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The global monkeypox virus (MPXV) outbreak in 2022 emphasizes the urgent need for effective and accessible new-generation vaccines and neutralizing antibodies. Herein, we identified MPXV-neutralizing antibodies using high-throughput single-cell RNA and V(D)J sequencing of antigen-sorted B cells from patients with convalescent monkeypox. IgG1-expressing B cells were obtained from 34 paired heavy- and light-chain B cell receptor sequences. Subsequently, three potent neutralizing antibodies, MV127, MV128, and MV129, were identified and reacted with the MPXV A35 protein. Among these, MV129, which has a half-maximal inhibitory concentration of 2.68μg/mL against authentic MPXV, was considered to be the putative candidates for MPXV neutralization in response to monkeypox disease.

Lung cancer is the most common in incidence and mortality worldwide. With the development of next generation sequencing (NGS) detection technology, more and more patients with rare anaplastic lymphoma kinase (ALK) fusion mutations were detected. A case of advanced lung adenocarcinoma with rare COX7A2L-ALK (C2:A20) fusion detected by NGS was reported in Peking Union Medical College Hospital, and all cases with rare ALK fusion mutations were searched from medical datebase from January 1, 2014 to March 31, 2021, to investigate the treatment of rare ALK fusion mutations with ALK inhibitors. The best response of the patient was assessed as partial response (PR) with Ceritinib treatment. By literature review, 22 cases of rare ALK fusion were reported in 19 articles. Combined with this case, 23 cases were analyzed. The objective response rate (ORR) was 82.6% (19/23) and disease control rate (DCR) was 95.7% (22/23) for rare ALK fusions patients treated with ALK inhibitors. Lung adenocarcinoma patients with rare ALK fusion could benefit from ALK inhibitors.

Abstract Background Long intergenic non-coding RNA 326 (LINC00326) modulates hepatocarcinogenic lipid metabolism. However, the ability of LINC00326 to modulate the highly aggressive non-small cell lung carcinoma (NSCLC) is unknown. Here, LINC00326 in NSCLC was investigated, together with its effects on tumor malignancy and the underlying mechanisms of action. Methods LINC00326 levels in tumor tissues and cell lines were measured by Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and RNA fluorescence in situ hybridization (FISH). Proliferation and apoptosis were assessed in cell lines by Cell Counting Kit-8 (CCK-8), EdU staining assays and flow cytometry, respectively, and tumor growth was measured in mouse models. Possible microRNA targets of LINC00326 were predicted by bioinformatics and verified by RNA pull-down and immunoprecipitation and luciferase reporter assays. Western blotting was used to evaluate the expression of Wnt/β-catenin-associated proteins. Results LINC00326 was downregulated in tumor tissues and cell lines. Knockdown of LINC00326 stimulated NSCLC cell proliferation and suppressed apoptosis in vitro, as well as enhancing xenograft tumor growth. LINC00326 sponged miR-657, and dickkopf WNT signaling pathway inhibitor 2 (DKK2) was found to be directly targeted by miR-657, with LINC00326 positively regulating its expression through sponging miR-657. The actions of LINC00326 knockdown on proliferation and apoptosis were reversed by stimulation of the miR-657/DKK2 axis. Furthermore, overexpression of miR-657 mitigated DKK2 inhibition on Wnt/β-catenin signaling. Conclusions LINC00326/miR-657/DKK2 axis signaling blocked tumor-associated functions in NSCLC cells through the targeting Wnt/β-catenin pathway. This suggests that this pathway could be a target for NSCLC treatment.

Precocious puberty in children is one of the common endocrine diseases in paediatrics. Epidemiological surveys have shown that the number of children with precocious puberty has significantly increased globally. Precocious puberty negatively affects the physical and mental health of children and may increase the risk of hypertension, diabetes, obesity and infertility in adulthood. Therefore, the initiating factors of adolescence have become core issues in the study of sexual development in children. Owing to developments in molecular genetics, many studies have been able to show that precocious puberty is mostly resulted in autosomal inheritance. For instance, makorin ring finger protein 3 gene (MKRN3) may be implicated in familial CPP. Gonadotropin-releasing hormone agonist (GnRHa) is the gold standard for treatment, but its safety still requires long-term evaluation and management. Traditional medicinal plants have been used in clinical treatments and in exploring novel treatment methods. From the collected datas, in Asia, traditional Chinese medicine treatment is based on the principles of nourishing Yin, lowering fire and draining fire from the liver to help precocious children and alleviate or delay the onset of precocious puberty by medicinal plants such as Anemarrhena asphodeloides Bge., Phellodendron amurense Rupr., Rehmannia glutinosa and Poria cocos Wolf. They play an important role in exploring the pharmacological mechanisms of precocious puberty treatment effects and drug development. Therefore, by elucidating the occurrence and development of precocious puberty, this review provides novel and valuable insights of paediatric endocrine therapy accessing the published researches on the effectiveness of traditional herbal medicine in the treatment of precocious puberty and its therapeutic mechanisms.

