artery endothelial cells and human embryonic stem cell-derived endothelial cells revealed that short-term hypoxia-induced SENP1 translocation to endothelial mitochondria to regulate deSUMOylation (the reversible process of SUMOylation) of mitochondrial fission protein FIS1 (mitochondrial fission 1), which facilitated FIS1 assembling with fusion protein MFN2 (mitofusin 2) and mitochondrial gatekeeper VDAC1 (voltage-dependent anion channel 1), and the membrane tethering activity of MFN2 by enhancing its oligomerization. Consequently, FIS1 deSUMOylation maintained the mitochondrial integrity and endoplasmic reticulum-mitochondria calcium communication across mitochondrial-associated membranes, subsequently preserving pulmonary endothelial function and vascular homeostasis. In contrast, prolonged hypoxia disabled the FIS1 deSUMOylation by diminishing the availability of SENP1 in mitochondria via inducing miR (micro RNA)-138 and consequently resulted in mitochondrial dysfunction and metabolic reprogramming in pulmonary endothelium. Functionally, introduction of viral-packaged deSUMOylated FIS1 within pulmonary endothelium in mice improved pulmonary endothelial dysfunction and hypoxic PH development, while knock-in of SUMO (small ubiquitin-like modifier)-conjugated FIS1 in mice exaggerated the diseased cellular and tissue phenotypes. CONCLUSIONS: By maintaining endothelial mitochondrial homeostasis, deSUMOylation of FIS1 adaptively preserves pulmonary endothelial function against hypoxic stress and consequently protects against PH. The FIS1 deSUMOylation-SUMOylation transition in pulmonary endothelium is an intrinsic pathogenesis of hypoxic PH.

FGFR1 SUMOylation coordinates endothelial angiogenic signaling in angiogenesis.

Angiogenesis contributes fundamentally to embryonic development, tissue homeostasis, and wound healing. Basic fibroblast growth factor (FGF2) is recognized as the first proangiogenic molecule discovered, and it facilitates angiogenesis by activating FGF receptor 1 (FGFR1) signaling in endothelial cells. However, the precise roles of FGFR and the FGF/FGFR signaling axis in angiogenesis remain unclear, especially because of the contradictory phenotypes of in vivo FGF and FGFR gene deficiency models. Our previous study results suggested a potential role of posttranslational small ubiquitin-like modifier modification (SUMOylation), with highly dynamic regulatory features, in vascular development and disorder. Here, we identified SENP1-regulated endothelial FGFR1 SUMOylation at conserved lysines responding to proangiogenic stimuli, while SENP1 functioned as the deSUMOylase. Hypoxia-enhanced FGFR1 SUMOylation restricted the tyrosine kinase activation of FGFR1 by modulating the dimerization of FGFR1 and FGFR1 binding with its phosphatase PTPRG. Consequently, it facilitated the recruitment of FRS2α to VEGFR2 but limited additional recruitment of FRS2α to FGFR1, supporting the activation of VEGFA/VEGFR2 signaling in endothelial cells. Furthermore, SUMOylation-defective mutation of FGFR1 resulted in exaggerated FGF2/FGFR1 signaling but suppressed VEGFA/VEGFR2 signaling and the angiogenic capabilities of endothelial cells, which were rescued by FRS2α overexpression. Reduced angiogenesis and endothelial sprouting in mice bearing an endothelial-specific, FGFR1 SUMOylation-defective mutant confirmed the functional significance of endothelial FGFR1 SUMOylation in vivo. Our findings identify the reversible SUMOylation of FGFR1 as an intrinsic fine-tuned mechanism in coordinating endothelial angiogenic signaling during neovascularization; SENP1-regulated FGFR1 SUMOylation and deSUMOylation controls the competitive recruitment of FRS2α by FGFR1 and VEGFR2 to switch receptor-complex formation responding to hypoxia and normoxia angiogenic environments.

Optimization-derived blood input function using a kernel method and its evaluation with total-body PET for brain parametric imaging.

