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Abstract Objective The relationship between changes in Chinese visceral adiposity index (CVAI) and cardiometabolic diseases (CMD) in middle-aged and elderly individuals remains unclear. This study aimed to explore whether changes in the CVAI were associated with CMD incidence. Methods This study included 3,243 individuals aged over 45 years from the China Health and Retirement Longitudinal Study. The exposures were changes in the CVAI and cumulative CVAI from 2012 to 2015. Changes in the CVAI were classified using K-means clustering analysis, and the cumulative CVAI was calculated as follows: (CVAI2012 + CVAI2015)/2 × time (2015–2012). Multivariable logistic regression models were used to assess the relationship between different CVAI change classes and CMD incidence. Restricted cubic splines regression was used to assess the dose–response relationship between cumulative CVAI and CMD incidence. To investigate the relationship between combined exposure to each component of CAVI and CMD incidence, a weighted quantile sum regression analysis was employed. Results During the 5 years of follow-up, 776 (24%) incident CMD cases were identified. Changes in CVAI and cumulative CVAI were independently and positively associated with CMD. After adjusting for potential confounders, compared with Class 1, the adjusted ORs (95% CIs) for incident CMD were 1.18 (0.90–1.57) for Class 2, 1.40 (1.03–1.92) for Class 3, and 1.56 (1.04–2.34) for Class 4. When cumulative CVAI was categorized into quartiles, compared with Q1, the adjusted ORs (95% CIs) for incident CMD were 1.30 (1.00–1.70) for Q2, 1.34 (1.01–1.79) for Q3, and 1.63 (1.15–2.31) for Q4. In addition, cumulative CVAI in the overall population exhibited a linear association with CMD (P overall = 0.012, P non-linearity = 0.287), diabetes (P overall = 0.022, P non-linearity = 0.188), and stroke (P overall = 0.002, P non-linearity = 0.978), but showed no significant association with heart disease (P overall = 0.619, P non-linearity = 0.442). Conclusion Participants with higher baseline CVAI level and a change of elevating CVAI level may suffer an increased incidence of CMD. Furthermore, our findings elucidate the underlying mechanisms of the CVAI by highlighting TG as the primary contributor to the observed associations. Long-term CVAI monitoring is of significant importance for early identification and prevention of CMD, with significant implications for clinical practice.

Abstract Background The pathogenesis of osteoarthritis (OA) involves the progressive degradation of articular cartilage. Exosomes derived from mesenchymal stem cells (MSC-EXOs) have been shown to mitigate joint pathological injury by attenuating cartilage destruction. Optimization the yield and therapeutic efficacy of exosomes derived from MSCs is crucial for promoting their clinical translation. The preconditioning of MSCs enhances the therapeutic potential of engineered exosomes, offering promising prospects for application by enabling controlled and quantifiable external stimulation. This study aims to address these issues by employing pro-inflammatory preconditioning of MSCs to enhance exosome production and augment their therapeutic efficacy for OA. Methods The exosomes were isolated from the supernatant of infrapatellar fat pad (IPFP)-MSCs preconditioned with a pro-inflammatory factor, TNF-α, and their production was subsequently quantified. The exosome secretion-related pathways in IPFP-MSCs were evaluated through high-throughput transcriptome sequencing analysis, q-PCR and western blot analysis before and after TNF-α preconditioning. Furthermore, exosomes derived from TNF-α preconditioned IPFP-MSCs (IPFP-MSC-EXOsTNF−α) were administered intra-articularly in an OA mouse model, and subsequent evaluations were conducted to assess joint pathology and gait alterations. The expression of proteins involved in the maintenance of cartilage homeostasis within the exosomes was determined through proteomic analysis. Results The preconditioning with TNF-α significantly enhanced the exosome secretion of IPFP-MSCs compared to unpreconditioned MSCs. The potential mechanism involved the activation of the PI3K/AKT signaling pathway in IPFP-MSCs by TNF-α precondition, leading to an up-regulation of autophagy-related protein 16 like 1(ATG16L1) levels, which subsequently facilitated exosome secretion. The intra-articular administration of IPFP-MSC-EXOsTNF−α demonstrated superior efficacy in ameliorating pathological changes in the joints of OA mice. The preconditioning of TNF-α enhanced the up-regulation of low-density lipoprotein receptor-related protein 1 (LRP1) levels in IPFP-MSC-EXOsTNF−α, thereby exerting chondroprotective effects. Conclusion TNF-α preconditioning constitutes an effective and promising method for optimizing the therapeutic effects of IPFP-MSCs derived exosomes in the treatment of OA. Graphical Abstract

Abstract Lettuce (Lactuca sativa L., Asteraceae) is one of the most important vegetable crops, known for its various horticultural types and significant morphological variation. The first reference genome of lettuce, a crisphead type (L. sativa var. capitata cv. Salinas), was previously released. Here, we reported a near-complete chromosome-level reference genome for looseleaf lettuce (L. sativa var. crispa). PacBio high-fidelity sequencing, Oxford Nanopore, and Hi-C technologies were employed to produce genome assembly. The final assembly is 2.59 Gb in length with a contig N50 of 205.47 Mb, anchored onto nine chromosomes, containing 14 recognizable telomeres and only 11 gaps. Repetitive sequences account for 77.11% of the genome, and 41,375 protein-coding genes were predicted, with 99.10% of these assigned functional annotations. This chromosome-level genome enriched genomic resources for various horticultural types of lettuce and will facilitate the characterization of morphological variation and genetic improvement in lettuce.

Abstract Alkoxycarbonylation reactions are common in the chemical industry, yet process sustainability is limited by the inefficient utilization of CO. In this study, we address this issue and demonstrate that significant improvements can be achieved by adopting a heterogeneously catalyzed process, using a Ru/NbOx catalyst. The Ru/NbOx catalyst enables the direct synthesis of methyl propionate, a key industrial commodity, with over 98% selectivity from CO, ethylene and methanol, without any ligands or acid/base promoters. Under ambient CO pressure, a high CO utilization efficiency (336 mmolestermolCO −1h−1) is achieved. Mechanistic investigations reveal that CO undergoes a methoxycarbonyl (COOCH3) intermediate pathway, attacking the terminal carbon atom of alkene and yielding linear esters. The origins of prevailing linear regioselectivity in esters are revealed. The infrared spectroscopic feature of the key COOCH3 species is observed at 1750 cm−1 (C=O vibration) both experimentally and computationally. The broad substrate applicability of Ru/NbOx catalyst for ester production is demonstrated. This process offers a sustainable and efficient approach with high CO utilization and atom economy for the synthesis of esters.

Abstract NMDA receptor-dependent long-term depression (LTD) in the hippocampus is a well-known form of synaptic plasticity that has been linked to different cognitive functions. Although the underlying mechanisms remain unclear, this form of LTD cannot be induced by low-frequency stimulation (LFS) in adult mice. In this study, we found that LFS-induced LTD was not easily induced in adult animals and was age dependent. Interestingly, the level of the 5-HT1A receptor was correspondingly increased and exhibited an inverse correlation with the magnitude of LFS-LTD during development. Knockout or pharmacological inhibition of the 5-HT1A receptor reversed impaired LFS-LTD in adult mice (P60), while activation or inhibition of this receptor disturbed or enhanced LFS-LTD in adolescent mice (P21), respectively. Furthermore, the astrocytic 5-HT1A receptor in the hippocampus predominantly mediated age-dependent LFS-LTD through enhancing GABAergic neurotransmission. Finally, fear memory extinction differed among the above conditions. These observations enrich our knowledge of LTD at the cellular level and suggest a therapeutic approach for LTD-related psychiatric disorders.

