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Abstract Background The hippocampus, with its complex subfields, is linked to numerous neuropsychiatric traits. While most research has focused on its global structure or a few specific subfields, a comprehensive analysis of hippocampal substructures and their genetic correlations across a wide range of neuropsychiatric traits remains underexplored. Given the hippocampus’s high heritability, considering hippocampal and subfield volumes (HASV) as endophenotypes for neuropsychiatric conditions is essential. Methods We analyzed MRI-derived volumetric data of hippocampal and subfield structures from 41,525 UK Biobank participants. Genome-wide association studies (GWAS) on 24 HASV traits were conducted, followed by genetic correlation, overlap, and Mendelian randomization (MR) analyses with 10 common neuropsychiatric traits. Polygenic risk scores (PRS) based on HASV traits were also evaluated for predicting these traits. Results Our analysis identified 352 independent genetic variants surpassing a significance threshold of 2.1 × 10−9 within the 24 HASV traits, located across 93 chromosomal regions. Notably, the regions 12q14.3, 17q21.31, 12q24.22, 6q21, 9q33.1, 6q25.1, and 2q24.2 were found to influence multiple HASVs. Gene set analysis revealed enrichment of neural differentiation and signaling pathways, as well as protein binding and degradation. Of 240 HASV-neuropsychiatric trait pairs, 75 demonstrated significant genetic correlations (P

Satellite remote sensing, characterized by extensive coverage, frequent revisits, and continuous monitoring, provides essential data support for addressing global challenges. Over the past six decades, thousands of Earth observation satellites and sensors have been deployed worldwide. These valuable Earth observation assets are contributed independently by various nations and organizations employing diverse methodologies. This poses a significant challenge in effectively discovering global Earth observation resources and realizing their full potential. In this paper, we describe the development of GEOSatDB, the most complete semantic database of civil Earth observation satellites developed based on a unified ontology model. A similarity matching method is used to integrate satellite information and a prompt strategy is used to extract unstructured sensor information. The resulting semantic database contains 127,949 semantic statements for 2,340 remote sensing satellites and 1,021 observation sensors. The global Earth observation capabilities of 195 countries worldwide have been analyzed in detail, and a concrete use case along with an associated query demonstration is presented. This database provides significant value in effectively facilitating the semantic understanding and sharing of Earth observation resources.

Abstract Non-small cell lung cancer (NSCLC) is among the most prevalent cancers and a leading cause of cancer-related mortality globally. Extracellular vesicles (EVs) derived from NSCLC play a pivotal role in lung cancer progression. Our findings reveal a direct correlation between the abundance of EVs and the transfection efficiencies. Co-culturing two different lung cancer cell lines could enhance EVs formation, cell proliferation, migration and tumorigenicity. mRNA chip and metabolic analyses revealed significant alterations in the FOXO signaling pathway and unsaturated fatty acid metabolism within tumor tissues derived from co-cultured cells. Shotgun lipidomics studies and bioinformatics analyses guided our attention towards 4-Hydroxynonenal (4-HNE) and FOXO4. Elevating 4-HNE or FOXO4 levels could reduce the formation of EVs and impede cell growth and migration. While silencing FOXO4 expression lead to an increase in cell cloning rate and enhanced migration. These findings suggest that regulating the production of 4-HNE and FOXO4 might provide an effective therapeutic approach for the treatment of NSCLC.