Abstract Aims/Introduction Type 1 diabetes mellitus is a T cell‐mediated autoimmune disease. However, the determination of the autoimmune status of type 1 diabetes mellitus relies on islet autoantibodies (Abs), as T‐cell assay is not routinely carried out. This study aimed to investigate the diagnostic value of combined assay of islet antigen‐specific T cells and Abs in type 1 diabetes mellitus patients. Materials and Methods A total of 54 patients with type 1 diabetes mellitus and 56 healthy controls were enrolled. Abs against glutamic acid decarboxylase (GAD), islet antigen‐2 and zinc transporter 8 were detected by radioligand assay. Interferon‐γ‐secreting T cells responding to glutamic acid decarboxylase 65 and C‐peptide (CP) were measured by enzyme‐linked immunospot. Results The positive rate for T‐cell responses was significantly higher in patients with type 1 diabetes mellitus than that in controls (P

Tongcheng (TC) pigs, distinguished by their superior meat quality, are a Chinese indigenous pig breed. Recently, the genetic resources of TC pigs are under tremendous threat due to the introduction of cosmopolitan pig breeds and African swine fever disease. To promote their management and conservation, the present study assessed genetic diversity and population structure of TC pigs using single nucleotide polymorphism (SNP) markers. A total of 26, 999 SNPs were screened from 51, 315 SNPs in 68 TC pigs. The multi-dimensional scaling (MDS) analysis and neighbor-joining tree revealed that all 68 pigs were from a purebred population. The effective population size decreased over time, and it was 96 prior to generation 20. Both linkage disequilibrium (LD) and neutrality test indicated a low selection of TC pigs with average LD value of 0.15 ± 0.23. Genetic diversity results exhibited a minor allele frequency (MAF) of 0.23, observed heterozygosity (HO) of 0.32, expected heterozygosity (He) of 0.31, and nucleotide diversity (Pi) of 0.31. All these parameters indicated a remarkably high genetic diversity of TC pigs. Additionally, 184 runs of homozygosity (ROH) segments were detected from the whole genome of TC pigs with an average ROH length of 23.71Mb, ranging from 11.26Mb to 69.02 Mb. The highest ROH coverage was found on chromosome 1 (10.12%), while the lowest was on chromosome 18 (1.49%). The average inbreeding coefficients based on ROH (FROH) was 0.04%. Fourteen ROH islands containing 240 genes were detected on 9 different autosomes. Some of these 240 genes were overlapped with the genes related to biological processes such as immune function, reproduction, muscular development, and fat deposition, including FFAR2, FFAR4, MAPK8, NPY5R, KISS1, and these genes might be associated with such traits as meat quality and disease resistance in TC pigs. Taken together, population structure and genetic diversity results suggested that the TC pig represented a valuable genetic resource. However, TC pig breed conservation program remains to be further optimized to ensure adequate genetic diversity and avoid inbreeding depression. Our findings provide theoretical basis for formulating management and conservation strategies for TC pigs.

ObjectivePrevious studies have shown that there are significant regional and gender differences in the association between the phenotype of short stature and diabetes mellitus (DM). The purpose of this study was to investigate the gender difference between the phenotype of short stature and the risk of DM in the Chinese population.MethodsThe sample included 116,661 adults from 32 locations of 11 cities in China, of which the average height of men and women was 171.65 and 160.06 cm, respectively. Investigators retrospectively reviewed annual physical examination results for follow-up observations and set confirmed DM events as the outcome of interest. Multivariate Cox regression, restricted cubic spline, and piecewise regression models were used to check the association between height and DM risk.ResultsDuring an average observation period of 3.1 years, there were 2,681 of 116,661 participants who developed new-onset DM, with a male to female ratio of 2.4 to 1. After full adjustment for confounders, we confirmed that there was a significant negative correlation between height and DM risk in Chinese women (HR per 10 cm increase: 0.85, 95% CI: 0.74–0.98), but not in men (HR per 10 cm increase: 1.16, 95% CI: 0.98–1.14). Additionally, through restricted cubic spline and piecewise regression analysis, we determined that the height of 157–158 cm may be the critical point for short stature used to assess the risk of DM in Chinese women.ConclusionsIn the Chinese population, female short stature phenotype is related to increased DM risk, among which 157–158 cm may be the saturation effect point of female short stature for predicting DM risk.