Abstract Osteoarthritis (OA) is a chronic degenerative disease characterized by articular cartilage destruction and subchondral bone reconstruction in the early stages. Bergenin (Ber) is a cytoprotective polyphenol found in many medicinal plants. It has been proven to have anti-inflammatory, antioxidant, and other biological activities, which may reveal its potential role in the treatment of OA. This study aimed to determine the potential efficacy of Ber in treating OA and explore the possible underlying mechanism through network pharmacology and validation experiments. The potential co-targets and processes of Ber and OA were predicted by using network pharmacology, including a Venn diagram for intersection targets, a protein‒protein interaction (PPI) network to obtain key potential targets, and GO and KEGG pathway enrichment to reveal the probable mechanism of action of Ber on OA. Subsequently, validation experiments were carried out to investigate the effects and mechanisms of Ber in treating OA in vitro and vivo. Ber suppressed IL-1β-induced chondrocyte apoptosis and extracellular matrix catabolism by inhibiting the STAT3, NF-κB and Jun signalling pathway in vitro. Furthermore, Ber suppressed the expression of osteoclast marker genes and RANKL-induced osteoclastogenesis. Ber alleviated the progression of OA in DMM-induced OA mice model. These results demonstrated the protective efficacy and potential mechanisms of Ber against OA, which suggested that Ber could be adopted as a potential therapeutic agent for treating OA.

Abstract With the surge in Xinjiang jujube production, there has been a concurrent increase in storage losses, posing an ongoing challenge for farmers to preserve the freshness of the jujubes. To tackle this issue, a novel storage and freshness control system for jujubes, integrating Internet of Things technology, has been developed. The control system is centered around a programmable logic controller (PLC) and utilizes an HMI as the interface for human–computer interaction. It is structured with distinct layers, including equipment, transportation, and application layers. By integrating with the Internet of Things cloud platform, data transmission between the device layer and the cloud server is ensured through the use of the TCP/IP protocol over a 4G network. A mobile app enables remote control functionality for monitoring and managing the storage and preservation environment. Experimental results demonstrate the system's stable performance, enabling remote monitoring and convenient operation by management personnel during the jujube storage and preservation process. This contributes to enhancing automation levels in jujube storage, extending its storage cycle while maintaining quality standards, thus providing valuable insights into intelligent fruit and vegetable storage practices in Xinjiang.

Abstract Previous research has established associations between amygdala functional connectivity abnormalities and major depressive disorder (MDD). However, inconsistencies persist due to limited sample sizes and poorly elucidated transcriptional patterns. In this study, we aimed to address these gaps by analyzing a multicenter magnetic resonance imaging (MRI) dataset consisting of 210 first-episode, drug-naïve MDD patients and 363 age- and sex-matched healthy controls (HC). Using Pearson correlation analysis, we established individualized amygdala functional connectivity patterns based on the Automated Anatomical Labeling (AAL) atlas. Subsequently, machine learning techniques were employed to evaluate the diagnostic utility of amygdala functional connectivity for identifying MDD at the individual level. Additionally, we investigated the spatial correlation between MDD-related amygdala functional connectivity alterations and gene expression through Pearson correlation analysis. Our findings revealed reduced functional connectivity between the amygdala and specific brain regions, such as frontal, orbital, and temporal regions, in MDD patients compared to HC. Importantly, amygdala functional connectivity exhibited robust discriminatory capability for characterizing MDD at the individual level. Furthermore, we observed spatial correlations between MDD-related amygdala functional connectivity alterations and genes enriched for metal ion transport and modulation of chemical synaptic transmission. These results underscore the significance of amygdala functional connectivity alterations in MDD and suggest potential neurobiological mechanisms and markers for these alterations.

Abstract Roberts syndrome (RBS) is an autosomal recessive disorder with profound growth deficiency and limb reduction caused by ESCO2 loss-of-function variants. Here, we elucidate the pathogenesis of limb reduction in an Esco2 fl/fl;Prrx1-Cre Tg/0 mouse model using bulk- and single-cell-RNA-seq and gene co-expression network analyses during embryogenesis. Our results reveal morphological and vascular defects culminating in hemorrhage of mutant limbs at E12.5. Underlying this abnormal developmental progression is a pre-apoptotic, mesenchymal cell population specific to mutant limb buds enriched for p53-related signaling beginning at E9.5. We then characterize these p53-related processes of cell cycle arrest, DNA damage, cell death, and the inflammatory leukotriene signaling pathway in vivo. In utero treatment with pifithrin-α, a p53 inhibitor, rescued the hemorrhage in mutant limbs. Lastly, significant enrichments were identified among genes associated with RBS, thalidomide embryopathy, and other genetic limb reduction disorders, suggesting a common vascular etiology among these conditions.

Abstract Tandem repeats (TRs) are genomic regions that tandemly change in repeat number, which are often multiallelic. Their characteristics and contributions to gene expression and quantitative traits in rice are largely unknown. Here, we survey rice TR variations based on 231 genome assemblies and the rice pan-genome graph. We identify 227,391 multiallelic TR loci, including 54,416 TR variations that are absent from the Nipponbare reference genome. Only 1/3 TR variations show strong linkage with nearby bi-allelic variants (SNPs, Indels and PAVs). Using 193 panicle and 202 leaf transcriptomic data, we reveal 485 and 511 TRs act as QTLs independently of other bi-allelic variations to nearby gene expression, respectively. Using plant height and grain width as examples, we identify and validate TRs contributions to rice agronomic trait variations. These findings would enhance our understanding of the functions of multiallelic variants and facilitate rice molecular breeding.

Abstract Deep learning models have been developed for various predictions in glioma; yet, they were constrained by manual segmentation, task-specific design, or a lack of biological interpretation. Herein, we aimed to develop an end-to-end multi-task deep learning (MDL) pipeline that can simultaneously predict molecular alterations and histological grade (auxiliary tasks), as well as prognosis (primary task) in gliomas. Further, we aimed to provide the biological mechanisms underlying the model’s predictions. We collected multiscale data including baseline MRI images from 2776 glioma patients across two private (FAHZU and HPPH, n = 1931) and three public datasets (TCGA, n = 213; UCSF, n = 410; and EGD, n = 222). We trained and internally validated the MDL model using our private datasets, and externally validated it using the three public datasets. We used the model-predicted deep prognosis score (DPS) to stratify patients into low-DPS and high-DPS subtypes. Additionally, a radio-multiomics analysis was conducted to elucidate the biological basis of the DPS. In the external validation cohorts, the MDL model achieved average areas under the curve of 0.892–0.903, 0.710–0.894, and 0.850–0.879 for predicting IDH mutation status, 1p/19q co-deletion status, and tumor grade, respectively. Moreover, the MDL model yielded a C-index of 0.723 in the TCGA and 0.671 in the UCSF for the prediction of overall survival. The DPS exhibits significant correlations with activated oncogenic pathways, immune infiltration patterns, specific protein expression, DNA methylation, tumor mutation burden, and tumor-stroma ratio. Accordingly, our work presents an accurate and biologically meaningful tool for predicting molecular subtypes, tumor grade, and survival outcomes in gliomas, which provides personalized clinical decision-making in a global and non-invasive manner.