BackgroundNano-alumina (nano-Al2O3) is a widely utilized nanomaterial. Its impacts on the environment and biological systems have garnered significant attention. Zebrafish serves as a common model organism in scientific research due to its high homology with the human genome and is extensively used in toxicity studies. ObjectiveTo investigate the developmental toxicity and neurotoxicity of nano-Al2O3 exposure in zebrafish and the corresponding mechanisms of action. MethodZebrafish embryos at 6 h post-fertilization (hpf) were randomly assigned to a control group and five dose groups exposed to nano-Al2O3 at concentrations of 200, 400, 600, 800, and 1000 μg·mL−1, respectively. Thirty embryos were included in each group, and the culture medium was replaced every 24 h until 144 hpf. The hatching rates at 48 and 72 hpf and the cumulative malformation rates up to 144 hpf were calculated. At 144 hpf, a zebrafish behavior analyzer was used to record the movement trajectories of the zebrafish, and the total distance traveled and average speed were analyzed for each group. At 144 hpf, the development of dopaminergic neurons in transgenic zebrafish expressing vmat2: GFP, brain vessels in those expressing vegf: GFP, and central nervous system neurons in those expressing elavl3: EGFP were observed under a fluorescence microscope, and statistical analysis was conducted using Image Pro Plus. Real-time quantitative PCR was employed to detect the expression levels of neuron development-related genes (syn2α, gap43, dat), Lewy body formation-related gene (α-syn), and autophagy-related genes (pink1, parkin) at 144 hpf. ResultsCompared to the control group, the nano-Al2O3 exposed groups exhibited reduced hatching rates at 48 hpf and increased cumulative malformation rates (P

Abstract Background Dysregulation of enhancer transcription occurs in multiple cancers. Enhancer RNAs (eRNAs) are transcribed products from enhancers that play critical roles in transcriptional control. Characterizing the genetic basis of eRNA expression may elucidate the molecular mechanisms underlying cancers. Methods Initially, a comprehensive analysis of eRNA quantitative trait loci (eRNAQTLs) was performed in The Cancer Genome Atlas (TCGA), and functional features were characterized using multi-omics data. To establish the first eRNAQTL profiles for colorectal cancer (CRC) in China, epigenomic data were used to define active enhancers, which were subsequently integrated with transcription and genotyping data from 154 paired CRC samples. Finally, large-scale case-control studies (34,585 cases and 69,544 controls) were conducted along with multipronged experiments to investigate the potential mechanisms by which candidate eRNAQTLs affect CRC risk. Results A total of 300,112 eRNAQTLs were identified across 30 different cancer types, which exert their influence on eRNA transcription by modulating chromatin status, binding affinity to transcription factors and RNA-binding proteins. These eRNAQTLs were found to be significantly enriched in cancer risk loci, explaining a substantial proportion of cancer heritability. Additionally, tumor-specific eRNAQTLs exhibited high responsiveness to the development of cancer. Moreover, the target genes of these eRNAs were associated with dysregulated signaling pathways and immune cell infiltration in cancer, highlighting their potential as therapeutic targets. Furthermore, multiple ethnic population studies have confirmed that an eRNAQTL rs3094296-T variant decreases the risk of CRC in populations from China (OR = 0.91, 95%CI 0.88–0.95, P = 2.92 × 10−7) and Europe (OR = 0.92, 95%CI 0.88–0.95, P = 4.61 × 10−6). Mechanistically, rs3094296 had an allele-specific effect on the transcription of the eRNA ENSR00000155786, which functioned as a transcriptional activator promoting the expression of its target gene SENP7. These two genes synergistically suppressed tumor cell proliferation. Our curated list of variants, genes, and drugs has been made available in CancereRNAQTL ( http://canernaqtl.whu.edu.cn/#/ ) to serve as an informative resource for advancing this field. Conclusion Our findings underscore the significance of eRNAQTLs in transcriptional regulation and disease heritability, pinpointing the potential of eRNA-based therapeutic strategies in cancers.