Dynamic PET allows quantification of physiological parameters through tracer kinetic modeling. For dynamic imaging of brain or head and neck cancer on conventional PET scanners with a short axial field of view, the image-derived input function (ID-IF) from intracranial blood vessels such as the carotid artery (CA) suffers from severe partial volume effects. Alternatively, optimization-derived input function (OD-IF) by the simultaneous estimation (SIME) method does not rely on an ID-IF but derives the input function directly from the data. However, the optimization problem is often highly ill-posed. We proposed a new method that combines the ideas of OD-IF and ID-IF together through a kernel framework. While evaluation of such a method is challenging in human subjects, we used the uEXPLORER total-body PET system that covers major blood pools to provide a reference for validation. METHODS: The conventional SIME approach estimates an input function using a joint estimation together with kinetic parameters by fitting time activity curves from multiple regions of interests (ROIs). The input function is commonly parameterized with a highly nonlinear model which is difficult to estimate. The proposed kernel SIME method exploits the CA ID-IF as a priori information via a kernel representation to stabilize the SIME approach. The unknown parameters are linear and thus easier to estimate. The proposed method was evaluated using 18F-fluorodeoxyglucose studies with both computer simulations and 20 human-subject scans acquired on the uEXPLORER scanner. The effect of the number of ROIs on kernel SIME was also explored. RESULTS: The estimated OD-IF by kernel SIME showed a good match with the reference input function and provided more accurate estimation of kinetic parameters for both simulation and human-subject data. The kernel SIME led to the highest correlation coefficient (R = 0.97) and the lowest mean absolute error (MAE = 10.5 %) compared to using the CA ID-IF (R = 0.86, MAE = 108.2 %) and conventional SIME (R = 0.57, MAE = 78.7 %) in the human-subject evaluation. Adding more ROIs improved the overall performance of the kernel SIME method. CONCLUSION: The proposed kernel SIME method shows promise to provide an accurate estimation of the blood input function and kinetic parameters for brain PET parametric imaging.

Desorption Separation Ionization Mass Spectrometry (DSI-MS) for Rapid Analysis of COVID-19.

During the coronavirus disease 2019 (COVID-19) pandemic, which has witnessed over 772 million confirmed cases and over 6 million deaths globally, the outbreak of COVID-19 has emerged as a significant medical challenge affecting both affluent and impoverished nations. Therefore, there is an urgent need to explore the disease mechanism and to implement rapid detection methods. To address this, we employed the desorption separation ionization (DSI) device in conjunction with a mass spectrometer for the efficient detection and screening of COVID-19 urine samples. The study encompassed patients with COVID-19, healthy controls (HC), and patients with other types of pneumonia (OP) to evaluate their urine metabolomic profiles. Subsequently, we identified the differentially expressed metabolites in the COVID-19 patients and recognized amino acid metabolism as the predominant metabolic pathway involved. Furthermore, multiple established machine learning algorithms validated the exceptional performance of the metabolites in discriminating the COVID-19 group from healthy subjects, with an area under the curve of 0.932 in the blind test set. This study collectively suggests that the small-molecule metabolites detected from urine using the DSI device allow for rapid screening of COVID-19, taking just three minutes per sample. This approach has the potential to expand our understanding of the pathophysiological mechanisms of COVID-19 and offers a way to rapidly screen patients with COVID-19 through the utilization of machine learning algorithms.

Combined metabolome and transcriptome reveal HmF6'H1 regulating simple coumarin accumulation against powdery mildew infection in Heracleum moellendorffii Hance.