Abstract Background The interleukin-1 receptor accessory protein (IL1RAP) is highly expressed on acute myeloid leukemia (AML) bulk blasts and leukemic stem cells (LSCs), but not on normal hematopoietic stem cells (HSCs), providing an opportunity to target and eliminate the disease, while sparing normal hematopoiesis. Herein, we report the activity of BIF002, a novel anti-IL1RAP/CD3 T cell engager (TCE) in AML. Methods Antibodies to IL1RAP were isolated from CD138+ B cells collected from the immunized mice by optoelectric positioning and single cell sequencing. Individual mouse monoclonal antibodies (mAbs) were produced and characterized, from which we generated BIF002, an anti-human IL1RAP/CD3 TCE using Fab arm exchange. Mutations in human IgG1 Fc were introduced to reduce FcγR binding. The antileukemic activity of BIF002 was characterized in vitro and in vivo using multiple cell lines and patient derived AML samples. Results IL1RAP was found to be highly expressed on most human AML cell lines and primary blasts, including CD34+ LSC-enriched subpopulation from patients with both de novo and relapsed/refractory (R/R) leukemia, but not on normal HSCs. In co-culture of T cells from healthy donors and IL1RAPhigh AML cell lines and primary blasts, BIF002 induced dose- and effector-to-target (E:T) ratio-dependent T cell activation and leukemic cell lysis at subnanomolar concentrations. BIF002 administered intravenously along with human T cells led to depletion of leukemic cells, and significantly prolonged survival of IL1RAPhigh MOLM13 or AML patient-derived xenografts with no off-target side effects, compared to controls. Of note, BiF002 effectively redirects T cells to eliminate LSCs, as evidenced by the absence of disease initiation in secondary recipients of bone marrow (BM) from BIF002+T cells-treated donors (median survival not reached; all survived > 200 days) compared with recipients of BM from vehicle- (median survival: 26 days; p = 0.0004) or isotype control antibody+T cells-treated donors (26 days; p = 0.0002). Conclusions The novel anti-IL1RAP/CD3 TCE, BIF002, eradicates LSCs and significantly prolongs survival of AML xenografts, representing a promising, novel treatment for AML.

Abstract Sodium is crucial for maintaining cardiovascular health, especially in relation to heart failure. The impact of baseline serum sodium concentrations on the outcomes of newly diagnosed coronary heart disease (CHD) without heart failure remains unclear. This prospective cohort study included 681 patients who were newly diagnosed with CHD. Cox proportional hazards models and restricted cubic spline (RCS) analysis were used to assess the relationship between serum sodium concentrations and major adverse cardiovascular events. The improvement in traditional prediction models by the addition of serum sodium concentrations was assessed using changes in the C-statistic, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). During a median follow-up of 51.04 months (IQR: 40.88–53.80 months), 131 events were recorded. Multivariate Cox proportional hazards models showed that the L2 group (136–138.9 mmol/L) had the highest MACE risk. Compared to L2, the hazard ratios (HRs) and 95% confidence intervals (CIs) for the L1 (130–135.9 mmol/L), L3 (139–140.9 mmol/L), L4 (141–142.9 mmol/L), and L5 (143–147.0 mmol/L) groups were 0.31 (0.14–0.70, P = 0.005), 0.48 (030–0.78, P = 0.003), 0.56 (0.34–0.92, P = 0.022), and 0.37 (0.22–0.64, P

Abstract Lung adenocarcinoma (LUAD) is a leading cause of cancer mortality, with many patients facing poor prognosis, particularly those with metastatic or drug-resistant tumors. Homologous recombination genes (HRGs) are crucial in tumor progression and therapy resistance, but their clinical significance in LUAD is not well understood. In this study, we systematically characterize key HRGs in LUAD patients, identifying two distinct HR subtypes associated with different outcomes and biological functions. We establish a 5-gene scoring system (XRCC2, RAD51, BRCA1, FANCA, and CHEK1) that reliably predicts patient outcomes and immunotherapy responses in LUAD. Bioinformatics analysis and clinical validation highlight XRCC2 as a crucial biomarker in LUAD. Functional investigations through in vivo and in vitro experiments reveal the role of XRCC2 in promoting lung cancer migration and invasion. Mechanistically, XRCC2 stabilizes vimentin (VIM) protein expression through deubiquitylation. We predict c-MYC as a potential regulator of XRCC2 and demonstrate that inhibiting c-MYC with compound 10058-F4 reduces XRCC2 and VIM expression. Preclinical studies show the synergistic inhibition of metastasis in vivo when combining 10058-F4 with doxorubicin (Dox). Our findings present a potential personalized predictive tool for LUAD prognosis, identifying XRCC2 as a critical biomarker. The c-Myc-XRCC2-VIM axis emerges as a promising therapeutic target for overcoming lung metastasis. This study provides valuable insights into LUAD, proposing a prognostic tool for further clinical validation and unveiling a potential therapeutic strategy for combating lung metastasis by targeting c-Myc-XRCC2-VIM.

Abstract Natural killer (NK) cell-based therapies have made great progress in treating both hematological and solid tumors. Their unique mechanism of action does not rely on antigen presentation to recognize and eliminate tumor cells, making them a promising approach for cancer immunotherapy. In this review, we present a comprehensive summary of the latest clinical data of the novel NK cell-based therapies from the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, highlighting the potential of these advancements to revolutionize the treatment of hematologic malignancies and solid tumors.

Abstract Cochlear implants can directly activate the auditory system’s primary sensory neurons, the spiral ganglion neurons (SGNs), via circumvention of defective cochlear hair cells. This bypass restores auditory input to the brainstem. SGN loss etiologies are complex, with limited mammalian regeneration. Protecting and revitalizing SGN is critical. Tissue engineering offers a novel therapeutic strategy, utilizing seed cells, biomolecules, and scaffold materials to create a cellular environment and regulate molecular cues. This review encapsulates the spectrum of both human and animal research, collating the factors contributing to SGN loss, the latest advancements in the utilization of exogenous stem cells for auditory nerve repair and preservation, the taxonomy and mechanism of action of standard biomolecules, and the architectural components of scaffold materials tailored for the inner ear. Furthermore, we delineate the potential and benefits of the biohybrid neural interface, an incipient technology in the realm of implantable devices. Nonetheless, tissue engineering requires refined cell selection and differentiation protocols for consistent SGN quality. In addition, strategies to improve stem cell survival, scaffold biocompatibility, and molecular cue timing are essential for biohybrid neural interface integration. Graphical Abstract

Abstract It has been shown that the formation of filopodia is a key step in tumor cell metastasis, but there is limited research regarding its mechanism. In this study, we demonstrated that fatty acid synthase (FASN) promoted filopodia formation in liver cancer cells by regulating fascin actin-bundling protein 1 (FSCN1), a marker protein for filopodia. Mechanistically, on the one hand, the accumulation of FASN is caused by the enhanced deubiquitination of FASN mediated by UCHL5 (ubiquitin c-terminal hydrolase L5). In this pathway, low expression of SIAH1 (Seven in absentia homolog 1) can decrease the ubiquitination and degradation of ADRM1 (adhesion regulating molecule 1) thereby increasing its protein level, which will recruit and activate the deubiquitination enzyme UCHL5, leading to FASN undergo deubiquitination and escape from proteasomal degradation. On the other hand, the accumulation of FASN is related to its weakened ubiquitination, where SIAH1 directly acts as a ubiquitin ligase toward FASN, and low expression of SIAH1 reduces the ubiquitination and degradation of FASN. Both the two pathways are involved in the regulation of FASN in liver cancer. Our results reveal a novel mechanism for FASN accumulation due to the low expression of SIAH1 in human liver cancer and suggest an important role of FASN in filopodia formation in liver cancer cells.

