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Abstract Background Infantile Juvenile polyposis of infantile (JPI) is a rare and aggressive form of juvenile polyposis syndrome (JPS) typically diagnosed in the first year of life. It often carries a poor prognosis due to chronic gastrointestinal bleeding, protein-losing enteropathy, malnutrition and immune deficiency. Case presentation We report a case of a girl initially presented with pallor at 7 months of age, which progressed to gastrointestinal bleeding and protein-losing enteropathy. Endoscopic examination, which included both upper gastrointestinal endoscopy and enteroscopy, showed diffuse polyposis. Histopathology results indicated the presence of juvenile polyps with no dysplasia in all removed polyps. Genetic testing identified a 2.1 Mb deletion on chromosome 10q23.2q23.31 involving the phosphatase and tensin homolog (PTEN) and bone morphogenetic protein receptor type IA (BMPR1A) genes. Treatment with sirolimus initiated at 10 months of age led to a reduction in the need for blood and albumin infusions, improved patient growth, and quality of life. While the frequency of endoscopic evaluations decreased with sirolimus, regular endoscopic polypectomy every 5 months remained necessary. However, discontinuation of sirolimus resulted in polyp recurrence after 2 months due to pneumonia. Conclusion This case highlights sirolimus treatment can alleviate many complications of JPI, it does not eliminate the need for aggressive polypectomy.

Abstract While many countries employed digital contact tracing to contain the spread of SARS-CoV-2, the contribution of cospace-time interaction (i.e., individuals who shared the same space and time) to transmission and to super-spreading in the real world has seldom been systematically studied due to the lack of systematic sampling and testing of contacts. To address this issue, we utilized data from 2230 cases and 220,878 contacts with detailed epidemiological information during the Omicron outbreak in Beijing in 2022. We observed that contact number per day of tracing for individuals in dwelling, workplace, cospace-time interactions, and community settings could be described by gamma distribution with distinct parameters. Our findings revealed that 38% of traced transmissions occurred through cospace-time interactions whilst control measures were in place. However, using a mathematical model to incorporate contacts in different locations, we found that without control measures, cospace-time interactions contributed to only 11% (95%CI: 10%–12%) of transmissions and the super-spreading risk for this setting was 4% (95%CI: 3%–5%), both the lowest among all settings studied. These results suggest that public health measures should be optimized to achieve a balance between the benefits of digital contact tracing for cospace-time interactions and the challenges posed by contact tracing within the same setting.

Abstract Background Traditional Chinese medicine (TCM) has been found widespread application in neoplasm treatment, yielding promising therapeutic candidates. Previous studies have revealed the anti-cancer properties of Brevilin A, a naturally occurring sesquiterpene lactone derived from Centipeda minima (L.) A.Br. (C. minima), a TCM herb, specifically against lung cancer. However, the underlying mechanisms of its effects remain elusive. This study employs network pharmacology and experimental analyses to unravel the molecular mechanisms of Brevilin A in lung cancer. Methods The Batman-TCM, Swiss Target Prediction, Pharmmapper, SuperPred, and BindingDB databases were screened to identify Brevilin A targets. Lung cancer-related targets were sourced from GEO, Genecards, OMIM, TTD, and Drugbank databases. Utilizing Cytoscape software, a protein-protein interaction (PPI) network was established. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene set enrichment analysis (GSEA), and gene-pathway correlation analysis were conducted using R software. To validate network pharmacology results, molecular docking, molecular dynamics simulations, and in vitro experiments were performed. Results We identified 599 Brevilin A-associated targets and 3864 lung cancer-related targets, with 155 overlapping genes considered as candidate targets for Brevilin A against lung cancer. The PPI network highlighted STAT3, TNF, HIF1A, PTEN, ESR1, and MTOR as potential therapeutic targets. GO and KEGG analyses revealed 2893 enriched GO terms and 157 enriched KEGG pathways, including the PI3K-Akt signaling pathway, FoxO signaling pathway, and HIF-1 signaling pathway. GSEA demonstrated a close association between hub genes and lung cancer. Gene-pathway correlation analysis indicated significant associations between hub genes and the cellular response to hypoxia pathway. Molecular docking and dynamics simulations confirmed Brevilin A’s interaction with PTEN and HIF1A, respectively. In vitro experiments demonstrated Brevilin A-induced dose- and time-dependent cell death in A549 cells. Notably, Brevilin A treatment significantly reduced HIF-1α mRNA expression while increasing PTEN mRNA levels. Conclusions This study demonstrates that Brevilin A exerts anti-cancer effects in treating lung cancer through a multi-target and multi-pathway manner, with the HIF pathway potentially being involved. These results lay a theoretical foundation for the prospective clinical application of Brevilin A.

Summary: Understanding the adaptability of the motor cortex in response to bilateral motor tasks is crucial for advancing our knowledge of neural plasticity and motor learning. Here we aim to investigate the dynamic lateralization of contralateral-projecting corticospinal neurons (cpCSNs) during such tasks. Utilizing in vivo two-photon calcium imaging, we observe cpCSNs in mice performing a “left-right” lever-press task. Our findings reveal heterogeneous populational dynamics in cpCSNs: a marked decrease in activity during ipsilateral motor learning, in contrast to maintained activity during contralateral motor learning. Notably, individual cpCSNs show dynamic shifts in engagement with ipsilateral and contralateral movements, displaying an evolving pattern of activation over successive days. It suggests that cpCSNs exhibit adaptive changes in activation patterns in response to ipsilateral and contralateral movements, highlighting a flexible reorganization during motor learning This reconfiguration underscores the dynamic nature of cortical lateralization in motor learning and offers insights for neuromotor rehabilitation.

Abstract Ecological strategies identified by plant functional traits are valuable descriptors for understanding species, populations, communities, and ecosystems in response to environmental conditions. Ecological strategies, in conjunction with the functional structure of plant communities, serve as crucial tools for investigating complex relationships among the environment, vegetation, and ecosystem functions. However, it remains unclear whether the functional structure (specifically, community‐weighted mean [CWM] traits) accurately reflects the optimal ecological strategies in forest communities. Here, we gathered seven functional traits for each species from four distinct forest vegetation types across four climatic zones, including leaf area (LA), specific leaf area (SLA), leaf dry matter content (LDMC), leaf phosphorus concentration (LPC), leaf nitrogen concentration (LNC), wood density (WD) and maximum plant height (H). We based on CSR (Competitors, Stress‐tolerators, Ruderals) theory and “StrateFy” ordination method utilizing LA, LDMC and SLA to position them within CSR triangle and categorize them into four ecological strategy groups: Competitive, Stress‐tolerant, Intermediate, and Ruderal ecological strategy groups (C‐group, S‐group, Int‐group, and R‐group). We then determined the proportion of species in each group. Subsequently, we calculated the CWM trait values for the remaining four functional traits: WD (CWM‐WD), LPC (CWM‐LPC), LNC (CWM‐LNC) and H (CWM‐H). Non‐metric multidimensional scaling and hierarchical partitioning revealed that CWM‐WD, CWM‐LPC, CWM‐LNC and CWM‐H significantly influenced the ecological strategies of forest communities. The synergistic interaction of CWM‐WD and CWM‐LPC had the most significant impact on ecological strategies within forest communities. Notably, CWM‐WD emerged as the most crucial single CWM trait for explaining variation in ecological strategies within forest communities. In conclusion, our study demonstrates that CWM traits effectively reflect optimal CSR ecological strategies in forest communities across different climatic zones, with CWM‐WD serving as a preferred indicator. This can improve our critical insights into key ecological processes in forest communities using trait‐based approach.