Early Cenozoic "insectivorans" possess some of the most primitive morphologies among eutherian mammals. Studies of these archaic mammals offer insights into the early diversifications of basal eutherians. Despite such importance, early fossil "insectivorans" from Asia are poorly known due to a scarcity of fossil remains, which often consist only of fragmentary jaws and teeth. Discoveries of remarkably well-preserved fossil "insectivorans", including complete skulls and articulated postcranial skeletons, from the early Eocene Hengyang Basin in south-central Hunan Province, China, offer a rare opportunity to thoroughly study two taxa belonging to different families. Fine-grained red beds from Hengyang Basin preserve extraordinary fossils with morphological structures rarely seen elsewhere. Thin sections of a skull of Hsiangolestes youngiZheng and Huang, 1984, for example, reveal the extremely delicate nasal and maxillary turbinates, which, as far as we are aware, are the first known from fossils of this age. We thus take this opportunity to document in detail the cranial and dental morphology, as well as postcranial skeletons, of the Hengyang "insectivorans.". In this monograph, we describe several complete skulls and serial sections of a skull, as well as many partial skulls, mandibles, and postcranial skeletons of Hsiangolestes youngi, an Asian early Eocene insectivoran-grade mammal. We also report a new species of NaraniusRussell and Dashzeveg, 1986 - N. hengdongensis - an Asian early Eocene cimolestid and describe its well-preserved skulls and mandibles. Hsiangolestes is endemic to Asia. It is currently known only from the earliest Eocene Lingcha Formation, Hengyang Basin, Hunan Province, China. Naranius closely resembles CimolestesMarsh, 1889, the type genus of the family Cimolestidae. It is mainly distributed in Asia and known from the earliest Eocene deposits in the Bumban Member of the Naran Bulak Formation, Nemegt Basin, of Mongolia, and the Lingcha Formation, Hengyang Basin, Hunan Province, China. The only record of Naranius reported outside of Asia is N. americanus from the early Wasatchian Red Hot Local Fauna, Mississippi, United States. Using PAUP and TNT search algorithms, we place these Hengyang taxa within phylogenetic context of other fossil "insectivorans" from the Mesozoic and early Cenozoic of Asia together with some well-known Holarctic taxa. A phylogenetic analysis of 290 cranial and dental characters from 36 fossil and modern insectivoran-grade taxa is presented, focusing on new materials of Hsiangolestes youngi and Naranius hengdongensis. Based on the results of our phylogenetic analyses, we propose that (1) Hsiangolestes, Prosarcodon, Sarcodon, and Sinosinopa, form a monophyletic group, for which we propose the family name Sarcodontidae; (2) the family Cimolestidae should be restricted to Naranius and Cimolestes, which are sister taxa; (3) the systematic position of Naranius americanus is uncertain; and (4) the family Micropternodontidae should be restricted to Micropternodus and its allies in North America.

Abstract Background Unresectable intrahepatic cholangiocarcinoma (iCCA) has a poor prognosis despite treatment with standard combination chemotherapy. We aimed to evaluate the efficacy and safety of radiotherapy in combination with an anti-PD-1 antibody in unresectable iCCA without distant metastases. Methods In this phase II study, patients with histopathologically confirmed unresectable primary or postoperative recurrent iCCA without distant metastases were enrolled. Patients received external radiotherapy with a dose of ≥45 Gy (2-2.5 Gy per fraction), followed by anti-PD-1 immunotherapy (camrelizumab 200 mg once, every 3 weeks) initiated within 7 days after completion of radiotherapy as first-line therapy. The primary endpoint was 1-year progression-free survival (PFS) rate. The secondary end points included safety, objective response rate (ORR), disease control rate (DCR), and overall survival (OS). Results From December 2019 to March 2021, 36 patients completed radiotherapy and at least one cycle of immunotherapy and were included in efficacy and safety analyses. The median follow-up was 19.0 months (IQR 12.0-24.0), and the one-year PFS rate was 44.4% (95% CI, 30.8-64.0). The median PFS was 12.0 months (95% CI, 7.5-not estimable); the median OS was 22.0 months (95% CI, 15.0-not estimable). The ORR was 61.1% and the DCR was 86.1%. Seventeen of 36 (47.2%) patients experienced treatment-related adverse effects (AEs) of any grade. The most common AE was reactive cutaneous capillary endothelial proliferation (25.0%). Five (13.9%) patients experienced grade ≥3 treatment-related AEs, including decreased lymphocyte (5.6%), bullous dermatitis (2.8%), decreased platelet count (2.8%), and deep-vein thrombosis (2.8%). Conclusions External radiotherapy plus camrelizumab, as first-line therapy, met its primary endpoint and showed antitumor activity and low toxicity levels in patients with unresectable iCCA without distant metastases, warranting further investigation. Trial registration NCT03898895. Registered 2 April 2019.