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

Abstract Background The identification of cancer driver genes from sequencing data has been crucial in deepening our understanding of tumor biology and expanding targeted therapy options. However, apart from the most commonly altered genes, the mechanisms underlying the contribution of other mutations to cancer acquisition remain understudied. Leveraging on our whole-exome sequencing of the largest Asian lung adenocarcinoma (LUAD) cohort (n = 302), we now functionally assess the mechanistic role of a novel driver, PARP4. Methods In vitro and in vivo tumorigenicity assays were used to study the functional effects of PARP4 loss and mutation in multiple lung cancer cell lines. Interactomics analysis by quantitative mass spectrometry was conducted to identify PARP4’s interaction partners. Transcriptomic data from cell lines and patient tumors were used to investigate splicing alterations. Results PARP4 depletion or mutation (I1039T) promotes the tumorigenicity of KRAS- or EGFR-driven lung cancer cells. Disruption of the vault complex, with which PARP4 is commonly associated, did not alter tumorigenicity, indicating that PARP4’s tumor suppressive activity is mediated independently. The splicing regulator hnRNPM is a potentially novel PARP4 interaction partner, the loss of which likewise promotes tumor formation. hnRNPM loss results in splicing perturbations, with a propensity for dysregulated intronic splicing that was similarly observed in PARP4 knockdown cells and in LUAD cohort patients with PARP4 copy number loss. Conclusions PARP4 is a novel modulator of lung adenocarcinoma, where its tumor suppressive activity is mediated not through the vault complex—unlike conventionally thought, but in association with its novel interaction partner hnRNPM, thus suggesting a role for splicing dysregulation in LUAD tumorigenesis.

Abstract Background Late-onset Pompe disease (LOPD) is mainly characterized by progressive limb-girdle muscle weakness and respiratory impairment, whereas stroke and cerebrovascular abnormalities have been insufficiently studied in LOPD. This study aimed to evaluate the frequency and pattern of intracranial artery and brain parenchyma abnormalities in LOPD patients. Results Neuroimaging data from 30 Chinese adult LOPD patients were collected from our center. Seven patients (7/30) had acute cerebral infarction or hemorrhage. Brain magnetic resonance angiography (MRA) or computed tomography angiography (CTA) revealed artery abnormalities in 23 patients (23/30). Dilative arteriopathy was found in 19 patients (19/30), with vertebrobasilar dolichoectasia found in 17 patients and dilatation of the anterior circulation arteries found in 8 patients. The maximum diameter of the basilar artery was correlated with disease duration (p

Abstract Electrocatalytic semihydrogenation of acetylene (C2H2) provides a facile and petroleum-independent strategy for ethylene (C2H4) production. However, the reliance on the preseparation and concentration of raw coal-derived C2H2 hinders its economic potential. Here, a concave surface is predicted to be beneficial for enriching C2H2 and optimizing its mass transfer kinetics, thus leading to a high partial pressure of C2H2 around active sites for the direct conversion of raw coal-derived C2H2. Then, a porous concave carbon-supported Cu nanoparticle (Cu-PCC) electrode is designed to enrich the C2H2 gas around the Cu sites. As a result, the as-prepared electrode enables a 91.7% C2H4 Faradaic efficiency and a 56.31% C2H2 single-pass conversion under a simulated raw coal-derived C2H2 atmosphere (~15%) at a partial current density of 0.42 A cm−2, greatly outperforming its counterpart without concave surface supports. The strengthened intermolecular π conjugation caused by the increased C2H2 coverage is revealed to result in the delocalization of π electrons in C2H2, consequently promoting C2H2 activation, suppressing hydrogen evolution competition and enhancing C2H4 selectivity.

Abstract Background The monocot chimeric jacalins (MCJ) proteins, which contain a jacalin-related lectin (JRL) domain and a dirigent domain (DIR), are specific to Poaceae. MCJ gene family is reported to play an important role in growth, development and stress response. However, their roles in maize have not been thoroughly investigated. Results In this study, eight MCJ genes in the maize genome (designated as ZmMCJs) were identified, which displayed unequal distribution across four chromosomes. Phylogenetic relationships between the ZmMCJs were evident through the identification of highly conserved motifs and gene structures. Analysis of transcriptome data revealed distinct expression patterns among the ZmMCJ genes, leading to their classification into four different modules, which were subsequently validated using RT-qPCR. Protein structures of the same module are found to be relatively similar. Subcellular localization experiments indicated that the ZmMCJs are mainly located on the cell membrane. Additionally, hemagglutination and inhibition experiments show that only part of the ZmMCJs protein has lectin activity, which is mediated by the JRL structure, and belongs to the mannose-binding type. The cis-acting elements in the promoter region of ZmMCJ genes predicted their involvement response to phytohormones, such as abscisic acid and jasmonic acid. This suggests that ZmMCJ genes may play a significant role in both biotic and abiotic stress responses. Conclusions Overall, this study adds new insights into our understanding of the gene-protein architecture, evolutionary characteristics, expression profiles, and potential functions of MCJ genes in maize.

Abstract The cold tolerance of Litopenaeus vannamei is important for breeding in specific areas. To explore the cold tolerance mechanism of L. vannamei, this study analyzed biochemical indicators, cell apoptosis, and metabolomic responses in cold-tolerant (Lv-T) and common (Lv-C) L. vannamei under low-temperature stress (18 °C and 10 °C). TUNEL analysis showed a significant increase in apoptosis of hepatopancreatic duct cells in L. vannamei under low-temperature stress. Biochemical analysis showed that Lv-T had significantly increased levels of superoxide dismutase (SOD) and triglycerides (TG), while alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH-L), and uric acid (UA) levels were significantly decreased compared to Lv-C (p

Abstract Obesity shapes anti-tumor immunity through lipid metabolism; however, the mechanisms underlying how colorectal cancer (CRC) cells utilize lipids to suppress anti-tumor immunity remain unclear. Here, we show that tumor cell-intrinsic ATP6V0A1 drives exogenous cholesterol-induced immunosuppression in CRC. ATP6V0A1 facilitates cholesterol absorption in CRC cells through RAB guanine nucleotide exchange factor 1 (RABGEF1)-dependent endosome maturation, leading to cholesterol accumulation within the endoplasmic reticulum and elevated production of 24-hydroxycholesterol (24-OHC). ATP6V0A1-induced 24-OHC upregulates TGF-β1 by activating the liver X receptor (LXR) signaling. Subsequently, the release of TGF-β1 into the tumor microenvironment by CRC cells activates the SMAD3 pathway in memory CD8+ T cells, ultimately suppressing their anti-tumor activities. Moreover, we identify daclatasvir, a clinically used anti-hepatitis C virus (HCV) drug, as an ATP6V0A1 inhibitor that can effectively enhance the memory CD8+ T cell activity and suppress tumor growth in CRC. These findings shed light on the potential for ATP6V0A1-targeted immunotherapy in CRC.

Abstract Large language models (LLMs) are seen to have tremendous potential in advancing medical diagnosis recently, particularly in dermatological diagnosis, which is a very important task as skin and subcutaneous diseases rank high among the leading contributors to the global burden of nonfatal diseases. Here we present SkinGPT-4, which is an interactive dermatology diagnostic system based on multimodal large language models. We have aligned a pre-trained vision transformer with an LLM named Llama-2-13b-chat by collecting an extensive collection of skin disease images (comprising 52,929 publicly available and proprietary images) along with clinical concepts and doctors’ notes, and designing a two-step training strategy. We have quantitatively evaluated SkinGPT-4 on 150 real-life cases with board-certified dermatologists. With SkinGPT-4, users could upload their own skin photos for diagnosis, and the system could autonomously evaluate the images, identify the characteristics and categories of the skin conditions, perform in-depth analysis, and provide interactive treatment recommendations.

