Search

Wind and stratification play pivotal roles in shaping the structure of the Lagrangian residual velocity (LRV). However, the intricate dynamics by which wind and stratification modify the LRV remain poorly studied. This study derives numerical solutions of LRV components and eddy viscosity subcomponents to elucidate the dynamics within the periodically stratified Pearl River estuary. The vertical shear cross-estuary LRV (uL) is principally governed by the interplay among the eddy viscosity component (uLtu), the barotropic component (uLba), and the baroclinic component (uLgr) under stratified conditions. During neap tides, southwesterly winds notably impact uL by escalating uLtu by an order of magnitude within the upper layer. This transforms the eastward flow dominated by uLtu under wind influence into a westward flow dominated by uLba in upper shoal regions without wind forcing. The along-estuary LRV exhibits a gravitational circulation characterized by upper-layer outflow engendered by a barotropic component (vLba) and lower-layer inflow predominantly driven by a baroclinic component (vLgr). The presence of southwesterly winds suppresses along-estuary gravitational circulation by diminishing the magnitude of vLba and vLgr. The contributions of vLba and vLgr are approximately equal, while the ratio between uLba and uLgr (uLtu) fluctuates within the range of 1 to 2 in stratified waters. Under unstratified conditions, LRV exhibits a lateral shear structure due to differing dominant components compared to stratified conditions. In stratified scenarios, the eddy viscosity component of LRV is predominantly governed by the turbulent mean component, while it succumbs to the influence of the tidal straining component in unstratified waters.

The literature presents different views on how the stratosphere influences variability in surface nitrous oxide (N2O) and on whether that influence is outweighed by surface emission changes driven by the El Niño–Southern Oscillation (ENSO). These questions are investigated using a chemistry–climate model with a stratospheric N2O tracer; surface and aircraft-based N2O measurements; and indices for ENSO, polar lower stratospheric temperature (PLST), and the stratospheric quasi-biennial oscillation (QBO). The model simulates well-defined seasonal cycles in tropospheric N2O that are caused mainly by the seasonal descent of N2O-poor stratospheric air in polar regions with subsequent cross-tropopause transport and mixing. Similar seasonal cycles are identified in recently available N2O data from aircraft. A correlation analysis between the N2O atmospheric growth rate (AGR) anomaly in long-term surface monitoring data and the ENSO, PLST, and QBO indices reveals hemispheric differences. In the Northern Hemisphere, the surface N2O AGR is negatively correlated with winter (January–March) PLST. This correlation is consistent with an influence from the Brewer–Dobson circulation, which brings N2O-poor air from the middle and upper stratosphere into the lower stratosphere with associated warming due to diabatic descent. In the Southern Hemisphere, the N2O AGR is better correlated to QBO and ENSO indices. These different hemispheric influences on the N2O AGR are consistent with known atmospheric dynamics and the complex interaction of the QBO with the Brewer-Dobson circulation. More airborne surveys extending to the tropopause would help elucidate the stratospheric influence on tropospheric N2O, allowing for better understanding of surface sources.

Buried-interface engineering is crucial in the fabrication of perovskite solar cells (PSCs) due to its effectiveness in facilitating the deposition of perovskite absorbers. This technique is especially significant in inverted PSCs (IPSCs) where the dewetting materials are normally used as the bottom hole transporters. Here, we investigate the impact of buried-interface techniques on the optical and mechanical behavior of perovskites and the overall stability of IPSCs. Our findings demonstrate that the chemical treatment with fluorene-based conjugated polyelectrolyte (e.g., PFN-Br), in contrast to the physical UV-ozone method, induces distinct dendrite-like patterns at the buried interface. These changes profoundly impact the optical properties of the perovskite films, evidenced by red-shifted photoluminescence in these regions. Furthermore, the dendritic morphologies are shown to affect the mechanical properties of the as-crystallized perovskite films, such as a reduction in Young's modulus/hardness, which in turn modulate the device performance. The photovoltaic data indicate that these dendrite-like patterns are beneficial for the initial efficiencies but compromise the long-term stability of the derived IPSCs. This study provides valuable insights into buried-interface engineering strategies for achieving efficient and stable IPSCs.

Purpose: This study aims to assess anxiety trends over the COVID-19 pandemic and evaluate how pandemic-related adversities modify trajectories among underprivileged adolescents from two distinct settings., Methods: Data came from the Shanghai, China and Kinshasa, Democratic Republic of the Congo sites of the Global Early Adolescent Study. Data were collected three times over approximately two years: prior to the pandemic (T1) and during the pandemic (T2, T3). Analyses included adolescents (aged 10-16) with complete information on generalized anxiety disorder (GAD) across all time points (Shanghai N = 548; Kinshasa N = 334). Weighted Generalized Estimating Equations assessed anxiety at T2 and T3 relative to T1. Effect modification analyses were used to investigate if COVID-19-related adversities modified anxiety trajectories., Results: Six months into the pandemic, 15.3% (Shanghai) and 4.1% (Kinshasa) of adolescents reported having moderate-to-severe GAD. Adjusted Generalized Estimating Equation models did not suggest increases in GAD during the pandemic across both sites. However, female adolescents from Shanghai experienced increased anxiety (adjusted odds ratio [aOR]: 2.27, 95% confidence interval: 1.30-3.99) half a year into the pandemic. The trend was not sustained. COVID-related adversities did not modify anxiety trajectories in Kinshasa. In Shanghai, one year into the pandemic, we observed decreased odds of GAD among all (aOR: 0.31, 0.17-0.58) and female adolescents (aOR: 0.25, 0.08-0.75) without pandemic-associated negative household experiences., Discussion: The COVID-19 pandemic differentially affected adolescent anxiety by time, place, and gender. Future research should examine the roles of social context and resilience to better understand adolescents' mental distress and to guide health-promoting programs and policies for young people., (Copyright © 2024 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

In this study, we compare outcomes of older patients with primary diffuse large B-cell lymphoma of the central nervous system (PCNSL) undergoing autologous hematopoietic cell transplantation (autoHCT) with either thiotepa/carmustine (BCNU/Thio) or thiotepa/busulfan/cyclophosphamide (TBC) conditioning. We used a postpublication dataset made available by the Center for International Blood and Marrow Transplantation Research including patients who were ≥65 years in age with PCNSL and underwent autoHCT as consolidation with TBC or BCNU/Thio conditioning. Out of 147 patients; n = 84 received BCNU/Thio and n = 63 received TBC. The 1-year NRM in the BCNU/Thio group was 10% versus 22% in the TBC group (P = .05) and the 2-year relapse rate was 5% versus 5%, respectively (P = 1.00). The 2-year progression-free survival (PFS) in the BCNU/Thio group was 85% versus 71% in the TBC group (P = .05) and 2-year overall survival (OS) was 86% versus 74% (P = .08). In a multivariable regression model, BCNU/Thio was associated with a lower risk for NRM (hazard ratio [HR], 0.33, P = .009), improved PFS (HR, 0.41, P = .008) and OS (HR, 0.37, P = .007), but there was no association with relapse risk. We found that in older adults with PCNSL undergoing consolidation with autoHCT, BCNU/Thio conditioning is associated with lower NRM and improved OS compared to TBC., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

With the atypical rise of Mycoplasma pneumoniae infection (MPI) in 2023, prompt studies are needed to determine the current epidemic features and risk factors with emerging trends of MPI to furnish a framework for subsequent investigations. This multicentre, retrospective study was designed to analyse the epidemic patterns of MPI before and after the COVID-19 pandemic, as well as genotypes and the macrolide-resistance-associated mutations in MP sampled from paediatric patients in Southern China. Clinical data was collected from 1,33,674 patients admitted into investigational hospitals from 1 June 2017 to 30 November 2023. Metagenomic next-generation sequencing (mNGS) data were retrieved based on MP sequence positive samples from 299 paediatric patients for macrolide-resistance-associated mutations analysis. Pearson's chi-squared test was used to compare categorical variables between different time frames. The monthly average cases of paediatric common respiratory infection diseases increased without enhanced public health measures after the pandemic, especially for influenza, respiratory syncytial virus infection, and MPI. The contribution of MPI to pneumoniae was similar to that in the outbreak in 2019. Compared to mNGS data between 2019-2022 and 2023, the severity of MP did not grow stronger despite higher rates of macrolide-resistance hypervariable sites, including loci 2063 and 2064, were detected in childhood MP samples of 2023. Our findings indicated that ongoing surveillance is necessary to understand the impact of post pandemic on MP transmission disruption during epidemic season and the severity of clinical outcomes in different scenarios.