Abstract Introduction Observational studies and clinical trials have supported the association between gut microbiota and psoriatic arthritis. However, the causal link between gut microbiota and psoriatic arthritis is still unclear. Methods A two-sample bi-directional Mendelian randomization analysis was performed using the summary statistics of gut microbiota from the largest available genome-wide association study meta-analysis (n = 13,266) conducted by the MiBioGen consortium. The summary statistics of psoriatic arthritis were extracted directly from the FinnGen consortium, which consists of 3186 psoriatic arthritis patients and 24,086 controls. Sensitivity analyses were conducted to assess the validity of our findings. Enrichment analyses were used to investigate the biofunction and pathways. Results Inverse variance weighted (IVW) estimates suggested that family Rikenellaceae (P = 0.032) and genus Ruminococcaceae UCG011 (P = 0.014) had a detrimental effect on psoriatic arthritis. We also noticed the negative association between the class Methanobacteria (P = 0.032), order Methanobacteriales (P = 0.032), family Methanobacteriaceae (P = 0.032), genus Eubacterium fissicatena group (P = 0.010), genus Methanobrevibacter (P = 0.031), and genus Butyricicoccus (P = 0.041) with psoriatic arthritis. Sensitivity analyses showed that genus Butyricicoccus had pleiotropy and heterogeneity. According to the results of reverse MR analysis, the causal effect of psoriatic arthritis was found on six taxa, respectivelyc family Clostridiaceae1, family Defluviitaleaceae, genus Butyrivibrio, genus Defluviitaleaceae UCG011, genus Clostridium sensu stricto1, and genus Ruminococcaceae UCG011. Conclusion This two-sample bidirectional Mendelian randomization analysis suggested that the gut microbiota had a causal effect on psoriatic arthritis and implied the potential role of probiotics in the management and prevention of psoriatic arthritis.

Abstract Background The diagnosis of primary small intestinal lymphoma (PSIL) is difficult. This study aimed to evaluate the clinical, radiological and endoscopic characteristics of PSIL and provide clue for diagnosis. Methods A total of 30 patients diagnosed with PSIL who underwent double balloon endoscopy (DBE) in the First Affiliated Hospital of Zhejiang University were retrospectively analyzed. Clinical, radiological and endoscopic data were collected. Univariate analysis was used to determine significant indicators for differentiating three main subtypes of PSIL. Cox regression analysis was performed to assess the risk factors for survival. Results In this study, 10 patients were pathologically diagnosed as diffuse large B-cell lymphoma (DLBCL), 11 were indolent B-cell lymphoma (BCL) and 9 were T-cell lymphoma (TCL). Compared with DLBCL patients, the body mass index (BMI) of TCL patients was significantly lower (p = 0.004). Meanwhile, compared with patients with DLBCL, the patients with indolent BCL had lower levels of C-reactive protein, lactate dehydrogenase (LDH), fibrinogen and D-Dimer (p = 0.004, p = 0.004, p = 0.006, and p = 0.002, respectively), and lower proportion of thicker intestinal wall and aneurysmal dilation in CT scan (p = 0.003 and p = 0.020, respectively). In terms of ulcer morphology, patients with DLBCL had significantly higher proportion of deep ulcers than patients with indolent BCL (p = 0.020, respectively). Cox regression analysis showed that drink (p = 0.034), concomitant colonic ulcers (p = 0.034) and elevated LDH (p = 0.043) are risk factors for mortality in patients with PSIL. Conclusions This study provides clinical characteristics of patients with PSIL. Thicker intestinal wall and aneurismal dilation detected on CT scan and deeper ulcer on DBE examination helps to establish a diagnosis of DLBCL.