Abstract Red blood cells (RBCs) stressed by high temperature are similar to senescent or damaged RBCs in pathological conditions. RBCs can be efficiently labelled with 18F-fluorodeoxyglucose (FDG). The aim of this study was to assess stressed RBCs erythrophagocytosis and organ distribution in vivo with the application of 18F-FDG PET/CT. RBCs were induced under high temperature (48 °C) to prepare stressed RBCs. Fluorescence-activated cell sorting (FACS) was used to analyse reactive oxygen species (ROS) generation, intracellular Ca2+ concentration and membrane phosphatidylserine (PS) externalization of RBCs. 18F-FDG was used to label RBCs and assess the erythrophagocytosis. Finally, 18F-FDG PET/CT was applied to reveal and measure the organ distribution of stressed RBCs in mice. Compared with untreated RBCs, stressed RBCs decreased in cell volume and increased in ROS level, intracellular Ca2+ concentration, and PS exposure. RBCs could be labelled by 18F-FDG. Stressed RBCs tended to be phagocytosed by macrophages via assessment of FACS and radioactivity. 18F-FDG PET/CT imaging showed that stressed RBCs were mainly trapped in spleen, while untreated RBCs remained in circulation system. Thus, stressed RBCs can be effectively labelled by 18F-FDG and tend to be trapped in spleen of mice as assessed by PET/CT.

Immune checkpoint inhibitors (ICIs) have made great progress in the field of tumors and have become a promising direction of tumor treatment. With advancements in genomics and bioinformatics technology, it is possible to individually analyze the neoantigens produced by somatic mutations of each patient. Neoantigen load (NAL), a promising biomarker for predicting the efficacy of ICIs, has been extensively studied. This article reviews the research progress on NAL as a biomarker for predicting the anti-tumor effects of ICI. First, we provide a definition of NAL, and summarize the detection methods, and their relationship with tumor mutation burden. In addition, we describe the common genomic sources of NAL. Finally, we review the predictive value of NAL as a tumor prediction marker based on various clinical studies. This review focuses on the predictive ability of NAL’s ICI efficacy against tumors. In melanoma, lung cancer, and gynecological tumors, NAL can be considered a predictor of treatment efficacy. In contrast, the use of NAL for urinary system and liver tumors requires further research. When NAL alone is insufficient to predict efficacy, its combination with other indicators can improve prediction efficiency. Evaluating the response of predictive biomarkers before the treatment initiation is essential for guiding the clinical treatment of cancer. The predictive power of NAL has great potential; however, it needs to be based on more accurate sequencing platforms and technologies.

N6-methyladenine (6mA) DNA modification is a dynamic epigenetic mark in Drosophila embryos, but how 6mA is decoded is unclear. Here, the authors show that the protein Jumu binds 6mA-marked DNA to regulate the maternal-to-zygotic transition, partly through regulation the expression of the 6mA marked pioneer factor zelda.

Targeting histone acetylation modulators (HAMPs) is a promising avenue of drug discovery in cancer research. Here, the authors integrate multi-dimensional genomic profiles to systematically investigate recurrent genomic alterations in HAMPs, identifying potential therapeutic targets for precision epigenetic treatment.