Context: Pegpesen® is a novel Y-shape pegylated recombinant human growth hormone (rhGH) for once-weekly treatment of children with growth hormone deficiency (GHD)., Objective: To evaluate the efficacy and safety of Pegpesen® in children with GHD vs daily rhGH., Design: A multicenter, randomized, controlled phase 3 clinical trial with a duration of 52 weeks treatment., Setting: 23 centers in China., Participants: 391 pediatric participants diagnosed with GHD., Interventions: Participants were randomized 2:1 to the weekly Pegpesen® group (140 μg/kg/week) or the daily rhGH group (245 μg/kg/week) for 52 weeks., Main Outcome Measures: The primary endpoint was the growth velocity (GV) at 52 weeks, and the secondary endpoints mainly involved changes from baseline in height standard deviation scores for chronological age and bone age (ΔHt SDS CA and ΔHt SDS BA)., Results: At 52 weeks, the least squares mean (LS Means) of GV was 9.910 cm/year in the Pegpesen® group and 10.037 cm/year in the daily rhGH group. The LS Means difference between groups was -0.127 [95% CI (-0.4868, 0.2332)], confirming that weekly Pegpesen® is non-inferior to daily rhGH. The LS Means of ΔHt SDS CA, ΔHt SDS BA, were similar across both groups (all P > 0.05). Safety profiles and adherence were comparable., Conclusions: Pegpesen® was non-inferior to daily rhGH, with similar safety, lower dosage requirements, thus presenting a new therapeutic option for children with GHD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Lithium (Li) metal anode, one of the most promising candidates for next-generation rechargeable batteries, has always suffered from uneven Li deposition/stripping. To address this issue, this work designs a novel nickel-carbon composite modified Li metal anode (FNC-NF) by carbonizing fluoride nickel hydroxide nanosheet arrays grown on nickel foam (NF). These electrochemical tests present that the conductive and lithiophilic FNC can effectively restrain the growth of Li dendrites during the cycling of Li deposition/stripping at large capacities up to 10 mAh cm -2 . This result is attributed to the featured FNC composition combining a core of nickel hydroxide and a mixed coating of defective carbon and Ni nanoparticles, and the unique hierarchical morphology of the FNC-NF integrating porous NF and vertically aligned FNC nanosheets. Consequently, the FNC-NF presents a stable coulombic efficiency performance after 900 cycles with an average of 99.23% for half cells, a lifespan over 3200 h for symmetric cells at 1 mA cm -2 and 1 mAh cm -2 , and a remarkable cycling stability at large current densities of up to 15 mA cm -2 at 1 mAh cm -2 . Moreover, the Li||FNC-NF||LiFePO 4 full cells show superior capacity retention and cycling stability at 1 C., (© 2024 Wiley‐VCH GmbH.)

Rationale and Objectives: To develop and validate multiple machine learning predictive models incorporating clinical features and pretreatment multiparametric magnetic resonance imaging (MRI) radiomic features for predicting treatment response to transarterial chemoembolization combined with molecular targeted therapy plus immunotherapy in unresectable hepatocellular carcinoma (HCC)., Materials and Methods: This retrospective study involved 276 patients with unresectable HCC who received combination therapy from 4 medical centers. Patients were divided into one training cohort and two independent external validation cohorts. 16 radiomic features from six multiparametric MRI sequences and 2 clinical features were used to build six machine learning models. The models were evaluated using the area under the curve (AUC), decision curve analysis, and incremental predictive value., Results: Alpha-fetoprotein and neutrophil-to-lymphocyte ratio are clinical independent predictors of treatment response. In the training cohort and two external validation cohorts, the AUCs and 95% confidence intervals for predicting treatment response were respectively 0.782 (0.698-0.857) 0.695 (0.566-0.823), and 0.679 (0.542-0.810) for the clinical model; 0.942 (0.903-0.974), 0.869 (0.761-0.949), and 0.868 (0.769-0.942) for the radiomics model; and 0.956 (0.920-0.984), 0.895 (0.810-0.967), and 0.892 (0.804-0.957) for the combined clinical-radiomics model. In the three cohorts, the incremental predictive value of the radiomics model over the clinical model was 49.2% (P < 0.001), 28.8% (P < 0.001), and 31.5% (P < 0.001)., Conclusion: The combined clinical-radiomics model may provide a reliable and non-invasive tool to predict individual treatment responses and guide and improve clinical decision-making in combination therapy of HCC patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: The limited radiosensitivity of osteosarcoma poses a challenge in applying radiotherapy, necessitating the search for effective radiosensitizing targets., Methods: The lentiviral vectors were employed to establish CDKN2C-overexpressing (CDKN2C-OE) and CDKN2C-negative control (CDKN2C-NC) HOS and U2OS osteosarcoma cells. Cells were treated with or without irradiation (IR) to assess radiosensitization via viability, proliferation, apoptosis, and cell cycle analysis. A mouse model with subcutaneous tumors from CDKN2C-OE and CDKN2C-NC HOS cells evaluated tumor growth post-IR. Immunohistochemical staining and Western blot analysis were conducted to confirm model establishment and explore mechanisms., Results: CDKN2C-OE combined with IR inhibited cell viability and proliferation, promoting apoptosis in vitro and inhibiting tumor growth in vivo. CDKN2C-OE inhibited G1 phase progression post-IR by suppressing Cyclin-dependent kinase 4 (CDK4) expression and Thr172 phosphorylation, reducing retinoblastoma protein (RB) phosphorylation at Ser807/811. CDKN2C-OE did not primarily impact the cell cycle by regulating the expression of CDK6 and Cyclin D1. Furthermore, when CDKN2C-OE was combined with IR, the expression of BAX, Caspase-3, and its active cleavage product, cleaved Caspase-3, was upregulated., Conclusions: Our research results indicate that overexpression of CDKN2C enhances radiosensitivity in osteosarcoma through the induction of G1 phase arrest and subsequent apoptosis. G1 phase arrest is mediated by the suppression of CDK4 expression and Thr172 phosphorylation, which consequently affects the expression of phosphorylated RB at the Ser807/811 sites., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

This study investigates the role of RNF4-mediated ubiquitination and degradation of PDHA1 in colorectal cancer (CRC) metabolism and metastasis. Integrating (The Cancer Genome Atlas) TCGA and Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases, proteomic, clinical, and metabolomic analyses were performed, revealing PDHA1 as a prognostic marker in CRC. Immunohistochemical staining confirmed lower PDHA1 expression in metastatic CRC tissues. In vitro experiments demonstrated that PDHA1 overexpression inhibited CRC cell proliferation, migration, and invasion. RNF4 was identified as a key mediator in the ubiquitination degradation of PDHA1, influencing glycolytic pathways in CRC cells. Metabolomic analysis of serum samples from metastatic CRC patients further supported these findings. In vivo experiments, including xenograft and metastasis models, validated that RNF4 knockdown stabilized PDHA1, inhibiting tumor formation and metastasis. This study highlights the critical role of RNF4-mediated PDHA1 ubiquitination in promoting glycolytic metabolism, proliferation, and metastasis in CRC., (© 2024. The Author(s).)

The crosstalk between immune cells and the neurovascular unit plays a pivotal role in neural regeneration following central nervous system (CNS) injury. Maintaining brain immune homeostasis is crucial for restoring neurovascular function. In this study, an interactive bridge was developed via an immunomodulatory hydrogel microsphere to link the interaction network between microglia and the neurovascular unit, thereby precisely regulating immune-neurovascular crosstalk and achieving neural function recovery. This immunomodulatory crosstalk microsphere (MP/RIL4) was composed of microglia-targeted RAP12 peptide-modified interleukin-4 (IL-4) nanoparticles and boronic ester-functionalized hydrogel using biotin-avidin reaction and air-microfluidic techniques. We confirmed that the immunomodulatory microspheres reduced the expression of pro-inflammatory factors including IL-1β, iNOS, and CD86, while upregulating levels of anti-inflammatory factors such as IL-10, Arg-1, and CD206 in microglia. In addition, injection of the MP/RIL4 significantly mitigated brain atrophy volume in a mouse model of ischemic stroke, promoted neurobehavioral recovery, and enhanced the crosstalk between immune cells and the neurovascular unit, thus increasing angiogenesis and neurogenesis of stroke mice. In summary, the immunomodulatory microspheres, capable of orchestrating the interaction between immune cells and neurovascular unit, hold considerable therapeutic potential for ischemic stroke and other CNS diseases., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Purpose: The combination of transarterial chemoembolization, molecular targeted therapy, and immunotherapy (triple therapy) has shown promising outcomes in the treatment of unresectable hepatocellular carcinoma (HCC). This study aimed to build a prognostic model to identify patients who could benefit from triple therapy., Patients and Methods: This retrospective study encompassed 242 patients with HCC who underwent triple therapy from two centers (Training cohort: 158 patients from the Center 1; External validation cohort: 84 patients from the Center 2). Independent predictors of overall survival (OS) and progression-free survival (PFS) were identified through Cox regression analyses, and prognostic models based on Cox proportional hazards models were developed. Prognosis was assessed using Kaplan - Meier curves., Results: In the training cohort, independent predictors of PFS included vascular invasion and the C-reactive protein and alpha-fetoprotein in immunotherapy (CRAFITY) score. Independent predictors of OS were the CRAFITY score, extrahepatic metastasis, and the neutrophil-to-lymphocyte ratio. Prognostic prediction models were constructed based on these variables. The prognostic model for OS demonstrated a C-index of 0.715 (95% confidence interval (CI), 0.662-0.768) in the training cohort and 0.701 (95% CI, 0.628-0.774) in the validation cohort. Patients were divided into low- and high-risk categories using the predictive model (P<0.001). These findings were corroborated by the external validation cohort., Conclusion: The developed prognostic model serves as a reliable and convenient tool to predict outcomes in patients with unresectable HCC undergoing triple therapy. It aids clinicians in making informed treatment decisions., Competing Interests: The author(s) report no conflicts of interest in this work., (© 2024 Kang et al.)