Abstract The mechanisms responsible for invisible gold enrichment driven by coupled dissolution-reprecipitation reaction (CDR) are debated. Here we report the micro- to nano-scale textures of arsenian pyrite in a high-grade (>10 g/t) gold ore from the Chang’an deposit to trace the gold enrichment process. Our study records a CDR-driven evolution of mineral growth from an As-rich, Au-poor pyrite core, with numerous fine arsenopyrite inclusions, to an inclusion-free, As-Au-rich oscillatory pyrite rim. The reaction occurred at ~260 °C under 4.7 to 5.8 pH and –36.6 to –32.9 logfO2 conditions. The elevated As but depleted S contents in the pyrite core indicate a combined elevation of S fugacity and solubility of Au. The coprecipitation of arsenopyrite inclusions in the core caused a depletion of S fugacity to –13.8 ~ –11.7, triggering Au enrichment in the rim. This non-unique process has the potential to explain the upgrade of invisible Au in arsenian sulfides, worldwide.

Abstract Recent evidence has shed light on the significant role of FANCD2 in cancer initiation, development, and progression. However, a comprehensive pan-cancer analysis of FANCD2 has been lacking. In this study, we have conducted a thorough investigation into the expression profiles and prognostic significance of FANCD2, as well as its correlation with clinicopathological parameters and immune cell infiltration, using advanced bioinformatic techniques. The results demonstrate that FANCD2 is significantly upregulated in various common cancers and is associated with prognosis. Notably, higher expression levels of FANCD2 are linked to poor overall survival, as indicated by Cox regression and Kaplan-Meier analyses. Additionally, we have observed a decrease in the methylation of FANCD2 DNA in some cancers, and this decrease is inversely correlated with FANCD2 expression. Genetic alterations in FANCD2 predominantly manifest as mutations, which are associated with overall survival, disease-specific survival, disease-free survival, and progression-free survival in certain tumor types. Moreover, FANCD2 exhibits a strong correlation with infiltrating cell levels, immune checkpoint genes, tumor mutation burden (TMB), and microsatellite instability (MSI). Enrichment analysis further highlights the potential impact of FANCD2 on Fanconi anemia (FA) pathway and cell cycle regulation. Through this comprehensive pan-cancer analysis, we have gained a deeper understanding of the functions of FANCD2 in oncogenesis and metastasis across different types of cancer.

Abstract Raising the charging voltage and employing high‐capacity cathodes like lithium cobalt oxide (LCO) are efficient strategies to expand battery capacity. High voltage, however, will reveal major issues such as the electrolyte's low interface stability and weak electrochemical stability. Designing high‐performance solid electrolytes from the standpoint of substance genetic engineering design is consequently vital. In this instance, stable SEI and CEI interface layers are constructed, and a 4.7 V high‐voltage solid copolymer electrolyte (PAFP) with a fluoro‐cyanogen group is generated by polymer molecular engineering. As a result, PAFP has an exceptionally broad electrochemical window (5.5 V), a high Li+ transference number (0.71), and an ultrahigh ionic conductivity (1.2 mS cm−2) at 25 °C. Furthermore, the Li||Li symmetric cell possesses excellent interface stability and 2000 stable cycles at 1 mA cm−2. The LCO|PAFP|Li batteries have a 73.7% retention capacity after 1200 cycles. Moreover, it still has excellent cycling stability at a high charging voltage of 4.7 V. These characteristics above also allow PAFP to run stably at high loading, showing excellent electrochemical stability. Furthermore, the proposed PAFP provides new insights into high‐voltage resistant solid polymer electrolytes.

Deoxynivalenol (DON) is one of the most common mycotoxins distributed in food and feed, which causes severe liver injury in humans and animals. Cold atmospheric plasma (CAP) has received much attention in mycotoxin degradation due to the advantages of easy operation, high efficiency, and low temperature. So far, the majority of studies have focused on the degradation efficiency and mechanism of CAP on DON, while there is still little information available on the hepatotoxicity of DON after CAP treatment. Herein, this study aimed to investigate the effect of CAP on DON-induced hepatotoxicity both in vitro and in vivo and its underlying mechanisms. The results showed that 120-s CAP treatment achieved 97 % degradation of DON. The vitro hepatotoxicity of DON in L02 cells was significantly reduced with CAP treatment time. Meanwhile, CAP markedly alleviated DON-induced liver injury in mice including the balloon-like degeneration of liver tissues and elevation of AST and ALP level. The underlying mechanism for CAP detoxification of DON-induced hepatotoxicity was further elucidated. The results showed that DON caused severe oxidative stress in cells by suppressing the antioxidant signaling pathway of Nrf2/HO-1/NQO-1, consequently leading to mitochondrial dysfunction and cell apoptosis, accompanied by cellular senescence and inflammation. CAP blocked DON inhibition on the Nrf2/HO-1/NQO-1 signaling pathway through the efficient degradation of DON, accordingly alleviating the oxidative stress and liver injury induced by DON. Therefore, CAP is an effective method to eliminate DON hepatotoxicity, which can be applied in the detoxification of mycotoxin-contaminated food and feed to ensure human and animal health.

Abstract COVID‐19 is currently pandemic and the detection of SARS‐CoV‐2 variants in wastewater is causing widespread concern. Herein, cold atmospheric plasma (CAP) is proposed as a novel wastewater disinfection technology that effectively inactivates SARS‐CoV‐2 transcription‐ and replication‐competent virus‐like particles, coronavirus GX_P2V, pseudotyped SARS‐CoV‐2 variants, and porcine epidemic diarrhoea virus in a large volume of water within 180 s (inhibition rate > 99%). Further, CAP disinfection did not adversely affect the viability of various human cell lines. It is identified that CAP produced peroxynitrite (ONOO−), ozone (O3), superoxide anion radicals (O2−), and hydrogen peroxide (H2O2) as the major active substances for coronavirus disinfection. Investigation of the mechanism showed that active substances not only reacted with the coronavirus spike protein and affected its infectivity, but also destroyed the nucleocapsid protein and genome, thus affecting virus replication. This method provides an efficient and environmentally friendly strategy for the elimination of SARS‐CoV‐2 and other coronaviruses from wastewater.

Oral biofilm is the leading cause of dental caries, which is difficult to completely eradicate because of the complicated biofilm structure. What's more, the hypoxia environment of biofilm and low water-solubility of conventional photosensitizers severely restrict the therapeutic effect of photodynamic therapy (PDT) for biofilm. Although conventional photosensitizers could be loaded in nanocarriers, it has reduced PDT effect because of aggregation-caused quenching (ACQ) phenomenon. In this study, we fabricated an oxygen self-sufficient nanodroplet (PFC/TPA@FNDs), which was composed of fluorinated-polymer (FP), perfluorocarbons (PFC) and an aggregation-induced emission (AIE) photosensitizer (Triphenylamine, TPA), to eradicate oral bacterial biofilm and whiten tooth. Fluorinated-polymer was synthesized by polymerizing (Dimethylamino)ethyl methacrylate, fluorinated monomer and 1-nonanol monomer. The nanodroplets could be protonated and behave strong positive charge under bacterial biofilm acid environment promoting nanodroplets deeply penetrating biofilm. More importantly, the nanodroplets had extremely high PFC and oxygen loading efficacy because of the hydrophobic affinity between fluorinated-polymer and PFC to relieve the hypoxia environment and enhance PDT effect. Additionally, compared with conventional ACQ photosensitizers loaded system, PFC/TPA@FNDs could behave superior PDT effect to ablate oral bacterial biofilm under light irradiation due to the unique AIE effect. In vivo caries animal model proved the nanodroplets could reduce dental caries area without damaging tooth structure. Ex vivo tooth whitening assay also confirmed the nanodroplets had similar tooth whitening ability compared with commercial tooth whitener H2O2, while did not disrupt the surface microstructure of tooth. This oxygen self-sufficient nanodroplet provides an alternative visual angle for oral biofilm eradication in biomedicine.