Abstract Background Increasing evidence has demonstrated that mesenchymal stem cells (MSCs) play a role in the construction of tumor microenvironments. Co-culture between tumor cells and MSCs provides an easy and useful platform for mimicking tumor microenvironments and identifying the important members involved in tumor progress. The long non-coding RNAs (lncRNAs) have been shown to regulate different tumorigenic processes. In this study, we aimed to examine functional lncRNA deregulations associated with breast cancer malignancy instigated by MSC-MCF-7 co-culture. Methods The microarrays were used to profile the expression changes of lncRNAs in MCF-7 cells during epithelial-mesenchymal transition (EMT) induced by co-culture with MSCs. We found that an intergenic lncRNA KB-1732A1.1 (termed LincK, partly overlapped with GASL1) was significantly elevated. To investigate the biological function of LincK, the expression of EMT markers, cell migration, invasion, proliferation, and colony formation were evaluated in vitro and xenograft assay in nude mice were performed in vivo. Furthermore, we detected LincK expression in clinical samples using RNAscope® technology and verified aberrant expression of LincK in breast cancer data sets from The Cancer Genome Atlas (TCGA) by bioinformatic analysis. The underlying mechanisms of LincK were investigated using mRNA microarray analyses, Western blot, RNA pull down, and RNA immunoprecipitation. Results LincK induced an EMT progress in breast cancer cells (BCC) MCF-7, MDA-MB-453, and MDA-MB-231. The depletion of LincK decreased the growth, migration, and invasion in BCC, whereas the overexpression of LincK exerted the opposite effects. Moreover, knockdown of LincK repressed tumorigenesis, and ectopic expression of LincK promoted tumor growth in MCF-7 xenograft model. LincK ablation in MDA-MB-231 cells dramatically impaired lung metastasis when incubated intravenously into nude mice. Further, LincK was frequently elevated in breast cancer compared with normal breast tissue in clinical samples. Mechanistically, LincK may share common miRNA response elements with PBK and ZEB1 and regulate the effects of miR-200 s. Conclusion LincK plays a significant role in regulating EMT and tumor growth and could be a potential therapeutic target in breast cancer.

GFRP bars will be damaged due to a series of irreversible hygroscopic chemical reactions under humid and hot curing environmental conditions. The multiple factors related to the moisture absorption model were established through the moisture absorption test of GFRP bars embedded in steam-curing concrete, which considered different curing temperatures, different thicknesses of the protective layer, and different diameters of GFRP bars. Semi-reliability probability damage assessment of GFRP bars embedded in steam-curing concrete was described by introducing the reliability and stochastic theory. Subsequently, the tensile test of GFRP bars was carried out to verify the feasibility of the damage assessment. The results showed that the moisture absorption curves of GFRP bars were basically in line with Fick’s law. In addition, the influences of the curing temperature, the thickness of the protective layer, and the diameter on moisture absorption performance were presented. The semi-reliability probability damage assessment model of GFRP bars embedded in steam-curing concrete beams adequately considered the multiple factors related to moisture absorption and the uncertainty and randomness of the influencing factors during the process of moisture absorption.

Summary: Recurrent copy-number alterations, mutations, and transcript fusions of the genes encoding CDKs/cyclins are characterized in >10,000 tumors. Genomic alterations of CDKs/cyclins are dominantly driven by copy number aberrations. In contrast to cell-cycle-related CDKs/cyclins, which are globally amplified, transcriptional CDKs/cyclins recurrently lose copy numbers across cancers. Although mutations and transcript fusions are relatively rare events, CDK12 exhibits recurrent mutations in multiple cancers. Among the transcriptional CDKs, CDK7 and CDK12 show the most significant copy number loss and mutation, respectively. Their genomic alterations are correlated with increased sensitivities to DNA-damaging drugs. Inhibition of CDK7 preferentially represses the expression of genes in the DNA-damage-repair pathways and impairs the activity of homologous recombination. Low-dose CDK7 inhibitor treatment sensitizes cancer cells to PARP inhibitor-induced DNA damage and cell death. Our analysis provides genomic information for identification and prioritization of drug targets for CDKs and reveals rationales for treatment strategies.