Handwriting Brain-Computer Interfaces (BCIs) provides a promising communication avenue for individuals with paralysis. While English-based handwriting BCIs have achieved rapid typewriting with 26 lowercase letters (mostly containing one stroke each), it is difficult to extend to complex characters, especially those with multiple strokes and large character sets. The Chinese characters, including over 3500 commonly used characters with 10.3 strokes per character on average, represent a highly complex writing system. This paper proposes a Chinese handwriting BCI system, which reconstructs multi-stroke handwriting trajectories from brain signals. Through the recording of cortical neural signals from the motor cortex, we reveal distinct neural representations for stroke-writing and pen-lift phases. Leveraging this finding, we propose a stroke-aware approach to decode stroke-writing trajectories and pen-lift movements individually, which can reconstruct recognizable characters (accuracy of 86% with 400 characters). Our approach demonstrates high stability over 5 months, shedding light on generalized and adaptable handwriting BCIs.

The prognosis of osteosarcoma has not been improved for decades. As radioresistance is one of the major reasons, effective radiotherapy sensitization drugs need to be discovered. HOS and K7M2 osteosarcoma cell lines were treated with disulfiram (DSF) and radiation to assess cell viability, proliferation, migration ability, apoptosis level, ROS and Ca2+ level, and cell cycle in vitro. A HOS-derived subcutaneous tumor mouse model was constructed to evaluate tumor growth after DSF combined with radiation, and the Tunel assay and immunohistochemistry of Ki67 were conducted. Western blot was used to evaluate the protein expression level. The IC50 and working concentration of DSF in osteosarcoma cell lines were ascertained. When combined with radiation, DSF effectively suppressed cell viability, proliferation, and migration, while enhancing apoptosis in osteosarcoma cells. The cell cycle postirradiation exhibited a downward shift in the G1 phase, but the addition of DSF counteracted this trend. The combination of DSF and radiation exhibited inhibitory effects on tumor growth in vivo, which was corroborated by Ki67 staining and Tunel assay. Western blot analysis revealed that DSF upregulated the expression of P53, P21, CDKN2C, BAX, and cleaved Caspase-3 while downregulating BCL2, CDK4/6, and CyclinD1 after irradiation. Our results document that DSF exerts its radiosensitization effects in vivo and in vitro, and is a valuable radiosensitizing drug option for osteosarcoma. The radiosensitization effect is mainly achieved by activating the apoptotic pathway and promoting cell cycle arrest induced by P53/P21 and CDKN2C after irradiation., (© 2024 by Radiation Research Society. All rights of reproduction in any form reserved.)

Wood, as a renewable material, has been regarded as an emerging substrate for self-supporting electrodes in large-scale water electrolysis due to numerous merits such as rich pore structure, abundant hydroxyl groups, etc. However, poor conductivity of wood can greatly suppress the performance of wood-based electrodes. Carbonization process can improve wood's conductivity, but the loss of hydroxyl groups and the required high energy consumption are the drawbacks of such a process. Here, a facile strategy is developed to prepare pristine wood-supported electrode (Ni-NiP/W) for enhanced hydrogen evolution reaction (HER); this improves electrical conductivity of wood while retaining its excellent intrinsic properties. The preparation process involves the deposition of copper on the untreated wood followed with the loading of Ni-NiP catalyst at room temperature. Encouragingly, the Ni-NiP/W exhibits conductive and inherited pristine wood's superhydrophilic and superaerophobic properties, that effectively boost mass and charge transfer. It demonstrates high activity and excellent stability in acidic, alkali, and seawater conditions as well as high current densities of up to 2000 mA cm -2 ; particularly a record-low HER overpotential of 206 mV in acidic conditions at 1000 mA cm -2 . This work fully unlocks the admiring potential of pristine wood as superior substrate for high-performance electrochemical electrodes., (© 2024 Wiley‐VCH GmbH.)

Background: Tacrolimus is regarded as a cornerstone of immunosuppressive therapy after lung transplantation. Tacrolimus-induced neurotoxicity is common, while late-onset severe encephalopathy is rare., Case Presentation: We report a case of a 61-year-old woman who presented with confusion and limb stiffness 29 months after undergoing bilateral lung transplantation for bronchiectasis. She received immunosuppressive regimen consisting of low-dose tacrolimus, sirolimus, mycophenolate mofetil, and prednisone due to renal insufficiency. Neurological examination revealed gaze deviation towards the right side in both eyes, as well as nuchal rigidity. The muscle strength of her extremities was at grade 1-2, and muscle tone was increased, with a bilateral positive Babinski sign. Blood tests revealed that tacrolimus and sirolimus levels were within the therapeutic range. Brain magnetic resonance imaging revealed that periventricular white matter lesions were slightly more extensive than those observed prior to transplantation. Lumbar puncture showed that cerebrospinal fluid pressure and composition were normal. A diagnosis of tacrolimus-induced encephalopathy was made after a thorough clinical examination. Subsequently, cyclosporine was administered instead of tacrolimus for anti-rejection therapy, and she has remained free of neurological symptoms since then. The improvement of clinical symptoms following the withdrawal of tacrolimus supports the drug-induced etiology of this neurological disorder., Conclusions: We highlight that tacrolimus-induced encephalopathy can occur in a late stage after lung transplantation and may occur with tacrolimus whole blood concentrations within the therapeutic range., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Jujube (Ziziphus jujuba Mill.), belonging to the Rhamnaceae family, is gaining increasing prominence as a perennial fruit crop with significant economic and medicinal values. Here, we conduct de novo assembly of four reference-grade genomes, encompassing one wild and three cultivated jujube accessions. We present insights into the population structure, genetic diversity, and genomic variations within a diverse collection of 1059 jujube accessions. Analyzes of the jujube pan-genome, based on our four assemblies and four previously released genomes, reveal extensive genomic variations within domestication-associated regions, potentially leading to the discovery of a candidate gene that regulates flowering and fruit ripening. By leveraging the pan-genome and a large-scale resequencing population, we identify two candidate genes involved in domestication traits, including the seed-setting rate, the bearing-shoot length and the leaf size in jujube. These genomic resources will accelerate evolutionary and functional genomics studies of jujube., (© 2024. The Author(s).)

Carbon catabolite repression (CCR) is a common transcriptional regulatory mechanism that microorganisms use to efficiently utilize carbon nutrients, which is critical for the fitness of microorganisms and for pathogenic species to cause infection. Here, we characterized two CCR genes, VdCreA and VdCreC , in Verticillium dahliae that cause cotton Verticillium wilt disease. The VdCreA and VdCreC knockout mutants displayed slow growth with decreased conidiation and microsclerotium production and reduced virulence to cotton, suggesting that VdCreA and VdCreC are involved in growth and pathogenicity in V. dahliae . We further generated 36 highly reliable and stable ΔVdCreA and ΔVdCreC libraries to comprehensively explore the dynamic expression of genes and metabolites when grown under different carbon sources and CCR conditions. Based on the weighted gene co-expression network analysis (WGCNA) and correlation networks, VdCreA is co-expressed with a multitude of downregulated genes. These gene networks span multiple functional pathways, among which seven genes, including PYCR (pyrroline-5-carboxylate reductase), are potential target genes of VdCreA . Different carbon source conditions triggered entirely distinct gene regulatory networks, yet they exhibited similar changes in metabolic pathways. Six genes, including 6-phosphogluconolactonase and 2-ODGH (2-oxoglutarate dehydrogenase E1), may serve as hub genes in this process. Both VdCreA and VdCreC could comprehensively influence the expression of plant cell wall-degrading enzyme (PCWDE) genes, suggesting that they have a role in pathogenicity in V. dahliae . The integrated expression profiles of the genes and metabolites involved in the glycolysis/gluconeogenesis and pentose phosphate pathways showed that the two major sugar metabolism-related pathways were completely changed, and GADP (glyceraldehyde-3-phosphate) may be a pivotal factor for CCR under different carbon sources. All these results provide a more comprehensive perspective for further analyzing the role of Cre in CCR.

The genetic analysis of potato is hampered by the complexity of tetrasomic inheritance. An ongoing effort aims to transform the clonally propagated tetraploid potato into a seed-propagated diploid crop, which would make genetic analyses much easier owing to disomic inheritance. Here, we construct and report the large-scale genetic and heterotic characteristics of a diploid F 2 potato population derived from the cross of two highly homozygous inbred lines. We investigate 20,382 traits generated from multi-omics dataset and identify 25,770 quantitative trait loci (QTLs). Coupled with gene expression data, we construct a systems-genetics network for gene discovery in potatoes. Importantly, we explore the genetic basis of heterosis in this population, especially for yield and male fertility heterosis. We find that positive heterotic effects of yield-related QTLs and negative heterotic effects of metabolite QTLs (mQTLs) contribute to yield heterosis. Additionally, we identify a PME gene with a dominance heterotic effect that plays an important role in male fertility heterosis. This study provides genetic resources for the potato community and will facilitate the application of heterosis in diploid potato breeding., (© 2024. The Author(s).)