Background: Deposition of immune complexes drives podocyte injury acting in the initial phase of lupus nephritis (LN), a process mediated by B cell involvement. Accordingly, targeting B cell subsets represents a potential therapeutic approach for LN. Ginsenoside compound K (CK), a bioavailable component of ginseng, possesses nephritis benefits in lupus-prone mice; however, the underlying mechanisms involving B cell subpopulations remain elusive. Methods: Female MRL/lpr mice were administered CK (40 mg/kg) intragastrically for 10 weeks, followed by measurements of anti-dsDNA antibodies, inflammatory chemokines, and metabolite profiles on renal samples. Podocyte function and ultrastructure were detected. Publicly available single-cell RNA sequencing data and flow cytometry analysis were employed to investigate B cell subpopulations. Metabolomics analysis was adopted. SIRT1 and AMPK expression were analyzed by immunoblotting and immunofluorescence assays. Results: CK reduced proteinuria and protected podocyte ultrastructure in MRL/lpr mice by suppressing circulating anti-dsDNA antibodies and mitigating systemic inflammation. It activated B cell-specific SIRT1 and AMPK with Rhamnose accumulation, hindering the conversion of renal B cells into plasma cells. This cascade facilitated the resolution of local renal inflammation. CK facilitated the clearance of deposited immune complexes, thus reinstating podocyte morphology and mobility by normalizing the expression of nephrin and SYNPO. Conclusions: Our study reveals the synergistic interplay between SIRT1 and AMPK, orchestrating the restoration of renal B cell subsets. This process effectively mitigates immune complex deposition and preserves podocyte function. Accordingly, CK emerges as a promising therapeutic agent, potentially alleviating the hyperactivity of renal B cell subsets during LN.

Mentha spicata is a popular herb used in foods, cosmetics, and medicines. In the present study, liquid chromatography-mass spectrometry-based metabolomics analysis and the zebrafish model were used to investigate the potential biomarkers of M. spicata growing in Shanghe County (Shandong Province, China) and their anti-inflammatory properties. Network pharmacology and molecular docking were performed to screen the main targets of the characteristic compounds to understand their mechanisms of action. Nine potential markers including sugars (1,2), polyphenolic acids (3–5), and flavonoids (6–9) were identified from the species. The inhibitory effects on leukocyte migration confirmed that compounds 1 and 3–9 played a positive role in the protective effect of Shanghe M. spicata (SM) extract against inflammation. Akt (protein kinase B), EGFR (epidermal growth factor receptor), and MMP9 (matrix metalloproteinase 9) were the core target proteins of the identified compounds in the anti-inflammatory process. The most significant Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment terms were response to abiotic stimulus (Biological Process), carbohydrate derivative binding (Molecular Function), and pathways in cancer. In docking simulations, 3-p-coumaroylquinic acid (3-PC, 4) and cirsimaritin (CN, 7) exhibited the highest potential affinity to the active sites of Akt and EGFR proteins, respectively; additionally, 5-demethylsinensetin (5-DS, 9) and luteolin (LN, 6) were considered the most suitable ligands for the MMP9 protein. The present study highlighted the use of SM resources as functional products with health benefits.