Abstract Background β-Arbutin, a hydroquinone glucoside found in pears, bearberry leaves, and various plants, exhibits antioxidant, anti-inflammatory, antimicrobial, and anticancer effects. β-Arbutin has wide applications in the pharmaceutical and cosmetic industries. However, the limited availability of high-performance strains limits the biobased production of β-arbutin. Results This study established the β-arbutin biosynthetic pathway in C. glutamicum ATCC13032 by introducing codon-optimized ubiC, MNX1, and AS. Additionally, the production titer of β-arbutin was increased by further inactivation of csm and trpE to impede the competitive metabolic pathway. Further modification of the upstream metabolic pathway and supplementation of UDP-glucose resulted in the final engineered strain, C. glutamicum AR11, which achieved a β-arbutin production titer of 7.94 g/L in the optimized fermentation medium. Conclusions This study represents the first successful instance of de novo β-arbutin production in C. glutamicum, offering a chassis cell for β-arbutin biosynthesis.

Abstract Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples, assuming it is an accurate representation of RNA biology in the living brain. We challenge this assumption by comparing A-to-I editing between postmortem and living prefrontal cortical tissues. Major differences were found, with over 70,000 A-to-I sites showing higher editing levels in postmortem tissues. Increased A-to-I editing in postmortem tissues is linked to higher ADAR and ADARB1 expression, is more pronounced in non-neuronal cells, and indicative of postmortem activation of inflammation and hypoxia. Higher A-to-I editing in living tissues marks sites that are evolutionarily preserved, synaptic, developmentally timed, and disrupted in neurological conditions. Common genetic variants were also found to differentially affect A-to-I editing levels in living versus postmortem tissues. Collectively, these discoveries offer more nuanced and accurate insights into the regulatory mechanisms of RNA editing in the human brain.

Abstract Objective This study was based on MRI features and number of tumor-infiltrating CD8 + T cells in post-operative pathology, in predicting meningioma recurrence risk. Methods Clinical, pathological, and imaging data of 102 patients with surgically and pathologically confirmed meningiomas were retrospectively analyzed. Patients were divided into recurrence and non-recurrence groups based on follow-up. Tumor-infiltrating CD8 + T cells in tissue samples were quantitatively assessed with immunohistochemical staining. Apparent diffusion coefficient (ADC) histogram parameters from preoperative MRI were quantified in MaZda. Considering the high correlation between ADC histogram parameters, we only chose ADC histogram parameter that had the best predictive efficacy for COX regression analysis further. A visual nomogram was then constructed and the recurrence probability at 1- and 2-years was determined. Finally, subgroup analysis was performed with the nomogram. Results The risk factors for meningioma recurrence were ADCp1 (hazard ratio [HR] = 0.961, 95% confidence interval [95% CI]: 0.937 ~ 0.986, p = 0.002) and CD8 + T cells (HR = 0.026, 95%CI: 0.001 ~ 0.609, p = 0.023). The resultant nomogram had AUC values of 0.779 and 0.784 for 1- and 2-years predicted recurrence rates, respectively. The survival analysis revealed that patients with low CD8 + T cells counts or ADCp1 had higher recurrence rates than those with high CD8 + T cells counts or ADCp1. Subgroup analysis revealed that the AUC of nomogram for predicting 1-year and 2-year recurrence of WHO grade 1 and WHO grade 2 meningiomas was 0.872 (0.652) and 0.828 (0.751), respectively. Conclusions Preoperative ADC histogram parameters and tumor-infiltrating CD8 + T cells may be potential biomarkers in predicting meningioma recurrence risk. Clinical relevance statement The findings will improve prognostic accuracy for patients with meningioma and potentially allow for targeted treatment of individuals who have the recurrent form.

ABSTRACT Importance Postzygotic mutations in the GNAQ/GNA11 genes, which encode the G‐protein nucleotide binding protein alpha subunits, have been identified in patients with phakomatosis pigmentovascularis (PPV). However, little is known about the Chinese population. Objective To identify pathogenic mutations in pediatric patients with PPV within the Chinese population. Methods We performed whole‐exome sequencing (WES) using skin lesion tissues from pediatric patients diagnosed with PPV. Additionally, ultradeep‐targeted sequencing was conducted to validate the somatic mutations. A genotype‐phenotype correlation was analyzed by integrating data from previous reports with the findings of the present study. Results Thirteen patients were enrolled, all diagnosed with the cesioflammea type of PPV, except for one patient with an unclassifiable type. We identified somatic GNA11 c.547C>T (p.R183C) variant in seven patients and GNAQ c.548G>A (p.R183Q) in four patients, with low allelic fractions ranging from 2.1% to 8.6% through ultradeep sequencing. Besides, a GNAQ c.548G>A (p.R183Q) variant was detected through targeted sequencing in one of two patients who did not exhibit detectable variants via WES. The genotype‐phenotype correlation analysis, involving 15 patients with a GNA11 variant and 10 with a GNAQ variant, revealed that facial capillary malformation (87% vs. 50%, P = 0.075) and ocular melanocytosis (80% vs. 40%, P = 0.087) appeared to be more frequent in patients with GNA11 mutation compared to those with GNAQ mutations. All four patients diagnosed with cesiomarmorata type or overlapping cesioflammea and cesiomarmorata type PPV carried the GNA11 variant. Interpretation Our study demonstrated that the majority of PPV patients in the Chinese population carried a postzygotic variant of GNAQ/GNA11, thus further confirming the pathogenic role of GNAQ/GNA11 mosaicism in the development of PPV cesioflammea type.

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

Abstract The high Faradaic efficiency (FE) of the electrocatalytic deuteration of organics with D2O at a large current density is significant for deuterated electrosynthesis. However, the FE and current density are the two ends of a seesaw because of the severe D2 evolution side reaction at nearly industrial current densities. Herein, we report a combined scenario of a nanotip-enhanced electric field and surfactant-modified interface microenvironment to enable the electrocatalytic deuteration of arylacetonitrile in D2O with an 80% FE at −100 mA cm−2. The increased concentration with low activation energy of arylacetonitrile due to the large electric field along the tips and the accelerated arylacetonitrile transfer and suppressed D2 evolution by the surfactant-created deuterophobic microenvironment contribute to breaking the trade-off between a high FE and large current density. Furthermore, the application of our strategy in other deuteration reactions with improved Faradaic efficiencies at −100 mA cm−2 rationalizes the design concept.

Abstract Given the marginal penetration of most drugs across the blood-brain barrier, the efficacy of various agents remains limited for glioblastoma (GBM). Here we employ low-intensity pulsed ultrasound (LIPU) and intravenously administered microbubbles (MB) to open the blood-brain barrier and increase the concentration of liposomal doxorubicin and PD-1 blocking antibodies (aPD-1). We report results on a cohort of 4 GBM patients and preclinical models treated with this approach. LIPU/MB increases the concentration of doxorubicin by 2-fold and 3.9-fold in the human and murine brains two days after sonication, respectively. Similarly, LIPU/MB-mediated blood-brain barrier disruption leads to a 6-fold and a 2-fold increase in aPD-1 concentrations in murine brains and peritumoral brain regions from GBM patients treated with pembrolizumab, respectively. Doxorubicin and aPD-1 delivered with LIPU/MB upregulate major histocompatibility complex (MHC) class I and II in tumor cells. Increased brain concentrations of doxorubicin achieved by LIPU/MB elicit IFN-γ and MHC class I expression in microglia and macrophages. Doxorubicin and aPD-1 delivered with LIPU/MB results in the long-term survival of most glioma-bearing mice, which rely on myeloid cells and lymphocytes for their efficacy. Overall, this translational study supports the utility of LIPU/MB to potentiate the antitumoral activities of doxorubicin and aPD-1 for GBM.