M1 macrophages induce protective immunity against infection, but also contribute to metabolic and inflammatory diseases. Here we show that the E3 ubiquitin ligase, MDM2, promotes the glycolytic and inflammatory activities of M1 macrophage by increasing the production of IL-1β, MCP-1 and nitric oxide (NO). Mechanistically, MDM2 triggers the ubiquitination and degradation of E3 ligase, SPSB2, to stabilize iNOS and increases production of NO, which s-nitrosylates and activates HIF-1α for triggering the glycolytic and pro-inflammatory programs in M1 macrophages. Myeloid-specific haplodeletion of MDM2 in mice not only blunts LPS-induced endotoxemia and NO production, but also alleviates obesity-induced adipose tissue-resident macrophage inflammation. By contrast, MDM2 haplodeletion induces higher mortality, tissue damage and bacterial burden, and also suppresses M1 macrophage response, in the cecal ligation and puncture-induced sepsis mouse model. Our findings thus identify MDM2 as an activator of glycolytic and inflammatory responses in M1 macrophages by connecting the iNOS-NO and HIF-1α pathways., (© 2024. The Author(s).)

Key Message: We report the mitochondrial genome of 39 diploid potatoes and identify a candidate ORF potentially linked to cytoplasmic male sterility in potatoes. Potato (Solanum tuberosum L.) holds a critical position as the foremost non-grain food crop, playing a pivotal role in ensuring global food security. Diploid potatoes constitute a vital genetic resource pool, harboring the potential to revolutionize modern potato breeding. Nevertheless, diploid potatoes are relatively understudied, and mitochondrial DNA can provide valuable insights into key potato breeding traits such as CMS. In this study, we examine and assemble the mitochondrial genome evolution and diversity of 39 accessions of diploid potatoes using high-fidelity (HiFi) sequencing. We annotated 54 genes for all the investigated accessions, comprising 34 protein-coding genes, 3 rRNA genes, and 17 tRNA genes. Our analyses revealed differences in repeats sequences between wild and cultivated landraces. To understand the evolution of diploid maternal lineage inheritance, we conducted phylogenetic analysis, which clearly distinguished mitochondrial from nuclear gene trees, further supporting the evidence-based of clustering between wild and cultivated landraces accessions. Our study discovers new candidate ORFs associated with CMS in potatoes, including ORF137, which is homologous to other CMS in Solanaceae. Ultimately, this work bridges the gap in mitochondrial genome research for diploid potatoes, providing a steppingstone into evolutionary studies and potato breeding., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: In the randomized phase II LOTUS trial, combining ipatasertib with first-line paclitaxel for triple-negative breast cancer (TNBC) improved progression-free survival (PFS), particularly in patients with PIK3CA/AKT1/PTEN-altered tumors. We aimed to validate these findings in a biomarker-selected TNBC population., Patients and Methods: In Cohort A of the randomized double-blind placebo-controlled phase III IPATunity130 trial, taxane-eligible patients with PIK3CA/AKT1/PTEN-altered measurable advanced TNBC and no prior chemotherapy for advanced disease were randomized 2:1 to ipatasertib (400 mg, days 1-21) or placebo, both plus paclitaxel (80 mg/m2, days 1, 8, and 15), every 28 days until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed PFS., Results: Between February 2018 and April 2020, 255 patients were randomized (168 to ipatasertib, 87 to placebo). At the primary analysis, there was no significant difference between treatment arms in PFS [hazard ratio 1.02, 95% confidence interval (CI), 0.71-1.45; median 7.4 months with ipatasertib vs. 6.1 months with placebo]. The final analysis showed no difference in overall survival between treatment arms (hazard ratio 1.08, 95% CI, 0.73-1.58; median 24.4 vs. 24.9 months, respectively). Ipatasertib was associated with more grade ≥3 diarrhea (9% vs. 2%) and adverse events leading to dose reduction (39% vs. 14%) but similar incidences of grade ≥3 adverse events (51% vs. 46%). Exploratory subgroup analyses by PAM50 and Burstein gene expression showed inconsistent results., Conclusions: Adding ipatasertib to paclitaxel did not improve efficacy in PIK3CA/AKT1/PTEN-altered advanced TNBC. Biomarkers for benefit from PI3K/AKT pathway inhibition in TNBC remain poorly understood., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: RNA sequencing is a vital technique for analyzing RNA behavior in cells, but it often suffers from various biases that distort the data. Traditional methods to address these biases are typically empirical and handle them individually, limiting their effectiveness. Our study introduces the Gaussian Self-Benchmarking (GSB) framework, a novel approach that leverages the natural distribution patterns of guanine (G) and cytosine (C) content in RNA to mitigate multiple biases simultaneously. This method is grounded in a theoretical model, organizing k-mers based on their GC content and applying a Gaussian model for alignment to ensure empirical sequencing data closely match their theoretical distribution., Results: The GSB framework demonstrated superior performance in mitigating sequencing biases compared to existing methods. Testing with synthetic RNA constructs and real human samples showed that the GSB approach not only addresses individual biases more effectively but also manages co-existing biases jointly. The framework's reliance on accurately pre-determined parameters like mean and standard deviation of GC content distribution allows for a more precise representation of RNA samples. This results in improved accuracy and reliability of RNA sequencing data, enhancing our understanding of RNA behavior in health and disease., Conclusions: The GSB framework presents a significant advancement in RNA sequencing analysis by providing a well-validated, multi-bias mitigation strategy. It functions independently from previously identified dataset flaws and sets a new standard for unbiased RNA sequencing results. This development enhances the reliability of RNA studies, broadening the potential for scientific breakthroughs in medicine and biology, particularly in genetic disease research and the development of targeted treatments., (© 2024. The Author(s).)

Indian jujube (Ziziphus mauritiana) holds a prominent position in the global fruit and pharmaceutical markets. Here, we report the assemblies of haplotype-resolved, telomere-to-telomere genomes of autotetraploid wild and cultivated Indian jujube plants using a two-stage assembly strategy. The generation of these genomes permitted in-depth investigations into the divergence and evolutionary history of this important fruit crop. Using a graph-based pan-genome constructed from eight monoploid genomes, we identified structural variation (SV)-FST hotspots and SV hotspots. Gap-free genomes provide a means to obtain a global view of centromere structures. We identified presence-absence variation-related genes in four monoploid genomes (cI, cIII, wI, and wIII) and resequencing populations. We also present the population structure and domestication trajectory of the Indian jujube based on the resequencing of 73 wild and cultivated accessions. Metabolomic and transcriptomic analyses of mature fruits of wild and cultivated accessions unveiled the genetic basis underlying loss of fruit astringency during domestication of Indian jujube. This study reveals mechanisms underlying the divergence, evolution, and domestication of the autotetraploid Indian jujube and provides rich and reliable genetic resources for future research., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society of Plant Biologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

We introduce a groundbreaking approach: the minimum free energy-based Gaussian Self-Benchmarking (MFE-GSB) framework, designed to combat the myriad of biases inherent in RNA-seq data. Central to our methodology is the MFE concept, facilitating the adoption of a Gaussian distribution model tailored to effectively mitigate all co-existing biases within a k-mer counting scheme. The MFE-GSB framework operates on a sophisticated dual-model system, juxtaposing modeling data of uniform k-mer distribution against the real, observed sequencing data characterized by nonuniform k-mer distributions. The framework applies a Gaussian function, guided by the predetermined parameters-mean and SD-derived from modeling data, to fit unknown sequencing data. This dual comparison allows for the accurate prediction of k-mer abundances across MFE categories, enabling simultaneous correction of biases at the single k-mer level. Through validation with both engineered RNA constructs and human tissue RNA samples, its wide-ranging efficacy and applicability are demonstrated., (© The Author(s) 2024. Published by Oxford University Press.)

Hepatocellular carcinoma (HCC) is a prevalent and aggressive malignancy associated with high risks of recurrence and metastasis. Liver cancer stem cells (CSCs) are increasingly recognized as pivotal drivers of these processes. In our previous research, we demonstrated the involvement of TFCP2L1 in maintaining the pluripotency of embryonic stem cells. However, its relevance to liver CSCs remains unexplored. In this study, we report an inverse correlation between TFCP2L1 protein levels in HCC tissue and patient outcomes. The knockdown of TFCP2L1 significantly reduced HCC cell proliferation, invasion, metastasis, clonal formation, and sphere-forming capacity, while its overexpression enhanced these functions. In addition, experiments using a nude mouse model confirmed TFCP2L1's essential role in liver CSCs' function and tumorigenic potential. Mechanistically, we showed that TFCP2L1 promotes the stemness of CSCs by upregulating NANOG, which subsequently activates the JAK/STAT3 pathway, thereby contributing to HCC pathogenesis. Importantly, we identified a specific small molecule targeting TFCP2L1's active domain, which, in combination with Sorafenib, sensitizes hepatoma cells to treatment. Together, these findings underscore TFCP2L1's pathological significance in HCC progression, supporting its potential as a prognostic biomarker and therapeutic target in this disease., (© 2024. The Author(s).)