Abstract. Background:. Findings on the association of genetic factors and colorectal cancer (CRC) survival are limited and inconsistent, and revealing the mechanism underlying their prognostic roles is of great importance. This study aimed to explore the relationship between functional genetic variations and the prognosis of CRC and further reveal the possible mechanism. Methods:. We first systematically performed expression quantitative trait locus (eQTL) analysis using The Cancer Genome Atlas (TCGA) dataset. Then, the Kaplan-Meier analysis was used to filter out the survival-related eQTL target genes of CRC patients in two public datasets (TCGA and GSE39582 dataset from the Gene Expression Omnibus database). The seven most potentially functional eQTL single nucleotide polymorphisms (SNPs) associated with six survival-related eQTL target genes were genotyped in 907 Chinese CRC patients with clinical prognosis data. The regulatory mechanism of the survival-related SNP was further confirmed by functional experiments. Results:. The rs71630754 regulating the expression of endoplasmic reticulum aminopeptidase 1 (ERAP1) was significantly associated with the prognosis of CRC (additive model, hazard ratio [HR]: 1.43, 95% confidence interval [CI]: 1.08-1.88, P = 0.012). The results of dual-luciferase reporter assay and electrophoretic mobility shift assay showed that the A allele of the rs71630754 could increase the binding of transcription factor 3 (TCF3) and subsequently reduce the expression of ERAP1. The results of bioinformatic analysis showed that lower expression of ERAP1 could affect the tumor immune microenvironment and was significantly associated with severe survival outcomes. Conclusion:. The rs71630754 could influence the prognosis of CRC patients by regulating the expression of the immune-related gene ERAP1. Trial Registration:. No. NCT00454519 (https://clinicaltrials.gov/)

Deflectors offer a cost-effective solution for enhancing airflow distribution. The purpose of this paper is to investigate the effect of the deflector on the indoor airflow velocity distribution under natural ventilation conditions. The results obtained from numerical simulations are validated through experimental measurements using a reduced-scale model. Subsequently, the validated reduced-scale numerical model was extended to full-size rooms. A full-size numerical simulation method is used to analyze the effect of no deflector, deflectors with different opening width-to-height ratios and deflectors with different opening shapes on the percentage of indoor velocity partitions under natural ventilation conditions. The findings reveal that the judicious installation of deflectors can enhance indoor airflow velocity distribution and increase the percentage of the indoor comfort zone. Deflectors with different opening width-to-height ratios exert distinct influences on indoor airflow velocity distribution. When the deflector opening width-to-height ratio is set at 7/6, the indoor comfort zone percentage reaches its maximum at 75.98%. Furthermore, the shape of the deflector’s opening significantly affects indoor airflow velocity distribution, and when the opening shape is a rhombus shape of 4.00 cm × 9.00 cm, the proportion of indoor velocity comfort zone is the largest, which is 75.56%. This study provides a reference for the design and practice of natural ventilation in buildings.

Abstract Left ventricular regional wall thickness (LVRWT) is an independent predictor of morbidity and mortality in cardiovascular diseases (CVDs). To identify specific genetic influences on individual LVRWT, we established a novel deep learning algorithm to calculate 12 LVRWTs accurately in 42,194 individuals from the UK Biobank with cardiac magnetic resonance (CMR) imaging. Genome-wide association studies of CMR-derived 12 LVRWTs identified 72 significant genetic loci associated with at least one LVRWT phenotype (P

Summary Background Autoimmune enteropathy (AIE) defined by intractable diarrhoea and nonceliac enteropathy with villous atrophy, is a rare digestive disease. Case reports of this disease are sporadic and the clinical characteristics of AIE is seldom discussed. Purpose We evaluate the clinical, laboratory, histopathological features, response to therapy and outcome of AIE in children. Method We conducted a retrospective analysis of five children with AIE in our hospital. A comprehensive search of MEDLINE was performed using PubMed, through keywords of “autoimmune enteropathy, pediatric or children”. The clinical manifestations, endoscopic results, pathological results, and medication therapy of these children were collected and the cases were divided into two groups, infants (≤ 1 year old) and children (> 1 year old). Results Five cases treated in our department: one case took eight years to make the final diagnosis; one case was positive for anti-intestinal epithelial cell (AE) antibody; three cases showed crypt apoptosis in histopathology; and two cases showed celiac-like changes. All cases were responsive to glucocorticoid therapy in the early stage of treatment, while three cases required immunosuppressant maintenance. After reviewing the literature, we performed a statistical analysis of 50 cases with a male-to-female ratio of 31:19. Among them, 35 patients (70%) were within 1 year of age, and their clinical manifestations were mainly watery stool (43 cases, 86%), weight loss (28 cases, 56%), abdominal distension (3 cases, 6%), serum AE or anti-goblet cell (AG) antibody positivity (32 cases, 64%), other immune-related antibodies (21 cases, 42%), gene mutations (9 cases, 18%), and family history (21 cases, 42%). All the children showed different degrees of intestinal villous atrophy. Thirty-seven (74%) of the children were treated early, and their clinical symptoms were relieved. Comparing the cases between different age groups, it was found that the mortality rate of children with onset in infancy was higher (P 0.05) through analysis of mortality and clinical remission cases. Conclusion Endoscopic examination and mucosal pathological examination should be performed to diagnose AIE in children with watery stool and weight loss who fail to be treated with diet therapy. Immunotherapy is the core of medical management of AIE and can improve prognosis. Children with a poor prognosis in infancy should be actively treated to reduce mortality rates associated with AIE.