BACKGROUND: Powdery mildew, caused by Eeysiphe heraclei, seriously threatens Heracleum moellendorffii Hance. Plant secondary metabolites are essential to many activities and are necessary for defense against biotic stress. In order to clarify the functions of these metabolites in response to the pathogen, our work concentrated on the variations in the accumulation of secondary metabolites in H. moellendorffii during E. heraclei infection. RESULTS: Following E. heraclei infection, a significant upregulation of coumarin metabolites-particularly simple coumarins and associated genes was detected by RNA-seq and UPLC-MS/MS association analysis. Identifying HmF6'H1, a Feruloyl CoA 6'-hydroxylase pivotal in the biosynthesis of the coumarin basic skeleton through ortho-hydroxylation, was a significant outcome. The cytoplasmic HmF6'H1 protein was shown to be able to catalyze the ortho-hydroxylation of p-coumaroyl-CoA and caffeoyl-CoA, resulting in the formation of umbelliferone and esculetin, respectively. Over-expression of the HmF6'H1 gene resulted in increased levels of simple coumarins, inhibiting the biosynthesis of furanocoumarins and pyranocoumarins by suppressing PT gene expression, enhancing H. moellendorffii resistance to powdery mildew. CONCLUSIONS: These results established HmF6'H1 as a resistance gene aiding H. moellendorffii in combatting E. heraclei infection, offering additional evidence of feruloyl-CoA 6'-hydroxylase role in catalyzing various types of simple coumarins. Therefore, this work contributes to our understanding of the function of simple coumarins in plants' defense against powdery mildew infection.

Organic Dye Molecule Intercalated Vanadium Oxygen Hydrate Enables High-Performance Aqueous Zinc-Ion Storage.

Although the layered vanadium oxide-based materials have been considered to be one of the candidates for aqueous Zn-ion batteries (AZIBs), it still faces inevitable challenges of unsatisfactory capacities and sluggish kinetics because of strong electrostatic interactions between Zn-ions and structure lattice. This work addresses the strategy of pre-inserting guest materials to vanadium oxide cathode using different intercalants. To achieve this goal, the small organic dye molecules, methyl orange (MO), and methylene blue (MB) are proposed as the intercalants for vanadium oxygen hydrate (VOH). It has been demonstrated that use of these intercalants can facilitate reaction kinetics between Zn2+ and VOH, leading to an improvement of specific capacity (293 mAh g-1 at 0.3 A g-1 for MO-VOH and 311 mAh g-1 for MB-VOH) compared to VOH, a large enhancement of excellent energy density (237.1 Wh kg-1 for MO-VOH, 232.3 Wh kg-1 for MB-VOH), and a prolong lifespan operation at 3 A g-1 . The mechanism studies suggest that the weakened electrostatic interactions between the Zn-ions and V-O lattice after intercalating organic molecules contribute to boosting the electrochemical performance of AZIBs unveiled by charge density difference and binding energy.

Diverse Murine Vaccinations Reveal Distinct Antibody Classes to Target Fusion Peptide and Variation in Peptide Length to Improve HIV Neutralization.

While neutralizing antibodies that target the HIV-1 fusion peptide have been elicited in mice by vaccination, antibodies reported thus far have been from only a single antibody class that could neutralize ~30% of HIV-1 strains. To explore the ability of the murine immune system to generate cross-clade neutralizing antibodies and to investigate how higher breadth and potency might be achieved, we tested 17 prime-boost regimens that utilized diverse fusion peptide-carrier conjugates and HIV-1 envelope trimers with different fusion peptides. We observed priming in mice with fusion peptide-carrier conjugates of variable peptide length to elicit higher neutralizing responses, a result we confirmed in guinea pigs. From vaccinated mice, we isolated 21 antibodies, belonging to 4 distinct classes of fusion peptide-directed antibodies capable of cross-clade neutralization. Top antibodies from each class collectively neutralized over 50% of a 208-strain panel. Structural analyses - both X-ray and cryo-EM - revealed each antibody class to recognize a distinct conformation of fusion peptide and to have a binding pocket capable of accommodating diverse fusion peptides. Murine vaccinations can thus elicit diverse neutralizing antibodies, and altering peptide length during prime can improve the elicitation of cross-clade responses targeting the fusion peptide site of HIV-1 vulnerability. IMPORTANCE The HIV-1 fusion peptide has been identified as a site for elicitation of broadly neutralizing antibodies, with prior studies demonstrating that priming with fusion peptide-based immunogens and boosting with soluble envelope (Env) trimers can elicit cross-clade HIV-1-neutralizing responses. To improve the neutralizing breadth and potency of fusion peptide-directed responses, we evaluated vaccine regimens that incorporated diverse fusion peptide-conjugates and Env trimers with variation in fusion peptide length and sequence. We found that variation in peptide length during prime elicits enhanced neutralizing responses in mice and guinea pigs. We identified vaccine-elicited murine monoclonal antibodies from distinct classes capable of cross-clade neutralization and of diverse fusion peptide recognition. Our findings lend insight into improved immunogens and regimens for HIV-1 vaccine development.