Men of predominantly African Ancestry (AA) have higher prostate cancer (CaP) incidence and worse survival than men of predominantly European Ancestry (EA). While socioeconomic factors drive this disparity, genomic factors may also contribute to differences in the incidence and mortality rates. To compare the prevalence of prostate tumor genomic alterations and transcriptomic profiles by patient genetic ancestry, we evaluated genomic profiles from The Cancer Genome Atlas (TCGA) CaP cohort (n = 498). Patient global and local genetic ancestry were estimated by computational algorithms using genotyping data; 414 (83.1%) were EA, 61 (12.2%) were AA, 11 (2.2%) were East Asian Ancestry (EAA), 10 (2.0%) were Native American (NA), and 2 (0.4%) were other ancestry. Genetic ancestry was highly concordant with self-identified race/ethnicity. Subsequent analyses were limited to 61 AA and 414 EA cases. Significant differences were observed by ancestry in the frequency of SPOP mutations (20.3% AA vs. 10.0% EA; p = 5.6×10-03), TMPRSS2-ERG fusions (29.3% AA vs. 39.6% EA; p = 4.4×10-02), and PTEN deletions/losses (11.5% AA vs. 30.2% EA; p = 3.5×10-03). Differentially expressed genes (DEGs) between AAs and EAs showed significant enrichment for prostate eQTL target genes (p = 8.09×10-48). Enrichment of highly expressed DEGs for immune-related pathways was observed in AAs, and for PTEN/PI3K signaling in EAs. Nearly one-third of DEGs (31.3%) were long non-coding RNAs (DE-lncRNAs). The proportion of DE-lncRNAs with higher expression in AAs greatly exceeded that with lower expression in AAs (p = 1.2×10-125). Both ChIP-seq and RNA-seq data suggested a stronger regulatory role for AR signaling pathways in DE-lncRNAs vs. non-DE-lncRNAs. CaP-related oncogenic lncRNAs, such as PVT1, PCAT1 and PCAT10/CTBP1-AS, were found to be more highly expressed in AAs. We report substantial heterogeneity in the prostate tumor genome and transcriptome between EA and AA. These differences may be biological contributors to racial disparities in CaP incidence and outcomes.

At present, the research on detection of lung cancer includes the sample image segmentation, extracting visual features of lung cancer and generating the classification model by training learning, then according to the classification model generated to classify the inspected images. But this kind of method usually needs a large amount of calculation and speed is slow. In order to find the region of interest as soon as possible and improve the detection speed, this paper attempts to introduce the current popular Itti visual attention model into the lung cancer detection. However, because medical images usually have low contrast, the Itti method is not directly applied to extract the region of interest in medical image. Therefore the selective visual attention mechanism combined with shape feature of target is proposed. Firstly some primary features are chosen, such as gray scale, direction, corner point and edge to generate saliency map, and then the significant regions are segmented and judged. Compared to popular lung cancer detection method, this method can improve the detection rate of suspected lung cancer and has great significance for the early detection, early diagnosis and treatment of lung cancer.

Introduction. Small noncoding RNAs have important regulatory functions in different cell pathways. It is believed that most of them mainly play role in gene post-transcriptional regulation in the cytoplasm. Recent evidence suggests miRNA and siRNA activity in the nucleus. Here, we show distinct genome-wide sub-cellular localization distribution profiles of small noncoding RNAs in human breast cancer cells. Methods. We separated breast cancer cell nuclei from cytoplasm, and identified small RNA sequences using a high-throughput sequencing platform. To determine the relationship between miRNA sub-cellular distribution and cancer progression, we used microarray analysis to examine the miRNA expression levels in nucleus and cytoplasm of three human cell lines, one normal breast cell line and two breast cancer cell lines. Logistic regression and SVM were used for further analysis. Results. The sub-cellular distribution of small noncoding RNAs shows that numerous miRNAs and their isoforms (isomiR) not only locate to the cytoplasm but also appeare in the nucleus. Subsequent microarray analyses indicated that the miRNA nuclear-cytoplasmic-ratio is a significant characteristic of different cancer cell lines. Conclusions. Our results indicate that the sub-cellular distribution is important for miRNA function, and that the characterization of the small RNAs sub-cellular localizome may contribute to cancer research and diagnosis.

Aspergillus flavus is notorious for contaminating food with its secondary metabolite—highly carcinogenic aflatoxins. In this study, we found that exogenous nitric oxide (NO) donor could influence aflatoxin production in A. flavus. Flavohemoglobins (FHbs) are vital functional units in maintaining nitric oxide (NO) homeostasis and are crucial for normal cell function. To investigate whether endogenous NO changes affect aflatoxin biosynthesis, two FHbs, FHbA and FHbB, were identified in this study. FHbA was confirmed as the main protein to maintain NO homeostasis, as its absence led to a significant increase in intracellular NO levels and heightened sensitivity to SNP stress. Dramatically, FHbA deletion retarded aflatoxin production. In addition, FHbA played important roles in mycelial growth, conidial germination, and sclerotial development, and response to oxidative stress and high-temperature stress. Although FHbB did not significantly impact the cellular NO level, it was also involved in sclerotial development, aflatoxin synthesis, and stress response. Our findings provide a new perspective for studying the regulatory mechanism of the development and secondary mechanism in A. flavus. [ABSTRACT FROM AUTHOR]