Abstract Background Female fertility declines with increased maternal age, and this decline is even more rapid after the age of 35 years. Follicular fluid (FF) is a crucial microenvironment that plays a significant role in the development of oocytes, permits intercellular communication, and provides the oocytes with nutrition. Exosomes have emerged as being important cell communication mediators that are linked to age-related physiological and pathological conditions. However, the metabolomic profiling of FF derived exosomes from advanced age females are still lacking. Methods The individuals who were involved in this study were separated into two different groups: young age with a normal ovarian reserve and advanced age. The samples were analysed by using gas chromatography–time of flight mass spectrometry (GC–TOFMS) analysis. The altered metabolites were analysed by using Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis to identify the functions and pathways that were involved. Results Our data showed that metabolites in exosomes from FF were different between women of young age and women of advanced age. The set of 17 FF exosomal metabolites (P ≤ 0.05) may be biomarkers to differentiate between the two groups. Most of these differentially expressed metabolites in FF were closely involved in the regulation of oocyte number and hormone levels. Conclusions In this study, we identified differences in the metabolites of exosomes from FF between women of young age and women of advanced age. These different metabolites were tightly related to oocyte count and hormone levels. Importantly, these findings elucidate the metabolites of the FF exosomes and provide a better understanding of the nutritional profiles of the follicles with age.

Falling damage is the most common form of damage sustained by kiwifruit during the process of picking and post-processing, and it is difficult to conduct a quantitative analysis of this phenomenon through traditional experimental methods. In order to deeply understand the sensitivity of kiwifruit to falling collision damage, the finite element numerical simulation method was used to evaluate and predict the sensitivity of kiwifruit to falling collision damage during harvesting. First, we obtained the appearance characteristics of kiwifruit through reverse engineering technology and determined the geometric and mechanical property parameters of kiwifruit through physical mechanics experiments. Then, according to the characteristics of fruit tissue structure, a multiscale finite element model, including the skin, pulp, and core, was constructed to simulate the effects of different falling heights, collision angles, and contact surface materials on fruit damage, and the accuracy of the model was verified through falling experiments. Finally, based on the simulation results, the Box–Behnken design was employed within the response surface methodology to establish a sensitivity prediction model for the drop damage sensitivity of kiwifruit across different contact materials. The results showed that the maximum relative error between the speed change obtained using finite element simulation and the speed obtained by the high-speed camera was 5.19%. The model showed high rationality in energy distribution, with the maximum value of hourglass energy not exceeding 0.08% of the internal energy. On the contact surface material with a large elastic modulus, a higher falling height and larger collision angle will significantly increase the risk of fruit bruise. When the contact surface material was a steel plate, the falling height was 1 m, and the collision angle was 90°; the maximum bruise sensitivity of kiwifruit reached 6716.07 mm3 J−1. However, when the contact surface material was neoprene, the falling height was 0.25 m, and the collision angle was 0°, the damage sensitivity was the lowest, at 1570.59 mm3 J−1. The multiscale finite element model of kiwifruit falling collision constructed in this study can accurately predict the damage of kiwifruit during falling collision and provide an effective tool for the quantitative analysis of kiwifruit falling collision damage. At the same time, this study can also provide guidance for the design and optimization of the loss reduction method of the harvesting mechanism, which has important theoretical significance and practical value.

Based on a multi-locus phylogeny of a combined dataset of ITS, LSU, tef1-α, and rpb2 and comprehensive morphological analyses, we describe three new species from the Melanosporum group of genus Tuber and synonymize T. pseudobrumale and T. melanoexcavatum. Phylogenetically, the three newly described species, T. yunnanense, T. melanoumbilicatum and T. microexcavatum, differ significantly in genetic distance from any previously known species. Morphologically, T. yunnanense is distinctly different from its closest phylogenetically related species, T. longispinosum, due to its long shuttle-shape spores (average the ratio of spore length to spore width for all spores (Qm) = 1.74). Tuber melanoumbilicatum differs from the other species in having a cavity and long shuttle-shaped spores (Qm = 1.65). Although T. microexcavatum sampled ascomata have relatively low maturity, they can be distinguished from its closely related species T. pseudobrumale by the ascomata size, surface warts, and spore number per asci; additionally, phylogenetic analysis supports it as a new species. In addition, molecular analysis from 22 newly collected specimens and Genebank data indicate that T. pseudobrumale and T. melanoexcavatum are clustered into a single well-supported clade (Bootstrap (BS) = 100, posterior probabilities (PP) = 1.0); and morphological characteristics do not differ. Therefore, based on the above evidence and publication dates, we conclude that T. melanoexcavatum is a synonym of T. pseudobrumale. By taking into account current knowledge and combining the molecular, multigene phylogenetic clade arrangement and morphological data, we propose that the Melanosporum group should be divided into four subgroups. Diagnostic morphological features and an identification key of all known species in the Melanosporum group are also included. Finally, we also provide some additions to the knowledge of the characterization of T. pseudobrumale, T. variabilisporum, and T. pseudohimalayense included in subgroup 1 of the Melanosporum group.

Tripartite motif 21 (TRIM21) is a cytosolic Fc receptor that targets antibody-bound, internalized pathogens for destruction. Apart from this intrinsic defense role, TRIM21 is implicated in autoimmune diseases, inflammation, and autophagy. Whether TRIM21 participates in host interactions with influenza A virus (IAV), however, is unknown. By computational modeling of body weight and lung transcriptome data from the BXD parents (C57BL/6 J (B6) and DBA/2 J (D2)) and 41 BXD mouse strains challenged by IAV, we reveal that a Trim21-associated gene network modulates the early host responses to IAV infection. Trim21 transcripts were significantly upregulated in infected mice of both B6 and D2 backgrounds. Its expression was significantly higher in infected D2 than in infected B6 early after infection and significantly correlated with body weight loss. We identified significant trans-eQTL on chromosome 14 that regulates Trim21 expression. Nr1d2 and Il3ra were among the strongest candidate genes. Pathway analysis found Trim21 to be involved in inflammation and immunity related pathways, such as inflammation signaling pathways (TNF, IL-17, and NF-κB), viral detection signaling pathways (NOD-like and RIG-I-like), influenza, and other respiratory viral infections. Knockdown of TRIM21 in human lung epithelial A549 cells significantly augmented IAV-induced expression of IFNB1, IFNL1, CCL5, CXCL10, and IFN-stimulated genes including DDX58 and IFIH1, among others. Our data suggest that a TRIM21-associated gene network is involved in several aspects of inflammation and viral detection mechanisms during IAV infection. We identify and validate TRIM21 as a critical regulator of innate immune responses to IAV in human lung epithelial cells.

ObjectiveThe purpose of this meta-analysis was to investigate the effect of high-intensity interval training (HIIT) on arterial stiffness (AS) and vascular function in persons at high risk of cardiovascular disease (CVD).MethodsWe conducted a comprehensive search of randomized controlled trials (RCTs) published in electronic databases (PubMed, Web of Science, Cochrane, Embase, and Ebsco) since their inception through October 2023 to evaluate the effect of HIIT on AS and vascular function in persons at high risk for CVD. The weighted mean difference (WMD) and 95% confidence intervals (95% CI) were calculated, and heterogeneity was assessed using the I2 test.ResultsThis study included 661 participants from 16 studies. HIIT significantly reduced pulse wave velocity (PWV) in persons at high risk for CVD [weighted mean difference (WMD), −0.62; 95% CI, −0.86–−0.38; P

The pyridine alkaloid nicotine acts as one of best-studied plant resistant traits in tobacco. Previous research has shown that NtERF199 and NtERF189, acting as master regulators within the NIC1 and NIC2 locus, quantitatively contribute to nicotine accumulation levels in N. tabacum. Genome editing-created Nic1(Nterf199) and Nic2 (Nterf189) double mutant provides an ideal platform for precisely dissecting the defensive role of nicotine and the connection between the nicotine biosynthetic pathway with other putative metabolic networks. Taking this advantage, we performed a comparative transcriptomic analysis to reevaluate the potential physiological and metabolic changes in response to nicotine synthesis defect by comparing the nic1nic2 and NIC1NIC2 plants. Our findings revealed that nicotine reduction could systematically diminishes the expression intensities of genes associated with stimulus perception, signal transduction and regulation, as well as secondary metabolic flux. Consequently, this global expression reduction might compromise tobacco adaptions to environmental fitness, herbivore resistances, and plant growth and development. The up-regulation of a novel set of stress-responsive and metabolic pathway genes might signify a newly established metabolic reprogramming to tradeoff the detrimental effect of nicotine loss. These results offer additional compelling evidence regarding nicotine’s critical defensive role in nature and highlights the tight link between nicotine biosynthesis and gene expression levels of quantitative resistance-related genes for better environmental adaptation.