Association between triglyceride-glucose index trajectories and radiofrequency ablation outcomes in patients with stage 3D atrial fibrillation.

BACKGROUND: This study investigates the relationship between triglyceride-glucose (TyG) index trajectories and the results of ablation in patients with stage 3D atrial fibrillation (AF). METHODS: A retrospective cohort study was carried out on patients who underwent AF Radiofrequency Catheter Ablation (RFCA) at the Cardiology Department of the Fourth Affiliated Hospital of Zhejiang University and Taizhou Hospital of Zhejiang Province from January 2016 to December 2022. The main clinical endpoint was determined as the occurrence of atrial arrhythmia for at least 30 s following a 3-month period after ablation. Using a latent class trajectory model, different trajectory groups were identified based on TyG levels. The relationship between TyG trajectory and the outcome of AF recurrence in patients was assessed through Kaplan-Meier survival curve analysis and multivariable Cox proportional hazards regression model. RESULTS: The study included 997 participants, with an average age of 63.21 ± 9.84 years, of whom 630 were males (63.19%). The mean follow-up period for the participants was 30.43 ± 17.75 months, during which 200 individuals experienced AF recurrence. Utilizing the minimum Bayesian Information Criterion (BIC) and the maximum Entropy principle, TyG levels post-AF RFCA were divided into three groups: Locus 1 low-low group (n = 791), Locus 2 low-high-low group (n = 14), and Locus 3 high-high group (n = 192). Significant differences in survival rates among the different trajectories were observed through the Kaplan-Meier curve (P < 0.001). Multivariate Cox regression analysis showed a significant association between baseline TyG level and AF recurrence outcomes (HR = 1.255, 95% CI: 1.087-1.448). Patients with TyG levels above 9.37 had a higher risk of adverse outcomes compared to those with levels below 8.67 (HR = 2.056, 95% CI: 1.335-3.166). Furthermore, individuals in Locus 3 had a higher incidence of outcomes compared to those in Locus 1 (HR = 1.580, 95% CI: 1.146-2). CONCLUSION: The TyG trajectories in patients with stage 3D AF are significantly linked to the outcomes of AF recurrence. Continuous monitoring of TyG levels during follow-up may help in identifying patients at high risk of AF recurrence, enabling the early application of effective interventions.

Sub-100-fs Kerr-lens mode-locked Yb:Lu2O3 laser with more than 60% optical efficiency.

Yb-doped sesquioxides represent one of the most excellent laser crystals applying for high-power ultrafast lasers owing to their very high thermal conductivities and broadband emission spectra. Pumped by a high-brightness Yb-fiber laser at 976 nm, the Yb:Lu2O3 laser delivers a maximum output power that amounts to 3.55 W in the continuous-wave regime with an optical efficiency of 75%. In the mode-locked regime, 90-fs pulses were generated via soft-aperture Kerr-lens mode-locking at 1080.6 nm with an average output power of 2.85 W, which corresponds to an optical efficiency of 60.3% and a slope efficiency of 68.8%. Average output power of the mode-locked Yb:Lu2O3 laser can be further scaled to 3.05 W at the expense of the pulse duration (178 fs), which corresponds to an optical efficiency as high as 64.5%. To the best of our knowledge, it is the highest optical efficiency ever reported from any solid-state Kerr-lens mode-locked Yb lasers.