Abstract Background Infantile cholestasis (IC) is the most common hepatobiliary disease in infants, resulting in elevated direct bilirubin levels. Indeed, hepatointestinal circulation impacts bile acid and bilirubin metabolism. This study evaluates changes in the gut microbiota composition in children with IC and identifies abnormal metabolite profiles associated with microbial alterations. Results The gut microbiota in the IC group exhibits the higher abundance of Veillonella, Streptococcus and Clostridium spp. (P

Abstract Background Epidemiological studies demonstrated that multiple amino acids (AAs) were associated with cardiovascular diseases (CVDs), but whether these associations were causal remains unclear. This study aims to investigate the causal relationships between circulating levels of 20 AAs and 10 CVDs in European and East Asian populations by Mendelian randomization (MR). Methods This MR study utilized single-nucleotide polymorphisms that were significantly associated with AAs as instrumental variables. Summary-level data for AAs and CVDs were obtained from public genome-wide association studies. The causal effects were primarily estimated by inverse variance weighting with multiplicative random effect method. Sensitivity analyses, including weighted median, weighted mode, and MR Egger regression, were used to test the robustness of our results. Results In the European population, alanine and serine were inversely associated with angina pectoris (AP) and chronic heart failure, respectively. With each unit increase of leucine, the risk of ischemic stroke increased by 10%. Moreover, tyrosine was positively associated with AP and deep vein thrombosis. In the East Asian population, each unit increase in glycine was associated with 4.1% and 9.0% decreased risks of coronary artery disease (CAD) and myocardial infarction (MI), respectively. A unit increase in serine was associated with 13.1%, 12.6% and 15.5% decreased risks of AP, CAD and MI, respectively. Sensitivity analyses supported the robustness of our results. Conclusions This MR study demonstrated significant causal effects of circulating levels of AAs on CVDs, indicating the potential use of AAs as biomarkers or as therapeutic targets for CVD in clinical scenarios. Graphical Abstract

Abstract Background Genome-wide association studies (GWAS) are an effective way to explore genotype–phenotype associations in humans, animals, and plants. Various GWAS methods have been developed based on different genetic or statistical assumptions. However, no single method is optimal for all traits and, for many traits, the putative single nucleotide polymorphisms (SNPs) that are detected by the different methods do not entirely overlap due to the diversity of the genetic architecture of complex traits. Therefore, multi-tool-based GWAS strategies that combine different methods have been increasingly employed. To take this one step further, we propose an ensemble-like GWAS strategy (E-GWAS) that statistically integrates GWAS results from different single GWAS methods. Results E-GWAS was compared with various single GWAS methods using simulated phenotype traits with different genetic architectures. E-GWAS performed stably across traits with different genetic architectures and effectively controlled the number of false positive genetic variants detected without decreasing the number of true positive variants. In addition, its performance could be further improved by using a bin-merged strategy and the addition of more distinct single GWAS methods. Our results show that the numbers of true and false positive SNPs detected by the E-GWAS strategy slightly increased and decreased, respectively, with increasing bin size and when the number and the diversity of individual GWAS methods that were integrated in E-GWAS increased, the latter being more effective than the bin-merged strategy. The E-GWAS strategy was also applied to a real dataset to study backfat thickness in a pig population, and 10 candidate genes related to this trait and expressed in adipose-associated tissues were identified. Conclusions Using both simulated and real datasets, we show that E-GWAS is a reliable and robust strategy that effectively integrates the GWAS results of different methods and reduces the number of false positive SNPs without decreasing that of true positive SNPs.