Abstract Rational design of chimeric antigen receptor T (CAR-T) cells based on the recognition of antigenic epitopes capable of evoking the most potent CAR activation is an important objective in optimizing immune therapy. In solid tumors, the B7-H3 transmembrane protein is an emerging target that harbours two distinct epitope motifs, IgC and IgV, in its ectodomain. Here, we generate dromedary camel nanobodies targeting B7-H3 and demonstrate that CAR-T cells, based on the nanobodies recognizing the IgC but not IgV domain, had potent antitumour activity against large tumors in female mice. These CAR-T cells are characterized by highly activated T cell signaling and significant tumor infiltration. Single-cell transcriptome RNA sequencing coupled with functional T-cell proteomics analysis uncovers the top-upregulated genes that might be critical for the persistence of polyfunctional CAR-T cells in mice. Our results highlight the importance of the specific target antigen epitope in governing optimal CAR-T activity and provide a nanobody-based B7-H3 CAR-T product for use in solid tumor therapy.

Abstract Sertoli cell-only syndrome (SCOS), a severe testicular spermatogenic failure, is characterized by total absence of male germ cells. To better expand the understanding of the potential molecular mechanisms of SCOS, we used microarray datasets from the Gene Expression Omnibus (GEO) and ArrayExpress databases to determine the differentially expressed genes (DEGs). In addition, functional enrichment analysis including the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) was performed. Protein–protein interaction (PPI) networks, modules, and miRNA-mRNA regulatory networks were constructed and analyzed and the validation of hub genes was performed. A total of 601 shared DEGs were identified, including 416 down-regulated and 185 up-regulated genes. The findings of the enrichment analysis indicated that the shared DEGs were mostly enriched in sexual reproduction, reproductive process, male gamete generation, immune response, and immunity-related pathways. In addition, six hub genes (CCNA2, CCNB2, TOP2A, CDC20, BUB1, and BUB1B) were selected from the PPI network by using the cytoHubba and MCODE plug-ins. The expression levels of the hub genes were significantly decreased in patients with SCOS compared to that in normal spermatogenesis controls as indicated by the microarray data, single-cell transcriptomic data, and clinical sample levels. Furthermore, the potential miRNAs were predicted via the miRNA-mRNA network construction. These hub genes and miRNAs can be used as potential biomarkers that may be related to SCOS. However, it has not been proven that the differential expression of these biomarkers is the molecular pathogenesis mechanisms of SCOS. Our findings suggest that these biomarkers can be serve as clinical tool for diagnosis targets and may have some impact on the spermatogenesis of SCOS from a testicular germ cell perspective.

Abstract Hepatitis C virus (HCV) is a major global health burden as the leading causative agent of chronic liver disease and hepatocellular carcinoma. While the main antigenic target for HCV-neutralizing antibodies is the membrane-associated E1E2 surface glycoprotein, the development of effective vaccines has been hindered by complications in the biochemical preparation of soluble E1E2 ectodomains. Here, we present a cryo-EM structure of an engineered, secreted E1E2 ectodomain of genotype 1b in complex with neutralizing antibodies AR4A, HEPC74, and IGH520. Structural characterization of the E1 subunit and C-terminal regions of E2 reveal an overall architecture of E1E2 that concurs with that observed for non-engineered full-length E1E2. Analysis of the AR4A epitope within a region of E2 that bridges between the E2 core and E1 defines the structural basis for its broad neutralization. Our study presents the structure of an E1E2 complex liberated from membrane via a designed scaffold, one that maintains all essential structural features of native E1E2. The study advances the understanding of the E1E2 heterodimer structure, crucial for the rational design of secreted E1E2 antigens in vaccine development.

Lung cancer is a major public health challenge and, despite therapeutic improvements, is the first leading cause of cancer worldwide. The current cure rate from advanced cancer treatment is excessively low. Therefore, it is of great importance to identify novel, potent and less toxic anticancer agents for the treatment of lung cancer. The aim of our research is to synthesize a new biscoumarin 3,3'-((3,4,5-trifluorop -phenyl)methylene)bis(4-hydroxy-2H-chromen-2-one) (C35) as an anticancer agent. C35 was simply prepared by 4-hydroxycoumarin and 3,4,5-trifluorobenzaldehyde under ethanol and its structure was analyzed by spectroscopic analyses. The anti-proliferation effect of C35 was detected using CCK-8 assay. Migration abilities were measured by Transwell assay. The expression of correlated proteins was determined by Western blot. The results showed that C35 displayed strong cytostatic effects on lung cancer cell proliferation. In addition, C35 possessed a significant inhibition of migration by reducing the expression of matrix metalloproteinases-2 (MMP-2) and MMP-9 in lung cancer cells. Furthermore, C35 treatment suppressed the phosphorylation of p38 in lung cancer cells. Moreover, in vivo experiments were carried out, in which we treated Lewis tumor-bearing C57 mice via intraperitoneal injection of C35. Results showed that C35 inhibited tumor growth in vivo. In conclusion, our study demonstrated the anticancer activity of C35 via suppression of lung cancer cell proliferation and migration, which is possibly involved with the inhibition of the p38 pathway.

Summary: Aneuploidy can globally affect the expression of the whole genome, which is detrimental to organisms. Dosage-sensitive regulators usually have multiple intermolecular interactions, and changes in their stoichiometry are responsible for the dysregulation of the regulatory network. Currently, studies on noncoding genes in aneuploidy are relatively rare. We studied the characteristics and expression profiles of long noncoding RNAs (lncRNAs) and transposable elements (TEs) in aneuploid Drosophila. It is found that lncRNAs and TEs are affected by genomic imbalance and appear to be more sensitive to an inverse dosage effect than mRNAs. Several dosage-sensitive lncRNAs and TEs were detected for their expression patterns during embryogenesis, and their biological functions in the ovary and testes were investigated using tissue-specific RNAi. This study advances our understanding of the noncoding sequences in imbalanced genomes and provides a novel perspective for the study of aneuploidy-related human diseases such as cancer.

In the handling or processing process, fruits are easily crushed by external loads. This type of damage in fruit often leads to the internal pulp browning and rotting, with the severity largely dependent on the fruit tissue’s geometric and mechanical properties. In kiwifruits, with their thin skin and dark-colored flesh, it is particularly challenging to observe and analyze the damage caused by extrusion through traditional experimental methods. The objective of this research is to construct a multi-scale finite element model encompassing the skin, flesh, and core by measuring the geometric and mechanical properties of kiwifruit, to assess and predict the damage characteristics under compression, and to verify the accuracy of the finite element model through experiments. The results indicated that kiwifruits demonstrated different compressive strengths in different directions during compression. The compressive strength in the axial direction was higher than that in the radial direction, and there was little difference between the long and short radial directions. The flesh tissue is the most vulnerable to mechanical damage under external compression, followed by the core. At strain levels below 5%, there was no noticeable damage in the axial or radial directions of the kiwifruit. However, when strain exceeded 5%, damage began to manifest in some of the flesh tissue. To maintain fruit quality during storage and transportation, the stacking height should not exceed 77 fruits in the axial direction, 48 in the long direction, and 53 in the short direction. The finite element analysis showed that the established model can effectively simulate and predict the internal damage behavior of kiwifruits under compression loads, which is helpful for a deeper understanding of the mechanical properties of fruits and provides a theoretical basis and technical guidance for minimizing mechanical damage during fruit handling.