Ultrahigh Critical Current Density across Sliding Electrical Contacts in Structural Superlubric State.

In conventional sliding electrical contacts (SECs), large critical current density (CCD) requires a high ratio between actual and apparent contact area, while low friction and wear require the opposites. Structural superlubricity (SSL) has the characteristics of zero wear, near zero friction, and all-atoms in real contact between the contacting surfaces. Here, we show a measured current density up to 17.5 GA/m^{2} between microscale graphite contact surfaces while sliding under ambient conditions. This value is nearly 146 times higher than the maximum CCD of other SECs reported in literatures (0.12 GA/m^{2}). Meanwhile, the coefficient of friction for the graphite contact is less than 0.01 and the sliding interface is wear-free according to the Raman characterization, indicating the presence of the SSL state. Furthermore, we estimate the intrinsic CCD of single crystalline graphite to be 6.69 GA/m^{2} by measuring the scaling relation of CCD. Theoretical analysis reveals that the CCD is limited by thermal effect due to the Joule heat. Our results show the great potential of the SSL contacts to be used as SECs, such as micro- or nanocontact switches, conductive slip rings, or pantographs.

Factors associated with out-of-school physical activity among Chinese children and adolescents: A stratified cross-sectional study.

OBJECTIVE: This observational study examined the factors associated with the physical activity (PA) of children and adolescents outside of school within the framework of Problem Behavior Theory (PBT). METHODS: This cross-sectional study obtained data from 6528 children and adolescents aged 6-16 years recruited from ten schools in Shanghai, China. The questionnaire measured out-of-school PA and PBT-based correlates. A series of multiple linear regressions were used to explore the factors influencing children and adolescents' out-of-school PA separately. Structural equation modeling (SEM) was used to explore the association between the three systems of PBT and out-of-school PA. RESULTS: Higher intrinsic motivation is positively associated with increased PA for children (b = 1.038, 95%CI: 0.897-1.180) and adolescents (b = 1.207, 95%CI: 0.890-1.524). Greater frequency of parental involvement in PA correlates with elevated PA for both children (b = 2.859, 95%CI: 2.147-3.572) and adolescents (b = 2.147, 95%CI: 0.311-3.983). In children, increased use of community exercise areas or facilities (b = 1.705, 95%CI: 0.234-3.176) and higher recreational screen time (b = 9.732, 95%CI: 5.614-13.850) are associated with higher PA. The SEM showed that factors of the personality system had a significant direct effect on out-of-school PA among children and adolescents, and factors of the behavior system also had a significant effect on children. CONCLUSIONS: Our findings suggest that the personality system, particularly intrinsic motivation, is important in promoting out-of-school PA in children and adolescents. For children, modifiable health behaviors in the behavior system can similarly influence PA.

Comparison of Fluid Resuscitation with Lactate Ringer's Versus Normal Saline in Acute Pancreatitis: An Updated Meta-Analysis.

BACKGROUND: Fluid resuscitation is one of the main therapies for acute pancreatitis (AP). There is still no consensus on the type of fluid resuscitation. This study investigated the differences between lactate Ringer's (LR) and normal saline (NS) in treating AP. METHODS: Two authors systematically searched Web of Science, Embase (via OVID), Cochrane Library, and PubMed to find all published research before July, 2023. The odds of moderately severe/severe AP and intensive care unit (ICU) admission are set as primary endpoints. RESULTS: This meta-analysis included 5 RCTs and 4 observational studies with 1424 AP patients in LR (n = 651) and NS (n = 773) groups. The results suggested that the odds of moderately severe/severe AP (OR 0.48; 95%Cl 0.34 to 0.67; P < 0.001) and ICU admission (OR 0.37; 95%Cl 0.16 to 0.87; P = 0.02) were lower in the LR group compared to NS group. In addition, the LR group had lower rates of local complications (OR 0.54; 95%Cl 0.32 to 0.92; P = 0.02), lower level of CRP, as well as a shorter hospital stay (WMD, - 1.09 days; 95%Cl - 1.72 to - 0.47 days; P < 0.001) than the NS group. Other outcomes, such as mortality, the rate of organ failure, SIRS, acute fluid collection, pancreatic necrosis, pseudocysts, and volume overload, did not differ significantly between two groups (P > 0.05). CONCLUSIONS: LR is preferred over NS as it decreases the odds of moderately severe/severe AP, the rate of ICU admission, local complication, and length of hospital stay. However, large-scale RCT are lacking to support these evidence.