Abstract Proteins and nucleic-acids are essential components of living organisms that interact in critical cellular processes. Accurate prediction of nucleic acid-binding residues in proteins can contribute to a better understanding of protein function. However, the discrepancy between protein sequence information and obtained structural and functional data renders most current computational models ineffective. Therefore, it is vital to design computational models based on protein sequence information to identify nucleic acid binding sites in proteins. Here, we implement an ensemble deep learning model-based nucleic-acid-binding residues on proteins identification method, called SOFB, which characterizes protein sequences by learning the semantics of biological dynamics contexts, and then develop an ensemble deep learning-based sequence network to learn feature representation and classification by explicitly modeling dynamic semantic information. Among them, the language learning model, which is constructed from natural language to biological language, captures the underlying relationships of protein sequences, and the ensemble deep learning-based sequence network consisting of different convolutional layers together with Bi-LSTM refines various features for optimal performance. Meanwhile, to address the imbalanced issue, we adopt ensemble learning to train multiple models and then incorporate them. Our experimental results on several DNA/RNA nucleic-acid-binding residue datasets demonstrate that our proposed model outperforms other state-of-the-art methods. In addition, we conduct an interpretability analysis of the identified nucleic acid binding residue sequences based on the attention weights of the language learning model, revealing novel insights into the dynamic semantic information that supports the identified nucleic acid binding residues. SOFB is available at https://github.com/Encryptional/SOFB and https://figshare.com/articles/online_resource/SOFB_figshare_rar/25499452 .

Abstract Purpose To evaluate the intracavity left ventricular (LV) blood flow kinetic energy (KE) parameters using four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) in patients with acute myocardial infarction (AMI). Methods Thirty AMI patients and twenty controls were examined via CMR, which included cine imaging, late gadolinium enhancement (LGE) and global heart 4D flow imaging. The KE parameters were indexed to LV end-diastolic volume (EDV) to obtain average, systolic and diastolic KE as well as the proportion of LV in-plane KE (%). These parameters were compared between the AMI patients and controls and between the two subgroups. Results Analysis of the LV blood flow KE parameters at different levels of the LV cavity and in different segments of the same level showed that the basal level had the highest blood flow KE while the apical level had the lowest in the control group. There were no significant differences in diastolic KE, systolic in-plane KE and diastolic in-plane KE between the anterior wall and posterior wall (p > 0.05), only the systolic KE had a significant difference between them (p

For the pressurized water reactor two-step calculation, the traditional assembly homogenization and two-group neutron diffusion calculation have been widely used. When it comes to the core pin-by-pin simulation, many models and techniques are different and unsettled. In this paper, the homogenization methods based on the pin discontinuity factors and super homogenization factors are used to get the pin-cell homogenized parameters. The heterogeneous leakage model is applied to modify the infinite flux spectrum of the single assembly with reflective boundary condition and to determine the diffusion coefficients for the SP3 solver which is used in the core simulation. To reduce the environment effect of the single-assembly reflective boundary condition, the on-line method for the SPH factors updating is applied in this paper, and the functionalization of SPH factors based on the least-squares method will be pre-made alone with the table of the group constants. The fitting function will be used to update the thermal-group SPH factors with a whole-core pin-by-pin homogeneous solution on-line. The three-dimensional Watts Bar Nuclear Unit 1 (WBN1) problem was utilized to test the performance of pin-by-pin calculation. And numerical results have demonstrated that PWR pin-by-pin core calculation has more accurate results compared with the traditional assembly-homogenization scheme.

Acinetobacter baumannii is a pathogenic bacterium widespread in human environments, especially in intensive care units, and is associated with high morbidity and infection rates. Multiple drug resistance in A. baumannii frequently leads to the death of patients, making the development of multi-effect antibacterial agents against this bacterium a research hotspot. We have previously found that the X33 antimicrobial oligopeptide can effectively inhibit the growth of Penicillium digitatum and Candida albicans. Herein, we evaluated the antibacterial activity of X33 antimicrobial oligopeptide against A. baumannii by determining the minimum inhibitory concentration, inhibition zone, and growth curve. The increase in extracellular alkaline phosphatase and the leakage of intracellular compounds confirmed the effect of X33 antimicrobial oligopeptide on the cell wall and membrane. Changes in reactive oxygen species, malondialdehyde, ATP, reducing sugar, soluble protein, and pyruvate content demonstrated that the incubation with X33 antimicrobial oligopeptide affected energy metabolism and oxidative stress. Consistent with the physiological characteristics, transcriptomics analysis indicated that incubation with X33 antimicrobial oligopeptide significantly induced changes in the expression of 2339 genes, including 1262 upregulated and 1077 downregulated genes, which participate in oxidative phosphorylation, ribosome, quorum sensing, fatty acid degradation, glycolysis/gluconeogenesis, and citrate cycle pathways. These results provide a fundamental basis for investigating the mechanism of X33 antimicrobial oligopeptide as a potential drug against A. baumannii.

Objective To analyze the characteristics of blood transfusion consultation cases and establish the consultation route, so as to provide reference for blood transfusion doctors to participate in blood transfusion consultation practice. Methods The cases involved in clinical transfusion consultation in the blood transfusion department of our hospital from 2020 to 2023 were collected from the hospital information system (HIS), and then classified by department and consultation type to summarize the main points of transfusion consultation, formulate transfusion consultation routes, and conduct typical cases analysis. Results There were 315 clinical transfusion consultations from 2020 to 2023, with an increasing trend year by year (26 in 2020, 67 in 2021, 81 in 2022, 141 in 2023). The consultations involved 24 departments, including cardiovascular medicine 14.0%(44/315), orthopedics 12.7%(40/315), intensive care medicine 8.9%(28/315), general medicine 8.3%(28/315), cardiopulmonary disease 6.0%(19/315), etc. There were 8 categories of consultations, including 35.6%(112/315) autologous ozonized blood transfusion, 23.8%(75/315) plasma exchange, 14.9%(47/315) perioperative mass blood preparation (transfusion), 11.4%(36/315) platelet- rich plasma therapy and 6.3%(20/315) autologous blood collection, etc. The clinical blood transfusion consultation route was formulated according to the consultation points. Six patients with various diseases were treated by blood transfusion department. With effective treatment measures taken, all of them improved and were discharged. Conclusion The summary of key points of clinical blood transfusion consultation and formulation of the blood transfusion consultation route by department of blood transfusion are conducive to the implementation of blood transfusion consultation and guarantee the safety of patients.