This study aims to investigate the high-temperature phase stability and hot corrosion behavior of zirconia with triple doping of Sc3+, Ce4+ and Y3+ ions. FESEM result shows that the mean particle size of ScCeYSZ nanoparticles was 80–90 nm. Next, optimal samples regarding the highest high-temperature phase stability (1.9%Sc8.3%Ce1.8%YSZ, 1.1%Sc9.0%Ce1.8%YSZ and 0.5%Sc9.6%Ce1.8%YSZ) were consolidated at 1550 °C for 15 min via the spark plasma sintering (SPS) method. A hot corrosion test was done in the presence of 45%Na2SO4+%55V2O5 salts on three samples at 900 °C for 2 h. Also, the results of hot corrosion were compared with ceramic resulting from the nanostructured YSZ bulk sample (nanoYSZ).Based on the X-ray diffraction results, the formation of the non-transformable tetragonal phase is confirmed in the synthesized nanopowders. Also, the phase and microstructural results after hot corrosion of sintered samples show the formation of a monoclinic phase and destructive YVO4 crystals and quasi-cubic CeO2 crystals on the surface of sintered samples. The results indicated that the sample containing 1.8% scandia, 8.3% ceria, and 1.9% yttria had the highest phase stability and hot corrosion resistance (low monoclinic percentage and low leaching of stabilizer elements of Sc3+:Ce4+:Y3+ from zirconia lattice and low depth of molten salt).

China had conducted some of the most stringent public health measures to control the spread of successive SARS-CoV-2 variants. However, the effectiveness of these measures and their impacts on the associated disease burden have rarely been quantitatively assessed at the national level. To address this gap, we developed a stochastic age-stratified metapopulation model that incorporates testing, contact tracing and isolation, based on 419 million travel movements among 366 Chinese cities. The study period for this model began from September 2022. The COVID-19 disease burden was evaluated, considering 8 types of underlying health conditions in the Chinese population. We identified the marginal effects between the testing speed and reduction in the epidemic duration. The findings suggest that assuming a vaccine coverage of 89%, the Omicron-like wave could be suppressed by 3-day interval population-level testing (PLT), while it would become endemic with 4-day interval PLT, and without testing, it would result in an epidemic. PLT conducted every 3 days would not only eliminate infections but also keep hospital bed occupancy at less than 29.46% (95% CI, 22.73-38.68%) of capacity for respiratory illness and ICU bed occupancy at less than 58.94% (95% CI, 45.70-76.90%) during an outbreak. Furthermore, the underlying health conditions would lead to an extra 2.35 (95% CI, 1.89-2.92) million hospital admissions and 0.16 (95% CI, 0.13-0.2) million ICU admissions. Our study provides insights into health preparedness to balance the disease burden and sustainability for a country with a population of billions.

Opuntia ficus-indica is rich in a variety of active substances, and the anthocyanins contained in it play an important role in regulating gut microbiota. In this paper, the simulated digestion and in vitro anaerobic fermentation of Opuntia ficus-indica anthocyanins were studied in K group (blank), anthocyanin H (high dose 15 mg/mL), M group (medium dose 10 mg/mL), L group (low dose 5 mg/mL) on human gut microbes and metabolites short-chain fatty acids (SCFAs). The results showed that, using the pH test and difference method, and taking the digestibility as an indicator, the anthocyanins of Opuntia ficus-indica (10 mg/mL) were obtained, the digestibility was 11.4% after 3 h of gastric digestion, 23.5% after 4 h of intestinal digestion, the remaining 65.1% of anthocyanins were not digested by the gastrointestinal tract. Using high-throughput sequencing method, through α diversity and β diversity analysis, compared with K group, anthocyanin H, M, L group could significantly improve the diversity of gut microbiota (P

Objective: To explore the composition of limon peel polyphenols (LPP) and its influence on glucose metabolism in insulin resistance (IR) HepG2 cells. Methods: The composition of LPP was analyzed by HPLC-QTOF-MS. HepG2 cells were used to establish insulin resistance model, IR-HepG2 cells were treated with LPP, and the effect of LPP on glucose metabolism was preliminarily investigated by measuring glucose consumption. By determining glycogen content and hexokinase (HK), pyruvate kinase (PK), phosphoenol pyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) activities to explore the pathway of LPP regulating glucose metabolism in cells. Results: Twelve compounds were identified by HPLC-QTOF-MS, mainly flavonoids and their glycosides. In the study of glucose metabolism, compared with the model group, the concentration of 0.1~2 mg/mL lemon peel polyphenols significantly increased glucose consumption (P

Amino acids are often used as probiotic growth factors. Their addition to the growth medium is found to effectively enhance the resistance of the strain to adverse environments. In this research, we found that adding 0.05 g/L L-cysteine to culture medium improved the freeze-drying survival rate of the strain. We investigated the internal mechanism behind this phenomenon and found that the addition of L-cysteine can reduce DNA damage to bacterial cells during the freeze-drying process. In comparison to the control group without L-cysteine, the treatment group with the addition of 0.05 g/L of L-cysteine exhibited an up-regulation of the metC gene, leading to the metabolism of L-cysteine into pyruvate and NH3, which raised the intracellular pH, reduced DNA damage, and consequently enhanced the resistance of Lactiplantibacillus plantarum LIP-1 to freeze-drying.

Chemical agents pose a significant threat to social security, highlighting the crucial role of representative chemical agents adsorption in ensuring the safety our environment. This study explored the application of Magnetic Graphene Oxide Nanoplatelet Composites (MGONCs) in adsorbing the representative chemical agents such as Lewisite (L), O-ethyl S-2-diisopropylaminoethyl methylphosphonothiolate (VX), Sarin (GB), and Soman (GD). MGONCs were synthesized through a physical blending method, with the combination of graphene oxide (GO) and Fe3O4 nanoparticles at a mass ratio of 1:1. Optimization of the adsorption process involved investigating the effects of contact time, temperature, and adsorbent dosage. Remarkably, the adsorption rate of L and VX exceeded 99% when the dosage of MGONCs was 2.5 mg, with a contact time of 30 s at room temperature. Furthermore, GB and GD achieved maximum adsorption rates after a contact time of 20 min, with the dosages of MGONCs at 10 mg and 20 mg, respectively. Characterization of the magnetic composite was accomplished through XRD, TEM, VSM, FTIR, TGA, and BET analyses. Kinetical analysis revealed that the adsorption mechanism of GB and GD on MGONCs followed pseudo-second-order (PSO) kinetics, exhibiting a high regression coefficient. The calculated qe values were 0.103125 mg/g and 0.081349 mg/g, respectively. This research demonstrated the feasibility of utilizing MGONCs as highly efficient adsorbents for representative chemical agents, particularly in on-site sampling scenarios.

Coumarin has a variety of biological activities and widely exists in plants. Biscoumarin, derived from coumarin, their synthetic methods and bioactivities of biscoumarins is the hotspot of the current research. In this study, we evaluated for the first time the anticancer of a synthetic biscoumarin (3,3'-(4-chlorophenyl)methylene)bis(4-hydroxy-2H-chromen-2-one, C3) on lung cancer cells and explored the related mechanism. C3 was simply prepared by 4-hydroxycoumarin and 4-chlorobenzaldehyde under ethanol. The structure of C3 was elucidated by various spectroscopic analyses. The antiproliferation effect of C3 was evaluated by the cell counting kit-8 assay. Cell cycle and apoptosis analysis were detected by flow cytometry. The expression of correlated proteins was determined using Western blotting. The result showed that C3 displayed a strong cytostatic effect on Lewis lung cancer (LLC) cells. C3 inhibited the proliferation of LLC cells, and induced G2/M phase cell cycle arrest. In addition, C3 possessed a significant reduction on cell apoptosis by increasing of RIP1 expression. Our data showed that C3 suppresses lung cancer cell proliferation and induces cell apoptosis, which is possibly involved with the RIP1.