Self-assembled monolayers (SAMs) have become pivotal in achieving high-performance perovskite solar cells (PSCs) and organic solar cells (OSCs) by significantly minimizing interfacial energy losses. In this study, we propose a co-adsorb (CA) strategy employing a novel small molecule, 2-chloro-5-(trifluoromethyl)isonicotinic acid (PyCA-3F), introducing at the buried interface between 2PACz and the perovskite/organic layers. This approach effectively diminishes 2PACz's aggregation, enhancing surface smoothness and increasing work function for the modified SAM layer, thereby providing a flattened buried interface with a favorable heterointerface for perovskite. The resultant improvements in crystallinity, minimized trap states, and augmented hole extraction and transfer capabilities have propelled power conversion efficiencies (PCEs) beyond 25% in PSCs with a p-i-n structure (certified at 24.68%). OSCs employing the CA strategy achieve remarkable PCEs of 19.51% based on PM1:PTQ10:m-BTP-PhC6 photoactive system. Notably, universal improvements have also been achieved for the other two popular OSC systems. After a 1000-hour maximal power point tracking, the encapsulated PSCs and OSCs retain approximately 90% and 80% of their initial PCEs, respectively. This work introduces a facile, rational, and effective method to enhance the performance of SAMs, realizing efficiency breakthroughs in both PSCs and OSCs with a favorable p-i-n device structure, along with improved operational stability., (© 2024. The Author(s).)

Background: Sleep problems are prevalent. However, the impact of sleep patterns on digestive diseases remains uncertain. Moreover, the interaction between sleep patterns and genetic predisposition with digestive diseases has not been comprehensively explored., Methods: Four hundred ten thousand five hundred eighty-six participants from UK Biobank with complete sleep information were included in the analysis. Sleep patterns were measured by sleep scores as the primary exposure, based on five healthy sleep behaviors. Individual sleep behaviors were secondary exposures. Genetic risk of the digestive diseases was characterized by polygenic risk score. Primary outcome was incidence of 16 digestive diseases., Results: Healthy sleep scores showed dose-response associations with reduced risks of digestive diseases. Compared to participants scoring 0-1, those scoring 5 showed a 28% reduced risk of any digestive disease, including a 50% decrease in irritable bowel syndrome, 37% in non-alcoholic fatty liver disease, 35% in peptic ulcer, 34% in dyspepsia, 32% in gastroesophageal reflux disease, 28% in constipation, 25% in diverticulosis, 24% in severe liver disease, and 18% in gallbladder disease, whereas no correlation was observed with inflammatory bowel disease and pancreatic disease. Participants with poor sleep and high genetic risk exhibited approximately a 60% increase in the risk of digestive diseases. A healthy sleep pattern is linked to lower digestive disease risk in participants of all genetic risk levels., Conclusions: In this large population-based cohort, a healthy sleep pattern was associated with a reduced risk of digestive diseases, regardless of genetic susceptibility. The authors' findings underscore the potential impact of healthy sleep traits in mitigating the risk of digestive diseases., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The COVID-19 pandemic has caused profound changes in adolescent lives, including school closures, social isolation, family economic hardship, and sleep schedule. We aimed to assess the risk and protective factors of sufficient sleep among adolescents during COVID-19., Methods: We conducted secondary analysis based on the cross-sectional school-based Adolescent Behaviors and Experiences Survey in 2021 ( n  = 7,705). The ABES collected information on health-related experiences and behaviors during COVID-19. The outcome was sufficient sleep (eight and more hours of sleep on the average school night). The contributing factors included demographic, mental health, and adverse experiences indicators. We estimated the prevalence of sufficient sleep within each factor, and examined their associations using Chi-square test. We further investigated the contributing factors of sufficient sleep using multivariate logistic regression and reported the adjusted odds ratios (AORs) and 95% confidence intervals (CIs)., Results: During January-June 2021, 23.5% of the U.S. high school students reported getting sufficient sleep. The multivariate logistic regression indicated that younger age (AOR, 2.04; 95%CI, 1.59-2.62), heterosexual identity (AOR, 1.61; 95%CI, 1.19-2.18), no poor mental health during the past 30 days (AOR, 1.37; 95%CI, 1.03-1.82), no persistent feelings of sadness or hopelessness (AOR, 1.34; 95%CI, 1.09-1.66), no food and nutrition insecurity (AOR, 1.47; 95%CI, 1.17-1.85), never been abused by a parent emotionally (AOR, 1.38; 95%CI, 1.16-1.64), and no schoolwork difficulty (AOR, 1.24; 95%CI, 1.01-1.51) were associated with sufficient sleep., Conclusion: We estimated the national prevalence of adolescent sufficient sleep during the COVID-19 pandemic and found that younger students, sexual heterosexual students, and students without certain mental health conditions or adverse experiences are at higher likelihood of sufficient sleep. These findings can help develop effective interventions on sleep duration in the response to a possible future pandemic caused by Disease X., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Li, Liu and Lian.)

Background: Human adipose-derived stem cells (ADSCs) exert a strong anti-inflammatory effect, and synovium-derived stem cells (SDSCs) have high chondrogenic potential. Thus, this study aims to investigate whether a combination of human ADSCs and SDSCs will have a synergistic effect that will increase the chondrogenic potential of osteoarthritis (OA) chondrocytes in vitro and attenuate the cartilage degeneration of early and advanced OA in vitro., Methods: ADSCs, SDSCs, and chondrocytes were isolated from OA patients who underwent total knee arthroplasty. The ADSCs-SDSCs mixed cell ratios were 1:0 (ADSCs only), 8:2, 5:5 (5A5S), 2:8, and 0:1 (SDSCs only). The chondrogenic potential of the OA chondrocytes was evaluated in vitro with a transwell assay or pellet culture with various mixed cell groups. The mixed cell group with the highest chondrogenic potential was then selected and injected into the knee joints of nude rats of early and advanced OA stages in vivo. The animals were then evaluated 12 and 20 weeks after surgery through gait analysis, von frey test, microcomputed tomography, MRI, and immunohistochemical and histological analyses. Finally, the mechanisms underlying these findings were investigated through the RNA sequencing of tissue samples in vivo and Western blot of the OA chondrocyte autophagy pathway., Results: Among the MSCs treatment groups, 5A5S had the greatest synergistic effect that increased the chondrogenic potential of OA chondrocytes in vitro and inhibited early and advanced OA in vivo. The 5A5S group significantly reduced cartilage degeneration, synovial inflammation, pain sensation, and nerve invasion in subchondral nude rat OA, outperforming both single-cell treatments. The underlying mechanism was the activation of chondrocyte autophagy via the FoxO1 signaling pathway., Conclusion: A combination of human ADSCs and SDSCs demonstrated higher potential than a single type of stem cell, demonstrating potential as a novel treatment for OA., (© 2024. The Author(s).)

Background: Blinded independent central review (BICR) of radiographic images is frequently conducted in oncology trials to address the potential bias of local evaluation (LE) of endpoints such as progression-free survival (PFS) and objective response rate (ORR). Given that BICR is a complex and costly process, we evaluated the agreement between LE- and BICR-based treatment effect results and the impact of BICR on regulatory decision-making., Materials and Methods: Meta-analyses were performed using hazard ratios (HRs) for PFS and odds ratios (ORs) for ORR from all randomized Roche-supported oncology clinical trials during 2006-2020 that had both LE and BICR results (49 studies with a total of over 32 000 patients)., Results: Overall, the evaluation bias of LE overestimating the treatment effect compared with BICR based on PFS was numerically small and not clinically meaningful, especially for double-blind studies (HR ratio between BICR and LE: 1.044). A larger bias is more likely to occur in studies with open-label design, smaller sample sizes, or an unequal randomization ratio. The majority (87%) of the PFS comparisons led to the same statistical inference by BICR and LE. For ORR, a high degree of agreement between BICR and LE results was also observed (OR ratio of 1.065), although the agreement was slightly lower than for PFS., Conclusion: BICR did not notably impact the study interpretation nor drive the sponsor's regulatory submission decisions. Hence, if bias can be diminished by appropriate means, LE is deemed as reliable as BICR for certain study settings., (© The Author(s) 2023. Published by Oxford University Press.)