Abstract Lung adenocarcinoma (LUAD) is the most common and aggressive subtype of lung cancer, and coronavirus disease 2019 (COVID-19) has become a serious public health threat worldwide. Patients with LUAD and COVID-19 have a poor prognosis. Therefore, finding medications that can be used to treat COVID-19/LUAD patients is essential. Bioinformatics analysis was used to identify 20 possible metformin target genes for the treatment of COVID-19/LUAD. PTEN and mTOR may serve as hub target genes of metformin. Metformin may be able to cure COVID-19/LUAD comorbidity through energy metabolism, oxidoreductase NADH activity, FoxO signalling pathway, AMPK signalling system, and mTOR signalling pathway, among other pathways, according to the results of bioinformatic research. Metformin has ability to inhibit the proliferation of A549 cells, according to the results of colony formation and proliferation assays. In A549 cells, metformin increased glucose uptake and lactate generation, while decreasing ATP synthesis and the NAD+/NADH ratio. In summary, PTEN and mTOR may be potential targets of metformin for the treatment of COVID-19/LUAD. The mechanism by which metformin inhibits lung adenocarcinoma cell proliferation may be related to glucose metabolism regulated by PI3K/AKT signalling and mTOR signalling pathways. Our study provides a new theoretical basis for the treatment of COVID-19/LUAD.

Background: Reactive oxygen species (ROS), predominantly generated by mitochondria, play a crucial role in the pathogenesis of intervertebral disc degeneration (IVDD). Reduction of ROS levels may be an effective strategy to delay IVDD. In this study, we assessed whether umbilical cord mesenchymal stem cell-exosomes (UCMSC-exos) can be used to treat IVDD by suppressing ROS production caused by mitochondrial dysfunction. Materials and methods: Human UCMSC-exos were isolated and identified. Nucleus pulposus cells (NPCs) were stimulated with H2O2 in the presence or absence of exosomes. Then, 4D label free quantitative (4D-LFQ) proteomics were used to analyze the differentially expressed (DE) proteins. Mitochondrial membrane potential (MMP), mitochondrial ROS and protein levels were determined via immunofluorescence staining, flow cytometry and western blotting respectively. Additionally, high-throughput sequencing was performed to identify the DE miRNAs in NPCs. Finally, therapeutic effects of UCMSC-exos were investigated in a puncture-induced IVDD rat model. Degenerative grades of rat IVDs were assessed using magnetic resonance imaging and histochemical staining. Results: UCMSC-exos effectively improved the viability of NPCs and restored the expression of the extracellular matrix (ECM) proteins, collagen type II alpha-1 (COL2A1) and matrix metalloproteinase-13 induced by H2O2. Additionally, UCMSC-exos not only reduced the total intracellular ROS and mitochondrial superoxide levels, but also increased MMP in pathological NPCs. 4D-LFQ proteomics and western blotting further revealed that UCMSC-exos up-regulated the levels of the mitochondrial protein, mitochondrial transcription factor A (TFAM), in H2O2-induced NPCs. High-throughput sequencing and qRT-PCR uncovered that UCMSC-exos down-regulated the levels of miR-194-5p, a potential negative regulator of TFAM, induced by H2O2. Finally, in vivo results showed that UCMSC-exos injection improved the histopathological structure and enhanced the expression levels of COL2A1 and TFAM in the rat IVDD model. Conclusions: Our findings suggest that UCMSC-exos promote ECM synthesis, relieve mitochondrial oxidative stress, and attenuate mitochondrial dysfunction in vitro and in vivo, thereby effectively treating IVDD. The translational potential of this article: This study provides solid experimental data support for the therapeutic effects of UCMSC-exos on IVDD, suggesting that UCMSC-exos will be a promising nanotherapy for IVDD.

Abstract Biodetoxification fungus selectively degrades toxic inhibitors generated from pretreatment of lignocellulose without consuming fermentable sugars. However, one barrier for practical application is the sustained cell viability in the consequent fermentation step to compete the fermentable sugars with fermenting strains, resulting in sugar loss and reduced target product yield. This study investigated the competitive growth property between the biodetoxification fungus Paecilomyces variotii FN89 and the L-lactic acid bacterium Pediococcus acidilactici ZY271 under varying temperature and lactic acid osmatic stress. The results show that the L-lactic acid bacterium Ped. acidilactici ZY271 showed less thermotolerance to Pae. variotii FN89 at high temperature of 45 °C to 50 °C in both synthetic medium and wheat straw hydrolysate. In the higher temperature environment, the growth of the biodetoxification strian failed to compete with the lactic acid fermentation strain and was quickly eliminated from the fermentation system. The high temperature fermentation facilitated a fast transition from the detoxification stage to the fermentation stage for higher production of L-lactic acid.

Abstract The Porcine epidemic diarrhea virus (PEDV) presents a substantial risk to the domestic pig industry, resulting in extensive and fatal viral diarrhea among piglets. Recognizing the mucosal stimulation triggered by PEDV and harnessing the regulatory impact of lactobacilli on intestinal function, we have developed a lactobacillus-based vaccine that is carefully designed to elicit a strong mucosal immune response. Through bioinformatics analysis, we examined PEDV S proteins to identify B-cell linear epitopes that meet the criteria of being non-toxic, soluble, antigenic, and capable of neutralizing the virus. In this study, a genetically modified strain of Lactobacillus mucosae G01 (L.mucosae G01) was created by utilizing the S layer protein (SLP) as a scaffold for surface presentation. Chimeric immunodominant epitopes with neutralizing activity were incorporated at various sites on SLP. The successful expression of SLP chimeric immunodominant epitope 1 on the surface of L.mucosae G01 was confirmed through indirect immunofluorescence and transmission electron microscopy, revealing the formation of a transparent membrane. The findings demonstrate that the oral administration of L.mucosae G01, which expresses the SLP chimeric immunodominant gene epitope1, induces the production of secreted IgA in the intestine and feces of mice. Additionally, there is an elevation in IgG levels in the serum. Moreover, the levels of cytokines IL-2, IL-4, IFN-γ, and IL-17 are significantly increased compared to the negative control group. These results suggest that L. mucosae G01 has the ability to deliver exogenous antigens and elicit a specific mucosal immune response against PEDV. This investigation presents new possibilities for immunoprophylaxis against PEDV-induced diarrhea.

Abstract Immunotherapy, particularly immune checkpoint inhibitors (ICIs), such as anti-programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) therapy, has emerged as a pivotal treatment modality for solid tumors, including recurrent or metastatic nasopharyngeal carcinoma (R/M-NPC). Despite the advancements in the utilization of ICIs, there is still room for further improving patient outcomes. Another promising approach to immunotherapy for R/M-NPC involves adoptive cell therapy (ACT), which aims to stimulate systemic anti-tumor immunity. However, individual agent therapies targeting dendritic cells (DCs) appear to still be in the clinical trial phase. This current review underscores the potential of immunotherapy as a valuable adjunct to the treatment paradigm for R/M-NPC patients. Further research is warranted to enhance the efficacy of immunotherapy through the implementation of strategies such as combination therapies and overcoming immune suppression. Additionally, the development of a biomarker-based scoring system is essential for identifying suitable candidates for precision immunotherapy.