Previous studies have indicated that outdoor air pollution has a negative impact on semen quality; however, few studies have examined whether living in a recently renovated residence is one of the factors influencing semen parameters. We aimed to examine the association between household renovation and semen parameters among infertile men. Our study was conducted at the Reproductive Medicine Center, The First Hospital of Jilin University (Changchun, China) from July 2018 to April 2020. A total of 2267 participants were enrolled in the study. The participants completed the questionnaire and provided a semen sample. Univariate and multiple logistic regression models were used to estimate the association between household renovations and semen parameters. Of the participants, about one-fifth ( n = 523, 23.1%) had undergone renovations in the last 24 months. The median progressive motility was 34.50%. There was a significant difference between participants whose residences had been renovated in the last 24 months and those whose residences had not been recently renovated ( z = –2.114, p = .035). Compared with participants whose residences were not recently renovated, participants who moved into the residence within 3 months after renovation had a higher risk of abnormal progressive motility after adjusting for age and abstinence time (odds ratio [OR] = 1.537, 95% confidence interval [CI]: 1.088–2.172). Our findings indicated that progressive motility was significantly associated with household renovations.

ABSTRACT Pseudomonas aeruginosa is a major bacterial pathogen causing nosocomial infections and accounts for morbidity and mortality among patients with cystic fibrosis. An accurate, sensitive, and rapid method to detect P. aeruginosa is critical for the early control of infection and patient management. In this study, we established a P. aeruginosa clustered regularly interspaced short palindromic repeats testing in one pot (CRISPR-top) assay which detected P. aeruginosa with one fluid-handling step in one tube. The reaction was performed isothermally within 1 h; thus, specific instruments were not required. The optimal reaction conditions of this assay were determined to be a temperature of 55°C; working concentrations of 1 μM for the forward inner primer and backward inner primer, 0.5 μM for the loop forward primer and loop backward primer, and 0.25 μM for the forward outer primer and backward outer primer; as well as a 2 μM concentration single-stranded DNA reporter molecules. In terms of specificity, our assay showed 100% inclusivity and exclusivity among 48 strains, including 15 P. aeruginosa clinical isolates and 33 non-P. aeruginosa strains. The limit of detection of our method was 10 copies per reaction mixture. Forty-six human sputum specimens from patients with respiratory symptoms were tested. Using the results of quantitative real-time PCR as the gold standard, our method showed 85.3% (29/34) sensitivity, 100% (12/12) specificity, a positive predictive value of 100% (29/29), and a negative predictive value of 70.6% (12/17). In summary, the P. aeruginosa CRISPR-top assay developed in the present study is a high-efficiency alternative tool for the accurate and rapid detection of P. aeruginosa, especially in resource-limited settings. IMPORTANCE This study reports a P. aeruginosa CRISPR-top assay which can precisely identify P. aeruginosa using nucleic acids from pure cultures or clinical samples in one pot with one fluid-handling step. The P. aeruginosa CRISPR-top reaction is suitable for on-site testing, and its diagnostic performance can be compared with that of qPCR.

Background: Recently, UNC45 myosin chaperone A (UNC45A) deficiency was identified as a cause of osteo-oto-hepato-enteric syndrome (O2HE) characterized by congenital diarrhea, neonatal cholestasis, deafness, and bone fragility. To date, only a few O2HE cases have been reported in the literature.Case presentation: Here, we present a child from China diagnosed with O2HE with novel compound heterozygous variants in UNC45A. The patient suffered with neonatal jaundice, cholestasis, and intractable diarrhea after birth. Laboratory tests revealed highly elevated levels of total serum bilirubin (TB), direct bilirubin (DB), and total bile acid (TBA). The patient was managed with ursodeoxycholic acid (UDCA)-based treatments, and the clinical symptoms and abnormal liver functions were significantly relieved. The patient’s hearing was normal, and no sign of bone fragility was observed. Exome sequencing (ES) identified novel compound heterozygote variants c.292C>T (p.Arg98Trp)/c.2534-2545del (p.Leu845-Met848del) in UNC45A, which were inherited from her mother and father, respectively. Both variants are predicted to be deleterious by in silico predictors.Conclusion: We present an O2HE child from China with novel compound heterozygous variants in UNC45A. Our patient’s clinical manifestations were less severe than those of the previous reported cases, which expands the clinical spectrum of O2HE.

Abstract In this study, transients that can occur in the collection grids of offshore wind farms were investigated. On the basis of the multiple prestrike and reignition model that can reflect the actual operation of a vacuum circuit breaker (VCB), a switching transient simulation model of a typical offshore wind farm was built. The developed model included a VCB, a transformer, a cable, and an arrester. Issues concerning the closing time, length of the feeder, and topology of the collection grid were discussed. Results showed that the relationship between overvoltage amplitude and closing time was approximately sinusoidal and the maximum value was obtained when the closing time was near the peak of the power source. In addition, the overvoltage at the end of a feeder terminal was the largest among all of the transformer overvoltages of the same feeder. The overvoltage of the main transformer and that of the transformer located at the end of a feeder decreased slowly with the increase in feeder length during the closing of VCB. However, these overvoltages were positively related to feeder length during the opening of VCB. The star topology was superior to the other topologies in terms of coping with the overvoltage caused by switching transients. The effectiveness of a suppression measure, namely, installation of a resistance‐capacitor filter, was also verified.

Abstract The inverse dosage effect caused by chromosome number variations shows global consequences in genomic imbalance including sexual dimorphism and an X chromosome-specific response. To investigate the relationship of the MSL complex to genomic imbalance, we over-expressed MSL2 in autosomal and sex chromosomal aneuploids, and analyzed the different transcriptomes. Some candidate genes involved in regulatory mechanisms have also been tested during embryogenesis using TSA-FISH. Here we show that the de novo MSL complex assembled on the X chromosomes in females further reduced the global expression level on the basis of 2/3 down-regulation caused by the inverse dosage effect in trisomy through epigenetic modulations rather than induced dosage compensation. Plus, the sexual dimorphism effect in unbalanced genomes was further examined due to the pre-existing of the MSL complex in males. All these results demonstrate the dynamic functions of the MSL complex on global gene expression in different aneuploid genomes.

Accurate spike sorting to the appropriate neuron is crucial for neural activity analysis. To improve spike sorting performance, it is essential to fully leverage each processing step, including filtering, spike detection, feature extraction, and clustering. However, compared to the latter two steps that were widely studied and optimized, the filtering process was largely neglected. In this study, we proposed a fast and effective spike sorting method (MultiFq) based on multi-frequency composite waveform shapes acquired through an optimized filtering process. When combined with the classical PCA-Km spiking sorting algorithm, our proposed MultiFq significantly improved its sorting performance and achieved as high performance as the complex Wave-clus did in both the simulated and in vivo datasets. But, the combined method was about 10 times faster than Wave-clus (0.16 s vs. 2.06 s in simulated datasets; 0.46 s vs. 2.03 s in in vivo datasets). Furthermore, we demonstrated the compatibility of our MultiFq by combining it with other sorting algorithms, which consistently resulted in significant improvement in sorting accuracy with the maximum improvement at 35.04%. The above results demonstrated that our proposed method could significantly improve the sorting performance with low computation cost and good compatibility by leveraging the multi-frequency composite waveform shapes.