Carbon-defect engineering in single-atom metal-nitrogen-carbon (M─N─C) catalysts by straightforward and robust strategy, enhancing their catalytic activity for volatile organic compounds, and uncovering the carbon vacancy-catalytic activity relationship are meaningful but challenging. In this study, an iron-nitrogen-carbon (Fe─N─C) catalyst is intentionally designed through a carbon-thermal-diffusion strategy, exposing extensively the carbon-defective Fe─N 4 sites within a micro-mesoporous carbon matrix. The optimization of Fe─N 4 sites results in exceptional catalytic ozonation efficiency, surpassing that of intact Fe─N 4 sites and commercial MnO 2 by 10 and 312 times, respectively. Theoretical calculations and experimental data demonstrated that carbon-defect engineering induces selective cleavage of C─N bond neighboring the Fe─N 4 motif. This induces an increase in non-uniform charges and Fermi density, leading to elevated energy levels at the center of Fe d-band. Compared to the intact atomic configuration, carbon-defective Fe─N 4 site is more activated to strengthen the interaction with O 3 and weaken the O─O bond, thereby reducing the barriers for highly active surface atomic oxygen (*O/*OO), ultimately achieving efficient oxidation of CH 3 SH and its intermediates. This research not only offers a viable approach to enhance the catalytic ozonation activity of M─N─C but also advances the fundamental comprehension of how periphery carbon environment influences the characteristics and efficacy of M─N 4 sites., (© 2024 Wiley‐VCH GmbH.)

Inflammatory bowel diseases (IBDs) are prevalent and debilitating diseases with limited clinical treatment strategies. Mesenchymal stem cell (MSCs) are pluripotent stem cells with self-renewal capability and multiple immunomodulatory effects, which make them a promising therapeutic approach for IBDs. Thus, optimization of MSCs regimes is crucial for their further clinical application. Wogonin, a flavonoid-like compound with extensive immunomodulatory and adjuvant effects, has been investigated as a potential pretreatment for MSCs in IBD treatment. In this study, we employed the DSS-induced acute colitis mouse model to compare the therapeutic effectiveness of MSCs in pretreated with or without wogonin and further explore the underlying mechanism. Compared to untreated MSCs, MSC wogonin (pretreated with wogonin) showed greater effectiveness in the treatment of colitis. Further experiments revealed that wogonin treatment activated the AKT signaling pathway, resulting in higher cellular glycolysis. Inhibition of AKT phosphorylation by perifosine not only decreased glycolysis but impaired the therapeutic efficiency of MSC wogonin . Consistent with these results, qPCR data indicated that wogonin treatment induced the expression of immunomodulatory molecules IL-10, IDO, and AGR1, which were reduced by perifosine. Together, our data demonstrated that wogonin preconditioning strategy further augmented the therapeutic efficacy of MSCs via promoting glycolysis, which should be a promising strategy for optimizing MSCs therapy in IBDs., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Atrial fibrillation (AF) is a common persistent arrhythmia characterized by rapid and chaotic atrial electrical activity, potentially leading to severe complications such as thromboembolism, heart failure, and stroke, significantly affecting patient quality of life and safety. As the global population ages, the prevalence of AF is on the rise, placing considerable strains on individuals and healthcare systems. This study utilizes bioinformatics and Mendelian Randomization (MR) to analyze transcriptome data and genome-wide association study (GWAS) summary statistics, aiming to identify biomarkers causally associated with AF and explore their potential pathogenic pathways., Methods: We obtained AF microarray datasets GSE41177 and GSE79768 from the Gene Expression Omnibus (GEO) database, merged them, and corrected for batch effects to pinpoint differentially expressed genes (DEGs). We gathered exposure data from expression quantitative trait loci (eQTL) and outcome data from AF GWAS through the IEU Open GWAS database. We employed inverse variance weighting (IVW), MR-Egger, weighted median, and weighted model approaches for MR analysis to assess exposure-outcome causality. IVW was the primary method, supplemented by other techniques. The robustness of our results was evaluated using Cochran's Q test, MR-Egger intercept, MR-PRESSO, and leave-one-out sensitivity analysis. A "Veen" diagram visualized the overlap of DEGs with significant eQTL genes from MR analysis, referred to as common genes (CGs). Additional analyses, including Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and immune cell infiltration studies, were conducted on these intersecting genes to reveal their roles in AF pathogenesis., Results: The combined dataset revealed 355 differentially expressed genes (DEGs), with 228 showing significant upregulation and 127 downregulated. Mendelian randomization (MR) analysis identified that the autocrine motility factor receptor (AMFR) [IVW: OR = 0.977; 95% CI, 0.956-0.998; P  = 0.030], leucine aminopeptidase 3 (LAP3) [IVW: OR = 0.967; 95% CI, 0.934-0.997; P  = 0.048], Rab acceptor 1 (RABAC1) [IVW: OR = 0.928; 95% CI, 0.875-0.985; P  = 0.015], and tryptase beta 2 (TPSB2) [IVW: OR = 0.971; 95% CI, 0.943-0.999; P  = 0.049] are associated with a reduced risk of atrial fibrillation (AF). Conversely, GTPase-activating SH3 domain-binding protein 2 (G3BP2) [IVW: OR = 1.030; 95% CI, 1.004-1.056; P  = 0.024], integrin subunit beta 2 (ITGB2) [IVW: OR = 1.050; 95% CI, 1.017-1.084; P  = 0.003], glutaminyl-peptide cyclotransferase (QPCT) [IVW: OR = 1.080; 95% CI, 1.010-0.997; P  = 1.154], and tripartite motif containing 22 (TRIM22) [IVW: OR = 1.048; 95% CI, 1.003-1.095; P  = 0.035] are positively associated with AF risk. Sensitivity analyses indicated a lack of heterogeneity or horizontal pleiotropy ( P  > 0.05), and leave-one-out analysis did not reveal any single nucleotide polymorphisms (SNPs) impacting the MR results significantly. GO and KEGG analyses showed that CG is involved in processes such as protein polyubiquitination, neutrophil degranulation, specific and tertiary granule formation, protein-macromolecule adaptor activity, molecular adaptor activity, and the SREBP signaling pathway, all significantly enriched. The analysis of immune cell infiltration demonstrated associations of CG with various immune cells, including plasma cells, CD8T cells, resting memory CD4T cells, regulatory T cells (Tregs), gamma delta T cells, activated NK cells, activated mast cells, and neutrophils., Conclusion: By integrating bioinformatics and MR approaches, genes such as AMFR, G3BP2, ITGB2, LAP3, QPCT, RABAC1, TPSB2, and TRIM22 are identified as causally linked to AF, enhancing our understanding of its molecular foundations. This strategy may facilitate the development of more precise biomarkers and therapeutic targets for AF diagnosis and treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Zhang, Lian, Nie and Zhao.)

Modern plant breeding, such as genomic selection and gene editing, is based on the knowledge of the genetic architecture of desired traits. Quantitative trait loci (QTL) analysis, which combines high throughput phenotyping and genotyping of segregating populations, is a powerful tool to identify these genetic determinants and to decipher the underlying mechanisms. However, meiotic recombination, which shuffles genetic information between generations, is limited: Typically only one to two exchange points, called crossovers, occur between a pair of homologous chromosomes. Here we test the effect on QTL analysis of boosting recombination, by mutating the anti-crossover factors RECQ4 and FIGL1 in Arabidopsis thaliana full hybrids and lines in which a single chromosome is hybrid. We show that increasing recombination ~6-fold empowers the detection and resolution of QTLs, reaching the gene scale with only a few hundred plants. Further, enhanced recombination unmasks some secondary QTLs undetected under normal recombination. These results show the benefits of enhanced recombination to decipher the genetic bases of traits., (© 2024. The Author(s).)

Gene set scoring (GSS) has been routinely conducted for gene expression analysis of bulk or single-cell RNA sequencing (RNA-seq) data, which helps to decipher single-cell heterogeneity and cell type-specific variability by incorporating prior knowledge from functional gene sets. Single-cell assay for transposase accessible chromatin using sequencing (scATAC-seq) is a powerful technique for interrogating single-cell chromatin-based gene regulation, and genes or gene sets with dynamic regulatory potentials can be regarded as cell type-specific markers as if in single-cell RNA-seq (scRNA-seq). However, there are few GSS tools specifically designed for scATAC-seq, and the applicability and performance of RNA-seq GSS tools on scATAC-seq data remain to be investigated. Here, we systematically benchmarked ten GSS tools, including four bulk RNA-seq tools, five scRNA-seq tools, and one scATAC-seq method. First, using matched scATAC-seq and scRNA-seq datasets, we found that the performance of GSS tools on scATAC-seq data was comparable to that on scRNA-seq, suggesting their applicability to scATAC-seq. Then, the performance of different GSS tools was extensively evaluated using up to ten scATAC-seq datasets. Moreover, we evaluated the impact of gene activity conversion, dropout imputation, and gene set collections on the results of GSS. Results show that dropout imputation can significantly promote the performance of almost all GSS tools, while the impact of gene activity conversion methods or gene set collections on GSS performance is more dependent on GSS tools or datasets. Finally, we provided practical guidelines for choosing appropriate preprocessing methods and GSS tools in different application scenarios., (© The Author(s) 2024. Published by Oxford University Press and Science Press on behalf of the Beijing Institute of Genomics, Chinese Academy of Sciences / China National Center for Bioinformation and Genetics Society of China.)