Abstract We report the generation of a novel anti-LAG-3/TIGIT bispecific IgG4 antibody, ZGGS15, and evaluated its anti-tumor efficacy in mouse models as monotherapy or in combination with a PD-1 antibody. ZGGS15 exhibited strong affinities for human LAG-3 and TIGIT, with KDs of 3.05 nM and 2.65 nM, respectively. ZGGS15 has EC50s of 0.69 nM and 1.87 nM for binding to human LAG-3 and TIGIT on CHO-K1 cells, respectively. ZGGS15 competitively inhibited the binding of LAG-3 to MHC-II (IC50 = 0.77 nM) and the binding of TIGIT to CD155 (IC50 = 0.24 nM). ZGGS15 does not induce ADCC, CDC, or obvious cytokine production. In vivo results showed that ZGGS15 had better anti-tumor inhibition than single anti-LAG-3 or anti-TIGIT agents and demonstrated a synergistic effect when combined with nivolumab, with a significantly higher tumor growth inhibition of 95.80% (p = 0.001). The tumor volume inhibition rate for ZGGS15 at 2 mg/kg was 69.70%, and for ZGGS15 at 5 mg/kg plus nivolumab at 1 mg/kg, it was 94.03% (p

Abstract As a sustainable alternative to fossil fuel-based manufacture of bulk oxygenates, electrochemical synthesis using CO and H2O as raw materials at ambient conditions offers immense appeal. However, the upscaling of the electrosynthesis of oxygenates encounters kinetic bottlenecks arising from the competing hydrogen evolution reaction with the selective production of ethylene. Herein, a catalytic relay system that can perform in tandem CO capture, activation, intermediate transfer and enrichment on a Cu-Ag composite catalyst is used for attaining high yield CO-to-oxygenates electrosynthesis at high current densities. The composite catalyst Cu/30Ag (molar ratio of Cu to Ag is 7:3) enables high efficiency CO-to-oxygenates conversion, attaining a maximum partial current density for oxygenates of 800 mA cm−2 at an applied current density of 1200 mA cm−2, and with 67 % selectivity. The ability to finely control the production of ethylene and oxygenates highlights the principle of efficient catalyst design based on the relay mechanism.

Abstract Background Antibiotic exposure can occur in medical settings and from environmental sources. Long-term effects of brief antibiotic exposure in early life are largely unknown. Results Post a short-term treatment by ceftriaxone to C57BL/6 mice in early life, a 14-month observation was performed using 16S rRNA gene-sequencing technique, metabolomics analysis, and metagenomics analysis on the effects of ceftriaxone exposure. Firstly, the results showed that antibiotic pre-treatment significantly disturbed gut microbial α and β diversities (P

Abstract Objectives In middle-income countries, poor physician-patient communication remains a recognized barrier to enhancing healthcare quality and patient satisfaction. This study investigates the influence of provider-patient communication skills on healthcare quality and patient satisfaction in the rural primary healthcare setting in China. Methods Data were collected from 504 interactions across 348 rural primary healthcare facilities spanning 21 counties in three provinces. Using the Standardized Patient method, this study measured physician-patient communication behaviors, healthcare quality, and patient satisfaction. Communication skills were assessed using the SEGUE questionnaire framework. Multivariate linear regression models and multivariate logistic regression models, accounting for fixed effects, were employed to evaluate the impact of physicians’ communication skills on healthcare quality and patient satisfaction. Results The findings indicated generally low provider-patient communication skills, with an average total score of 12.2 ± 2.8 (out of 24). Multivariate regression models, which accounted for physicians’ knowledge and other factors, demonstrated positive associations between physicians’ communication skills and healthcare quality, as well as patient satisfaction (P

Abstract The need for tumor postoperative treatments aimed at recurrence prevention and tissue regeneration have raised wide considerations in the context of the design and functionalization of implants. Herein, an injectable hydrogel system encapsulated with anti-tumor, anti-oxidant dual functional nanoparticles has been developed in order to prevent tumor relapse after surgery and promote wound repair. The utilization of biocompatible gelatin methacryloyl (GelMA) was geared towards localized therapeutic intervention. Zeolitic imidazolate framework-8@ceric oxide (ZIF-8@CeO2, ZC) nanoparticles (NPs) were purposefully devised for their proficiency as reactive oxygen species (ROS) scavengers. Furthermore, injectable GelMA hydrogels loaded with ZC NPs carrying doxorubicin (ZC-DOX@GEL) were tailored as multifunctional postoperative implants, ensuring the efficacious eradication of residual tumor cells and alleviation of oxidative stress. In vitro and in vivo experiments were conducted to substantiate the efficacy in cancer cell elimination and the prevention of tumor recurrence through the synergistic chemotherapy approach employed with ZC-DOX@GEL. The acceleration of tissue regeneration and in vitro ROS scavenging attributes of ZC@GEL were corroborated using rat models of wound healing. The results underscore the potential of the multifaceted hydrogels presented herein for their promising application in tumor postoperative treatments.

Abstract During fatigued conditions, badminton players may experience adverse effects on their ankle joints during smash landings. In addition, the risk of ankle injury may vary with different landing strategies. This study aimed to investigate the influence of sport-specific fatigue factors and two backhand smash actions on ankle biomechanical indices. Thirteen female badminton players (age: 21.2 ± 1.9 years; height: 167.1 ± 4.1 cm; weight: 57.3 ± 5.1 kg; BMI: 20.54 ± 1.57 kg/m2) participated in this study. An 8-camera Vicon motion capture system and three Kistler force platforms were used to collect kinematic and kinetic data before and after fatigue for backhand rear-court jump smash (BRJS) and backhand lateral jump smash (BLJS). A 2 × 2 repeated measures analysis of variance was employed to analyze the effects of these smash landing actions and fatigue factors on ankle biomechanical parameters. Fatigue significantly affected the ankle-joint plantarflexion and inversion angles at the initial contact (IC) phase (p

Abstract This paper proposes an innovative global solution which is a pioneering work applying automated machine learning algorithms to remarkable precision sparse underwater direction-of-arrival (DOA) estimation that views the subaquatic sparse-sampling DOA estimation problem as a classification prediction task. The proposed solution, termed automated multi-layer perceptron discriminative neural network (AutoMPDNN), is built upon a Bayesian optimization framework. AutoMPDNN transforms sparsely sampled time-domain signals into the complex domain, preserving essential components in a one-source single-snapshot scenario. Leveraging Bayesian optimization principles, the algorithm embeds necessary hyperparameters into the loss function, effectively defining it as a maximum likelihood problem using the upper confidence bound function and incorporating sparse signal features. We also explore the model space architecture and introduce variants of AutoMPDNN, denoted as AutoMPDNNs_ln (n = 2,3,4). Through a series of plane wave simulation experiments, it is demonstrated that AutoMPDNN achieves the highest prediction performance for one-source single-snapshot scenarios compared to classical DOA estimation algorithms that incorporate sparse representation approaches, as well as contemporary deep learning DOA methods under varying conditions.

Abstract Background Risk factors of infant mortality in Africa and south Asian countries have been broadly discussed. However, infant morbidity is largely underestimated. We analyzed the data from a randomized vaccine trial in Bangladesh to identify and assess the effect of risk factors on infant morbidity. Methods Pregnant women were randomly assigned to receive either inactivated influenza vaccine or pneumococcal polysaccharide vaccine and the infants were randomly assigned to receive 7-valent pneumococcal conjugate vaccine or Hib conjugate vaccine at week 6, 10 and 14. The data were collected from August 2004 through December 2005. Each pair of infant and mother were followed for 24 weeks after birth with weekly visits. Generalized estimating equations (GEE) for repeated measurements and Poisson regression models were used to identify the risk factors and evaluate their effect on the longitudinal incidence and total number of episodes of respiratory illness with fever (RIF), diarrhea disease, ear problem and pneumonia. Results A total of 340 pregnant women were randomized with mean age of 25 years. The baseline mother and infant characteristics were similar between two treatment groups. Exclusive breastfeeding and higher paternal education level were common factors associated with lower infant morbidity of RIF (adjusted OR = 0.40 and 0.94 with p 0.05). Female infants had lower incidence of diarrhea disease (adjusted OR = 0.67; p = 0.01) and ear problem (adjusted OR = 0.12; p = 0.01). Conclusions Maternal influenza vaccination, exclusive breastfeeding, female children, and higher paternal education level significantly reduced the infant morbidity within the 24 weeks after birth in Bangladesh.