Sub-50-fs Kerr-lens mode-locked Yb-doped fluoride laser with 44% optical efficiency.

Yb-doped fluoride has been demonstrated to be potential crystals for application in efficient ultrafast lasers. However, the trade-off between the shorter pulses with higher efficiencies is a challenge. In this work, using Y b,G d:C a S r F 2 crystal, we report on a sub-50-fs Kerr-lens mode-locked oscillator with an optical efficiency up to 44%. Pumped by a 976-nm diffraction-limited fiber laser and using chirped mirrors combined with prism pairs for the dispersion compensation, a pulse as short as 46 fs was obtained with 620-mW output power, corresponding to an optical efficiency more than 40%. Stable Kerr-lens mode-locking with RMS of output power lower than 0.3% and beam quality factors M 2<1.14 were achieved. Moreover, a maximum output power of 780 mW was obtained in continuous-wave operation with 55.3% optical efficiency. To the best of our knowledge, the results in this work represent the shortest pulses generated from Yb-doped fluoride lasers as well as the highest optical efficiencies ever reported in sub-100 fs Yb bulk lasers.

The long-term changing patterns of suicide mortality in China from 1987 to 2020: continuing urban-rural disparity.

BACKGROUND: Over the past three decades, China has experienced significant changes in urban-rural, gender, and age-specific suicide mortality patterns. This study aimed to investigate the long-term trends in suicide mortality in China from 1987 to 2020. METHODS: Suicide mortality data were obtained from China's National Health Commission. Joinpoint regression analysis was used to examine changes in trends and age-period-cohort modeling to estimate age, period, and cohort effects on suicide mortality from 1987 to 2020. Net drift, local drift, longitudinal age curves, and period relative risks were also calculated. RESULTS: Crude and age-standardized suicide mortality in China showed continuing downward trends from 1987 to 2020, with a more pronounced decrease in rural areas (net drift = -7.07%, p<0.01) compared to urban areas (net drift = -3.41%, p<0.01). The decline curve of urban areas could be divided into three substages. Period and cohort effects were more prominent in rural areas. Suicide risk was highest among individuals aged 20-24 and gradually increased after age 60. Females, particularly those of childbearing age, had higher suicide risk than males, with a reversal observed after age 50. This gender reversal showed distinct patterns in urban and rural areas, with a widening gap in urban areas and a relatively stable gap in rural areas. CONCLUSIONS: Suicide mortality in China has consistently declined over the past three decades. However, disparities in age, gender, and urban-rural settings persist, with new patterns emerging. Targeted suicide prevention programs are urgently needed for high-risk groups, including females of childbearing age and the elderly, and to address the slower decrease and reversing urban-rural gender trends.

Mutational fitness landscapes reveal genetic and structural improvement pathways for a vaccine-elicited HIV-1 broadly neutralizing antibody.