Actin filaments and their associated actin-binding proteins play key roles in plant innate immune signaling. CAP1, or cyclase-associated protein 1, is an important regulatory factor of the actin cytoskeleton-associated signaling network and was hypothesized here to be involved in resistance against wheat stripe rust because TaCAP1 expression was upregulated in response to Puccinia striiformis f. sp. tritici ( Pst ). Downregulation of TaCAP1 expression led to decreased resistance against Pst , in contrast to increased resistance upon TaCAP1 overexpressing, as demonstrated by the changes of phenotypes and hyphal growth. We found increased expression of pathogenesis-responsive or relative related genes and disease grade changed in TaCAP1 overexpressing plants. Our results also showed TaCAP1- regulated host resistance to Pst by inducing the production and accumulation of reactive oxygen species and mediating the salicylic acid signaling pathway. Additionally, TaCAP1 interacted with chlorophyll a/b-binding proteins TaLHCB1.3 and TaLHCB1.4, also known as the light-harvesting chlorophyll-protein complex II subunit B, which belong to the light-harvesting complex II protein family. Silencing of two TaLHCB1 genes showed higher susceptibility to Pst , which reduced wheat resistance against Pst . Therefore, the data presented herein further illuminate our understanding that TaCAP1 interacts with TaLHCB1s and functions as a positive regulator of wheat resistance against stripe rust., Competing Interests: The author(s) declare no conflict of interest.

Background: Observational studies have established an association between serum uric acid and cardiovascular disease (CVD). However, these studies are susceptible to uncontrolled confounders and reverse causality bias. To overcome these challenges, we employed a two-sample Mendelian randomization (MR) approach to investigate the causal link between serum uric acid and CVD., Methods: We utilized Genome-wide association study (GWAS) data for serum uric acid and six CVD: coronary artery disease (CAD), hypertension, myocardial infarction (MI), heart failure (HF), angina, and coronary heart disease (CHD). MR analyses employed inverse variance weighting (IVW), MR-Egger, weighted median, and weighted model. Sensitivity analyses were conducted to assess result reliability, including Cochrane's Q test, MR-Egger intercept, MR-PRESSO, and the leave-one-out approach., Results: IVW analysis revealed that a genetic predisposition to elevated serum uric acid levels significantly increases the risk of CVD, with higher odds ratios (ORs) observed for CAD (OR: 1.227; 95 % CI: 1.107-1.360, P  = 0.0002), hypertension (OR: 1.318, 95 %CI: 1.184-1.466, P  = 2.13E-06), MI (OR: 1.184, 95 %CI: 1.108-1.266, P  = 2.13E-06), HF (OR: 1.158, 95 %CI: 1.066-1.258, P  = 2.13E-06), angina (OR: 1.150, 95 %CI: 1.074-1.231, P  = 0.0002) and CHD (OR: 1.170, 95 %CI: 1.072-1.276, P  = 0.0005). Sensitivity analysis research results have robustness., Conclusion: This MR study robustly demonstrates a significant causal relationship between genetically elevated serum uric acid and various cardiovascular diseases, suggesting that higher levels may enhance the risk of cardiovascular events. Consequently, patients with elevated uric acid levels warrant early and aggressive interventions to mitigate cardiovascular risks., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Introduction: The immunosuppressive capacity of mesenchymal stem cells (MSCs) is dependent on the "license" of several pro-inflammatory factors to express immunosuppressive molecular profiles, which determines the therapeutic efficacy of MSCs in immune-mediated inflammatory diseases. Of those, interferon-γ (IFN-γ) is a key inducer for the expression of immunosuppressive molecular profiles; however, the mechanism underlying this effect is unknown., Objectives: To elucidate the regulation mechanism and biological functions of N 6 -methyladenosine (m 6 A) modification in the immunosuppressive functions by the IFN-γ-licensing MSCs., Methods: Epitranscriptomic microarray analysis and MeRIP-qPCR assay were performed to identify the regulatory effect of WTAP in the IFN-γ-licensing MSCs. RIP-qPCR, western blot, qRT-PCR and RNA stability assays were used to determine the regulation of WTAP/m 6 A/YTHDF1 signaling axis in the expression of immunosuppressive molecules. Further, functional capacity of T cells was tested using flow cytometry, and both DSS-induced colitis mice and CIA mice were constructed to clarify the effect of WTAP and YTHDF1 in MSC-mediated immunosuppression., Results: We identified that IFN-γ increased the m 6 A methylation levels of immunosuppressive molecules, while WTAP deficiency abolished the IFN-γ-induced promotion of m 6 A modification. IFN-γ activated ERK signaling, which induced WTAP phosphorylation. Additionally, the stabilization of WTAP post-transcriptionally increased the mRNA expression of immunosuppressive molecules (IDO1, PD-L1, ICAM1, and VCAM1) in an m 6 A-YTHDF1-dependent manner; this effect further impacted the immunosuppressive capacity of IFN-γ licensing MSCs on activated T cells. Notably, WTAP/YTHDF1 overexpression enhanced the therapeutic efficacy of IFN-γ licensing MSCs and restructures the ecology of inflammation in both colitis and arthritis models., Conclusion: Our results showed that m 6 A modification of IDO1, PD-L1, ICAM1, and VCAM1 mRNA mediated by WTAP-YTHDF1 is involved in the regulation of IFN-γ licensing MSCs immunosuppressive abilities, and shed a light to enhance the clinical therapeutic potential of IFN-γ-licensing MSCs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Production and hosting by Elsevier B.V.)

Metachromatic leukodystrophy (MLD) is an inherited disease caused by a deficiency of the enzyme arylsulfatase A (ARSA). Lentivirus-modified autologous hematopoietic stem cell gene therapy (HSCGT) has recently been approved for clinical use in pre- and early-symptomatic children with MLD to increase ARSA activity. Unfortunately, this advanced therapy is not available for most patients with MLD who have progressed to more advanced symptomatic stages at diagnosis. Patients with late-onset juvenile MLD typically present with a slower neurological progression of symptoms and represent a significant burden to the economy and healthcare system, whereas those with early-onset infantile MLD die within a few years of symptom onset. We conducted a pilot study to determine the safety and benefit of HSCGT in patients with post-symptomatic juvenile MLD and report preliminary results. The safety profile of HSCGT was favorable in this long-term follow-up over nine years. The most common adverse events (AEs) within two months of HSCGT were related to busulfan conditioning, and all AEs resolved. No HSCGT-related AEs and no evidence of distorted hematopoietic differentiation during long-term follow-up for up to 9.6 years. Importantly, to date, patients have maintained remarkably improved ARSA activity with a stable disease state, including increased Functional Independence Measure (FIM) score and decreased magnetic resonance imaging (MRI) lesion score. This long-term follow-up pilot study suggests that HSCGT is safe and provides clinical benefit to patients with post-symptomatic juvenile MLD., (© The Author(s) 2024. Published by Oxford University Press on behalf of Higher Education Press.)

Background: Gender nonconformity (GNC) is an under-researched area of adolescent health that is of increasing interest to researchers and general public. However, little is known about whether it is associated with anabolic-androgenic steroids (AAS) misuse. We aimed to investigate the association among high school students using a cross-sectional design., Methods: We pooled the 6 school districts data from the Youth Risk Behavior Survey in 2017 and 2019. We compared the prevalence of AAS misuse among gender nonconforming and conforming students. AAS misuse was determined on the reported experience of lifetime non-prescription steroid use. GNC was derived from perceived gender expression and sex. We estimated the sex-stratified adjusted odds ratios (AORs) for the association of GNC with AAS misuse after adjusting for race/ethnicity, grade, and sexual orientation., Results: The study population consisted of 17,754 US high school students including 9143 (49.67%) female students. Among female students, GNC was significantly associated with moderate (AOR, 3.69; 95% CI 1.28-10.62; P = 0.016) and severe (AOR, 5.00; 95% CI 1.05-23.76; P = 0.043) AAS misuse, but not with any AAS misuse (AOR, 0.85; 95% CI 0.34-2.14; P = 0.734). Among male students, GNC was significantly associated with any (AOR, 4.75; 95% CI 2.93-7.69; P < 0.001), moderate (AOR, 4.86; 95% CI 2.66-8.89; P < 0.001) and severe (AOR, 4.13; 95% CI 1.43-11.95; P = 0.009) AAS misuse. We did not observe a dose-response relationship between GNC and any AAS misuse in female and male students., Conclusions: This study suggests that AAS misuse is associated with GNC among female and male adolescents., (© 2024. The Author(s).)

The development of metallic joint prostheses has been ongoing for more than a century alongside advancements in hip and knee arthroplasty. Among the materials utilized, the Cobalt-Chromium-Molybdenum (Co-Cr-Mo) and Titanium-Aluminum-Vanadium (Ti-Al-V) alloys are predominant in joint prosthesis construction, predominantly due to their commendable biocompatibility, mechanical strength, and corrosion resistance. Nonetheless, over time, the physical wear, electrochemical corrosion, and inflammation induced by these alloys that occur post-implantation can cause the release of various metallic components. The released metals can then flow and metabolize in vivo, subsequently causing potential local or systemic harm. This review first details joint prosthesis development and acknowledges the release of prosthetic metals. Second, we outline the metallic concentration, biodistribution, and elimination pathways of the released prosthetic metals. Lastly, we discuss the possible organ, cellular, critical biomolecules, and significant signaling pathway toxicities and adverse effects that arise from exposure to these metals., Competing Interests: The authors declare no competing interests in this work., (© 2024 Zhong et al.)