Thioesterases play an essential role in the metabolism of fatty acids since they are considered one of the key enzymes to change the total amount and composition of fatty acid in an organism’s cells. Acyl-coenzyme A thioesterase 8 (ACOT8) exhibits substrate specificity mainly for short- to long-chain acyl-CoA. To identify and characterize the ACOT8 enzyme’s superfamily in Mucor circinelloides, three genes were characterized and homologously expressed in M. circinelloides WJ11 which has been used as a model organism to investigate the mechanism of lipid accumulation. Multiple sequence alignment showed that McACOT8s had significant conserved motifs in the ACOT8 family. Experimental data indicated that the biomass of the three recombinant strains (McACOT8a, McACOT8b and McACOT8c) was slightly lower than that of the control strain Mc2075, but the total fatty acid (TFA) content was significantly increased by 30.3, 21.5 and 23.9%, respectively, and the free fatty acid production increased from 12.9% (control strain) to 19.2, 25.2 and 26.2% (recombinant types), respectively, with a maximum increase of 103.1% in McACOT8c. The three strains did not show any significant improvement in fatty acid composition compared to the control strain. However, in terms of fatty acid composition of free fatty acid, McACOT8b and McACOT8c contained γ-linolenic acid (C18:3), which was not detected in the control strain or in McACOT8a, indicating that ACOT8b and ACOT8c had substrate specificity for C18:3. These results displayed that ACOT8 can increase TFA accumulation and that it may be an important target of genetic manipulation for microbial oil production.

As green solvents, ionic liquids (ILs) are quite suitable for the absorption of volatile organic compounds (VOCs) such as benzene and its homologues. However, solvent selection is the key to the VOC absorption process. In the present study, a rapid solvent screening tool, Conductor-like Screening Model for Real Solvents (COSMO-RS), was used to predict the solubility of toluene in 816 ILs. The effects of four structure characters, namely, the type and alkyl chain length of the cations and anions on the solubility of toluene were discussed. The following conclusions were drawn from the results: (1) ILs with pyrrolidinium-based cations showed better solubility than pyridinium- and imidazolium-based ones. (2) The solubility of toluene in PF6-based ILs increased with the increasing alkyl chain length, while its solubility in Ac-based ILs exhibited the opposite trend. (3) Toluene showed greater solubility in Cl-based ILs than those based on other anions. (4) The solubility of toluene increased with the anion alkyl chain length. Ac-based ILs were chosen as the most promising potential solvents, and further studied to determine the relationship between various interaction energy parameters and toluene solubility. The results showed that the misfit energy played a dominant role during the absorption process. Furthermore, several ILs were selected for experimental verification of the predicted solubility behavior using liquid and gaseous toluene. The results demonstrated that COSMO-RS could be used to semi-quantitatively and qualitatively predict the solubility of toluene, and this model had promising prospects in screening ILs for VOCs absorption. In summary, this study provided a fundamental basis and practical data for the control and treatment of VOCs.

ABSTRACT Klebsiella pneumoniae (K. pneumoniae) is one of the most common pathogens causing nosocomial infection. A rapid, accurate, and convenient detection method is required for early diagnosis and directed therapy of K. pneumoniae infection. CRISPR-top (CRISPR-mediated testing in one pot) is a LAMP-CRISPR-based nucleic acid detection platform, which integrates target preamplification with CRISPR/Cas12b-based detection into a one-pot reaction mixture, performed at a constant temperature. In this study, we established the K. pneumoniae CRISPR-top assay to precisely identify K. pneumoniae at 56°C within 60 min. The reaction mixture with 0.53 μM (each) FIP and BIP, 0.27 μM LF, 0.13 μM (each) F3 and B3, and 2 μM ssDNA fluorescence probe was determined as the optimal reaction system of our assay. The limit of detection of this assay is 1 pg genomic DNA (equivalent to 160 K. pneumoniae cells and 1.6 × 105 CFU/mL for samples) per reaction, which is 10-fold more sensitive than LAMP. Up to 105 strains composed of K. pneumoniae clinical isolates and non-K. pneumoniae strains were correctly identified by our assay. A total of 58 sputum samples collected from patients with respiratory symptoms were used to evaluate the diagnostic performance of the K. pneumoniae CRISPR-top assay. As a result, the K. pneumoniae CRISPR-top assay yielded 100% (33/33) specificity and 96% (24/25) sensitivity, as well as a positive predictive value of 100% (24/24) and a negative predictive value of 97.1% (33/34), which were all higher than LAMP detection. In conclusion, the K. pneumoniae CRISPR-top assay developed in this study is a simple, rapid and ultra-specific method to detect K. pneumoniae. IMPORTANCE Klebsiella pneumoniae is a significant threat to global health. At present, the methods of K. pneumoniae detection are culture-based and instrument-dependent and are not suitable for rapid diagnostic. This study reports K. pneumoniae CRISPR-top assay, which can precisely identify K. pneumoniae using nucleic acids of pure cultures or clinical samples in one pot with one fluid-handling step. The K. pneumoniae CRISPR-top reaction can be completed within 60 min at a constant temperature, thus specific instruments are not required. Our results show that CRISPR-top assay yields enormous advantages compared with LAMP detection. The K. pneumoniae CRISPR-top assay can be a high-efficiency alternative tool for rapid and accurate diagnosis of K. pneumoniae infection, especially in resource-limited settings.

Oncolytic viruses have been emerging as a promising therapeutic option for cancer patients, including lung cancer. Orf virus (ORFV), a DNA parapoxvirus, can infect its natural ungulate hosts and transmit into humans. Moreover, the ORFV has advantages of low toxicity, high targeted, self-amplification and can induce potent Th1-like immunity. This study explored the therapeutic potential of ORFV infection for human lung cancer therapy and investigated the molecular mechanisms. We used a previously described ORFV NA1/11 strain and tested the oncolysis of ORFV NA1/11 in two lines of lung cancer cells in vitro and in vivo. Treatment of both cell lines with ORFV NA1/11 resulted in a decrease in cell viability by inducing cell cycle arrest in G2/M phase, suppressing cyclin B1 expression and increasing their apoptosis in a caspase-dependent manner. The ORFV NA1/11-infected lung cancer cells were highly immunogenic. Evidently, ORFV NA1/11 infection of lung cancer cells induced oncolysis of tumor cells to release danger-associated molecular patterns, and promoted dendritic cell maturation, and CD8 T cell infiltration in the tumors by enhancing CXCL16 secretion. These findings may help to understand the molecular mechanisms of ORFV oncolysis and aid in the development of novel therapies for lung cancer.

ObjectiveWe aimed to investigate the cost-effectiveness of nivolumab plus chemotherapy and nivolumab plus ipilimumab versus chemotherapy in the first-line treatment for advanced esophageal squamous-cell carcinoma (ESCC) patients from a healthcare system perspective in China.MethodsOn the basis of the CheckMate 648 trial, a partitioned survival model was constructed to estimate economic costs and health outcomes among overall and PD-L1-positive advanced ESCC patients over a 10-year lifetime horizon. The health-related costs and utilities were obtained from the local charges and published literature. The lifetime costs, life-years, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) were measured. One-way and probabilistic sensitivity analyses (PSA) were performed to assess the robustness of the model.ResultsIn the base-case analysis, in overall and PD-L1-positive advanced ESCC patients, the ICERs were $415,163.81/QALY and $216,628.00/QALY for nivolumab plus chemotherapy, and$430,704.11/QALY and $185,483.94/QALY for nivolumab plus ipilimumab, respectively, compared with chemotherapy. One-way sensitivity analyses revealed that patients’ weight was the most influential parameter on ICER. The PSA demonstrated that the probability of nivolumab combination therapy being cost-effective was 0% over chemotherapy at the current price and willingness-to-pay threshold ($38,351.20/QALY). When the price of nivolumab and ipilimumab decreased 80%, the cost-effective probability of nivolumab plus ipilimumab increased to 40.44% and 86.38% in overall and PD-L1-positive advanced ESCC patients, respectively.ConclusionNivolumab combination therapy could improve survival time and health benefits over chemotherapy for advanced ESCC patients, but it is unlikely to be a cost-effective treatment option in China.