Vaccine-based elicitation of broadly neutralizing antibodies holds great promise for preventing HIV-1 transmission. However, the key biophysical markers of improved antibody recognition remain uncertain in the diverse landscape of potential antibody mutation pathways, and a more complete understanding of anti-HIV-1 fusion peptide (FP) antibody development will accelerate rational vaccine designs. Here we survey the mutational landscape of the vaccine-elicited anti-FP antibody, vFP16.02, to determine the genetic, structural, and functional features associated with antibody improvement or fitness. Using site-saturation mutagenesis and yeast display functional screening, we found that 1% of possible single mutations improved HIV-1 envelope trimer (Env) affinity, but generally comprised rare somatic hypermutations that may not arise frequently in vivo. We observed that many single mutations in the vFP16.02 Fab could enhance affinity >1,000-fold against soluble FP, although affinity improvements against the HIV-1 trimer were more measured and rare. The most potent variants enhanced affinity to both soluble FP and Env, had mutations concentrated in antibody framework regions, and achieved up to 37% neutralization breadth compared to 28% neutralization of the template antibody. Altered heavy- and light-chain interface angles and conformational dynamics, as well as reduced Fab thermal stability, were associated with improved HIV-1 neutralization breadth and potency. We also observed parallel sets of mutations that enhanced viral neutralization through similar structural mechanisms. These data provide a quantitative understanding of the mutational landscape for vaccine-elicited FP-directed broadly neutralizing antibody and demonstrate that numerous antigen-distal framework mutations can improve antibody function by enhancing affinity simultaneously toward HIV-1 Env and FP.

Analysis of Influencing Factors of Professional Identity of Nurses in Infection Department in the Post-Epidemic Era.

Objective: The objective of this study was to understand the factors that influence the professional identity of nurses working in infectious diseases departments following the COVID-19 epidemic. Additionally, the research aims to provide a theoretical foundation for enhancing nurses' professional identity in these departments. Methods: A total of 155 nurses from the infection departments of 5 hospitals in Guangdong Province were selected using a convenience sampling method. A locally designed general questionnaire, nurse occupational benefit scale, and occupational identity scale were employed for data collection. Single-factor linear analysis and multiple linear regression analysis were conducted to analyze the data. Results: The average occupational identity score of nurses in the infection departments was 105.50±18.94. Multiple linear regression analysis results indicated that several factors influenced professional identity, including family support, recognition from doctors, participation in integrated medical and nursing ward rounds, positive perception of professional benefits, and a sense of belonging to a team. Conclusion: In the post-epidemic era, the professional identity of nurses working in the infection departments is moderately affected by various factors, particularly the perception of occupational advantages post-exposure to the epidemic.

Identification of Isthmin-1 in common carp (Cyprinus carpio L.) and the effects on glucose metabolism in vivo and in vitro.

Isthmin-1 (Ism1) plays roles in glucose uptake in mammals as an adipokine. To investigate its role in the glucose metabolism of common carp (Cyprinus carpio. L), the Ism1 sequence was cloned, and its expression and distribution in tissues were detected. In addition, we prepared and purified the recombinant Ism1 protein using the E. coli expression system and assessed changes in the expression of key genes related to glucose metabolism through both in vivo injection experiments and primary hepatocyte experiments in vitro. The results revealed that the open reading frame of Ism1 was 1377 bp long, encoding 458 amino acids. Similarity analysis indicated that Ism1 exhibited a close evolutionary relationship with goldfish (Carassius auratus), sharing 98.35% amino acid similarity. Ism1 was expressed in all tissues of common carp, with the highest level observed in the heart, followed by the gill, head kidney, and hepatopancreas. Distinct patterns of Ism1 expression were identified during the oral glucose tolerance test and long-term high-carbohydrate and high-fat diet feeding experiments. In vivo studies demonstrated that the serum glucose concentration was reduced on treatment with Ism1, accompanied by a significant upregulation of mRNA levels for gk, hk, and pfk genes in hepatopancreas; conversely pepck and g6pase mRNA levels were significantly downregulated in the hepatopancreas under these conditions as well. Furthermore, our primary hepatocyte experiment confirmed that Ism1 could inhibit pepck and g6pase mRNA expression, while promoting gk, hk, and pfk mRNA expression levels. In conclusion, Ism1, in common carp, could participate in the glucose metabolism, which provides essential information for future studies on the function of Ism1.