Additive manufacturing (3D printing) technology aligns with the direction of precision and customization in future medicine, presenting a significant opportunity for innovative development in high-end medical devices. Currently, research and industrialization of 3D printed medical devices mainly focus on nondegradable implants and degradable implants. Primary areas including metallic orthopaedic implants, polyether-ether-ketone (PEEK) bone implants, and biodegradable implants have been developed for clinical and industrial application. Recent research achievements in these areas are reviewed, with a discussion on the additive manufacturing technologies and applications for customized implants. Challenges faced by different types of implants are analyzed from technological, application, and regulatory perspectives. Furthermore, prospects and suggestions for future development are outlined.

It is well-established that most patients with systemic light chain (AL) amyloidosis have multi-organ involvement and are often diagnosed after a lag period of increasing symptoms. We leverage electronic health record (EHR) data from the TriNetX research network to describe the incidence, timing, and co-occurrence of precursor conditions of interests in a cohort of AL amyloidosis patients identified between October 2015-December 2020. Nineteen precursor diagnoses of interest representing features of AL amyloidosis were identified using ICD codes up to 36 months prior to AL amyloidosis diagnosis. Among 1,401 patients with at least 36 months of EHR data prior to AL amyloidosis diagnosis, 46% were females, 16% were non-Hispanic Black, and 6% were Hispanic. The median age was 71 (range, 21-91) years. The median number of precursor diagnoses was 5 with dyspnea and fatigue being the most prevalent. The time from the first occurrence of a precursor to AL diagnosis ranged from 3.2 to 21.4 months. Analyses of pairwise co-occurrence of specific diagnoses indicated a high association (Cole's coefficient >0.6) among the examined precursor diagnoses. These findings provide novel information about the timing and co-occurrence of key precursor conditions and could be used to develop algorithms for early identification of AL amyloidosis., (© 2024. The Author(s).)

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder for which current treatments are limited and drug development costs are prohibitive. Identifying drug targets for ASD is crucial for the development of targeted therapies. Summary-level data of expression quantitative trait loci obtained from GTEx, protein quantitative trait loci data from the ROSMAP project, and two ASD genome-wide association studies datasets were utilized for discovery and replication. We conducted a combined analysis using Mendelian randomization (MR), transcriptome-wide association studies, Bayesian colocalization, and summary-data-based MR to identify potential therapeutic targets associated with ASD and examine whether there are shared causal variants among them. Furthermore, pathway and drug enrichment analyses were performed to further explore the underlying mechanisms and summarize the current status of pharmacological targets for developing drugs to treat ASD. The protein-protein interaction (PPI) network and mouse knockout models were performed to estimate the effect of therapeutic targets. A total of 17 genes revealed causal associations with ASD and were identified as potential targets for ASD patients. Cathepsin B (CTSB) [odd ratio (OR) = 2.66 95, confidence interval (CI): 1.28-5.52, P = 8.84 × 10-3], gamma-aminobutyric acid type B receptor subunit 1 (GABBR1) (OR = 1.99, 95CI: 1.06-3.75, P = 3.24 × 10-2), and formin like 1 (FMNL1) (OR = 0.15, 95CI: 0.04-0.58, P = 5.59 × 10-3) were replicated in the proteome-wide MR analyses. In Drugbank, two potential therapeutic drugs, Acamprosate (GABBR1 inhibitor) and Bryostatin 1 (CASP8 inhibitor), were inferred as potential influencers of autism. Knockout mouse models suggested the involvement of the CASP8, GABBR1, and PLEKHM1 genes in neurological processes. Our findings suggest 17 candidate therapeutic targets for ASD and provide novel drug targets for therapy development and critical drug repurposing opportunities., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Lung adenocarcinoma (LUAD) is a highly morbid and fatal cancer. Despite advancements in modern medical treatment, the 5-year survival rate of patients remains suboptimal. Our previous study revealed that zinc finger SWIM-type containing 1 (ZSWIM1), a novel protein, promotes the proliferation, migration, and invasion of LUAD cells. The aim of this study is to investigate the impact of E3 ubiquitin ligase tripartite motif protein 21 (TRIM21) on ZSWIM1-mediated cell proliferation and migration., Methods: The interaction and co-localization between TRIM21 and ZSWIM1 were verified using co-immunoprecipitation (Co-IP) and immunofluorescence (IF). The effects of TRIM21 and ZSWIM1 on the proliferation and migration of LUAD cells were assessed through MTT and Transwell assays, respectively. Western blot (WB) analysis was conducted to evaluate the impact of TRIM21 and ZSWIM1 on the expression of epithelial-mesenchymal transition (EMT) markers in LUAD cells. The influence of TRIM21 on the ubiquitination of ZSWIM1 was examined using Co-IP combined with WB., Results: TRIM21 was found to interact and co-localize with ZSWIM1. Overexpression of TRIM21 inhibited the proliferation and migration of LUAD cells. Overexpression of TRIM21 reduced the promoting effect of ZSWIM1 on the proliferation, migration, and invasion of lung adenocarcinoma cells, and reversed the impact of ZSWIM1 on the expression of E-cadherin and Vimentin. Conversely, knockdown of TRIM21 further enhanced the promoting effect of ZSWIM1 on the proliferation and migration of LUAD cells. Mechanistically, we observed that overexpression of TRIM21 significantly enhanced the ubiquitination level of ZSWIM1, leading to a decrease in ZSWIM1 protein expression., Conclusions: TRIM21 binds to and promotes the ubiquitination of ZSWIM1, resulting in reduced protein expression of ZSWIM1, which leads to the inhibition of ZSWIM1-mediated promotion of proliferation, migration, and invasion in LUAD cells.

Large-scale transcriptomic data are crucial for understanding the molecular features of hepatocellular carcinoma (HCC). Integrated 15 transcriptomic datasets of HCC clinical samples, the first version of HCC database (HCCDB v1.0) was released in 2018. Through the meta-analysis of differentially expressed genes and prognosis-related genes across multiple datasets, it provides a systematic view of the altered biological processes and the inter-patient heterogeneities of HCC with high reproducibility and robustness. With four years having passed, the database now needs integration of recently published datasets. Furthermore, the latest single-cell and spatial transcriptomics have provided a great opportunity to decipher complex gene expression variations at the cellular level with spatial architecture. Here, we present HCCDB v2.0, an updated version that combines bulk, single-cell, and spatial transcriptomic data of HCC clinical samples. It dramatically expands the bulk sample size by adding 1656 new samples from 11 datasets to the existing 3917 samples, thereby enhancing the reliability of transcriptomic meta-analysis. A total of 182,832 cells and 69,352 spatial spots are added to the single-cell and spatial transcriptomics sections, respectively. A novel single-cell level and 2-dimension (sc-2D) metric is proposed as well to summarize cell type-specific and dysregulated gene expression patterns. Results are all graphically visualized in our online portal, allowing users to easily retrieve data through a user-friendly interface and navigate between different views. With extensive clinical phenotypes and transcriptomic data in the database, we show two applications for identifying prognosis-associated cells and tumor microenvironment. HCCDB v2.0 is available at http://lifeome.net/database/hccdb2., (© The Author(s) 2024. Published by Oxford University Press and Science Press on behalf of the Beijing Institute of Genomics, Chinese Academy of Sciences / China National Center for Bioinformation and Genetics Society of China.)

Highly aggressive gastric cancer (HAGC) is a gastric cancer characterized by bone marrow metastasis and disseminated intravascular coagulation (DIC). Information about the disease is limited. Here we employed single-cell RNA sequencing to investigate peripheral blood mononuclear cells (PBMCs), aiming to unravel the immune response of patients toward HAGC. PBMCs from seven HAGC patients, six normal advanced gastric cancer (NAGC) patients, and five healthy individuals were analysed by single-cell RNA sequencing. The expression of genes of interest was validated by bulk RNA-sequencing and ELISA. We found a massive expansion of neutrophils in PBMCs of HAGC. These neutrophils are activated, but immature. Besides, mononuclear phagocytes exhibited an M2-like signature and T cells were suppressed and reduced in number. Analysis of cell-cell crosstalk revealed that several signalling pathways involved in neutrophil to T-cell suppression including APP-CD74, MIF-(CD74+CXCR2), and MIF-(CD74+CD44) pathways were increased in HAGC. NETosis-associated genes S100A8 and S100A9 as well as VEGF, PDGF, FGF, and NOTCH signalling that contribute to DIC development were upregulated in HAGC too. This study reveals significant changes in the distribution and interactions of the PBMC subsets and provides valuable insight into the immune response in patients with HAGC. S100A8 and S100A9 are highly expressed in HAGC neutrophils, suggesting their potential to be used as novel diagnostic and therapeutic targets for HAGC., (© 2024 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)