An experiment was conducted to investigate the influences of supplemental lysophospholipids (LPL) on the growth performance, nutrient digestibility, and fecal bacterial profile, and short-chain fatty acids (SCFAs) of beef cattle. Thirty-six Angus beef cattle [565 ± 10.25 kg body weight (BW)] were grouped by BW and age, and randomly allocated to 1 of 3 treatment groups: (1) control (CON, basal diet); (2) LLPL [CON supplemented with 0.5 g/kg LPL, dry matter (DM) basis]; and (3) HLPL (CON supplemented with 0.75 g/kg, DM basis). The Angus cattle were fed a total mixed ration that consisted of 25% roughage and 75% concentrate (dry matter [DM] basis). The results reveal that LPL inclusion linearly increased the average daily gain (P = 0.02) and the feed efficiency (ADG/feed intake, P = 0.02), while quadratically increasing the final weight (P = 0.02) of the beef cattle. Compared with CON, the total tract digestibilities of DM (P < 0.01), ether extract (P = 0.04) and crude protein (P < 0.01) were increased with LPL supplementation. At the phylum-level, the relative abundance of Firmicutes (P = 0.05) and ratio of Firmicutes: Bacteroidetes (P = 0.04) were linearly increased, while the relative abundances of Bacteroidetes (P = 0.04) and Proteobacteria (P < 0.01) were linearly decreased with increasing LPL inclusion. At the genus-level, the relative abundances of Clostridium (P < 0.01) and Roseburia (P < 0.01) were quadratically increased, and the relative abundances of Ruminococcus was linearly increased (P < 0.01) with LPL supplementation. Additionally, increasing the dose of LPL in diets linearly increased the molar proportion of butyrate (P < 0.01) and total SCFAs (P = 0.01) concentrations. A conclusion was drawn that, as a promising feed additive, LPL promoted growth performance and nutrient digestibility, which may be associated with the change of fecal microbiome and SCFAs.

The dents and cracks of cabbage caused by mechanical damage during transportation have a direct impact on both commercial value and storage time. In this study, a method for surface defect detection of cabbage is proposed based on the curvature feature of the 3D point cloud. First, the red-green-blue (RGB) images and depth images are collected using a RealSense-D455 depth camera for 3D point cloud reconstruction. Then, the region of interest (ROI) is extracted by statistical filtering and Euclidean clustering segmentation algorithm, and the 3D point cloud of cabbage is segmented from background noise. Then, the curvature features of the 3D point cloud are calculated using the estimated normal vector based on the least square plane fitting method. Finally, the curvature threshold is determined according to the curvature characteristic parameters, and the surface defect type and area can be detected. The flat-headed cabbage and round-headed cabbage are selected to test the surface damage of dents and cracks. The test results show that the average detection accuracy of this proposed method is 96.25%, in which, the average detection accuracy of dents is 93.3% and the average detection accuracy of cracks is 96.67%, suggesting high detection accuracy and good adaptability for various cabbages. This study provides important technical support for automatic and non-destructive detection of cabbage surface defects.

Chen et al. describe a rational design of subtilisin mutants that degrade active RAS by cleaving a conserved sequence in switch 2. They further modified the active site to be dependent on a cofactor to generate high target specificity. Proteases engineered to cleave this region degraded RAS in vitro and in cells with a promise of adaptability for other target proteins too.

The inclusion of fluorine motifs in drugs and drug delivery systems is an established tool for modulating their biological potency. Fluorination can improve drug specificity or boost the vehicle’s ability to cross cellular membranes. However, the approach has yet to be applied to vaccine adjuvants. Herein, the synthesis of fluorinated bioisostere of a clinical stage immunoadjuvant—poly[di(carboxylatophenoxy)phosphazene], PCPP—is reported. The structure of water-soluble fluoropolymer—PCPP-F, which contains two fluorine atoms per repeat unit—was confirmed using 1H, 31P and 19F NMR, and its molecular mass and molecular dimensions were determined using size-exclusion chromatography and dynamic light scattering. Insertion of fluorine atoms in the polymer side group resulted in an improved solubility in acidic solutions and faster hydrolytic degradation rate, while the ability to self-assemble with an antigenic protein, lysozyme—an important feature of polyphosphazene vaccine adjuvants—was preserved. In vivo assessment of PCPP-F demonstrated its greater ability to induce antibody responses to Hepatitis C virus antigen when compared to its non-fluorinated counterpart. Taken together, the superior immunoadjuvant activity of PCPP-F, along with its improved formulation characteristics, demonstrate advantages of the fluorination approach for the development of this family of macromolecular vaccine adjuvants.

Background: Non-obstructive azoospermia (NOA) affects nearly 1% of men; however, the landscape of the causative genes is largely unknown.Objective: To explore the genetic etiology which is the fundamental cause of NOA, a prospective case-control study and parental–proband trio linkage analysis were performed.Materials: A total of 133 patients with clinicopathological NOA and 343 fertile controls were recruited from a single large academic fertility center located in Northeast China; in addition, eleven trio families were available and enrolled.Results: Whole exome sequencing-based rare variant association study between the cases and controls was performed using the gene burden association testing. Linkage analysis on the trio families was also interrogated. In total, 648 genes were identified to be associated with NOA (three of which were previously reported), out of which six novel genes were found further associated based on the linkage analysis in the trio families, and involved in the meiosis-related network.Discussion and Conclusion: The six currently identified genes potentially account for a fraction (3.76%, 5 out of 133 patients) of the heritability of unidentified NOA, and combining the six novel genes and the three previously reported genes together would potentially account for an overall 6.77% (9 out of 133 patients) heritability of unidentified NOA in this study.

Abstract Background Beckwith-Wiedemann syndrome (BWS) is a genetic overgrowth disorder with variable clinical features and cancer predisposition. In this study, we aim to characterize the clinical features and molecular defects of BWS patients in China. Methods Thirty-one patients with clinical suspicion of BWS were retrospectively recruited to the study from Shanghai Children’s Hospital between January 2014 and December 2017. Clinical data, including demographics, clinical features, and molecular testing results were extracted and systematically analyzed. Results Twenty-one patients with a BWS score ≥ 4 (6, IQR 4, 7) were clinically diagnosed with BWS, and 10 children with a BWS score ≥ 2 and

Background. Endotracheal intubation is a widely used treatment. Excessive pressure of the endotracheal tube cuff leads to a series of complications. Here, we used tracheae of sheep to analyze the relationship between the air injection volume and endotracheal tube cuff pressure so as to guide the doctors and nurses in controlling the pressure of the endotracheal tube cuff during clinical work and minimise the risk of complications. Materials and Methods. Forty sheep tracheae were utilised and were divided into five groups according to their diameters. Different sizes of endotracheal tubes were inserted into each trachea, and the cuff pressure with the increase of air injection volume was recorded. The formulas that reflect the relationship between air injection volume and cuff pressure were obtained. Then, sheep tracheae were randomly selected; different types of tubes were inserted, and the stipulated volume of air was injected. The actual pressure was measured and compared with the pressure predicted from the formulas. Statistical analysis was conducted to verify whether the formulas obtained from the first part of the experiment were in accordance with the expert evaluation table, which consists of opinions of several experts. Results. After obtaining 15 formulas, we collected the differences between the theoretical cuff pressure and the actual cuff pressure that satisfied the expert evaluation. Relying on the formulas, the medical turntable was obtained, which is a tool that consists of two round cards with data on them. The top card has a notch. The two cards are stacked together, and as the top card rotates, the data on the bottom card can be easily seen in a one-to-one relationship. Conclusion. The formulas are capable of showing the relationship between the cuff air injection volume and pressure of endotracheal tube cuff. The medical turntable can estimate the air injection volume to ensure that the pressure stays in an acceptable range.