Trichosanthis fruit (TF) is a classic medicinal material obtained from Shandong, China. The peel of this fruit (Trichosanthis pericarpium, TP) is known to exert anti-thrombotic effects. However, the anti-thrombotic active components and mechanisms of TP have yet to be fully elucidated. Combined with zebrafish models and high-performance liquid chromatography (HPLC), this study evaluated the endogenous anti-thrombotic effects with the combination of three compounds from TP. First, we used HPLC to investigate the components in the water extract of TP. Next, we used the zebrafish model to investigate the anti-thrombotic activity of the three compound combinations by evaluating a range of indicators. Finally, the expression of related genes was detected by real-time quantitative polymerase chain reaction (qPCR). HPLC detected a total of eight components in TP water extract, with high levels of paeonol (Pae), diosmetin-7-O-β-D-glucopyranoside (diosmetin-7-O-glucoside), and 5-hydroxymethylfurfural (5-HMF). The most significant anti-thrombotic activity was detected when the Pae: diosmetin-7-O-glucoside:5-HMF ratio was 4:3:3. qPCR analysis revealed that the abnormal expression levels of f2, fga, fgb, vwf, ptgs1, and tbxas1 induced by arachidonic acid (AA) were improved. The combination of Pae, diosmetin-7-O-glucoside, and 5-HMF may alleviate AA-induced thrombosis by inhibiting the inflammatory reaction, coagulation cascade reaction, and arachidonic acid metabolism pathways.

A 54-year-old female with diabetes was admitted with fever and altered consciousness. Laboratory tests revealed venous blood glucose level of 43.79 mmol/L. Computed tomography (CT) scans of the head, chest, and abdomen showed a right-sided pneumothorax, consolidation, and atelectasis in the right lung; a large heterogeneous density lesion with fluid and gas-fluid levels in the liver; and scattered gas shadows in both kidneys, respectively. Blood and puncture fluid cultures indicated infection with Klebsiella pneumoniae. Based on the susceptibility profiles of the isolates, imipenem was administered intravenously to treat the infection. On the third day of hospitalization, the patient's condition worsened, with head CT showing an extensive cerebral infarction and multiple gas accumulations in the right cerebral hemisphere, as well as a large-area cerebral infarction in the left parietal and occipital lobes. Ultimately, the patient died of multiple organ dysfunction on the fourth day after initial presentation. Although the Klebsiella pneumoniae isolates from the patient showed sensitivity to imipenem, this antibiotic shows poor entry into the central nervous system. The death of the patient indicates that the selection of antibiotics that can cross the blood-brain barrier may be crucial in the outcome of this type of case. Therefore, antibiotics that can penetrate the blood-brain barrier should be selected as soon as possible, and empirical treatment must be initiated immediately after clinical suspicion of invasive Klebsiella pneumoniae, even if the diagnosis has not been determined.

ING5 belongs to the inhibitor of growth (ING) candidate tumor suppressor family, which is involved in multiple cellular functions, such as cell cycle regulation, apoptosis, and chromatin remodelling. Previously, we reported that ING5 overexpression inhibits EMT by regulating EMT-related molecules, including Snail1, at the mRNA and protein levels. However, the mechanisms remain unclear. In the current study, we identify that ING5 overexpression induces the upregulation of miR-34c-5p. The expression levels of both ING5 and miR-34c-5p in NSCLC tissues from the TCGA database are decreased compared with that in adjacent tissues. Higher expression levels of both ING5 and miR-34c-5p predict longer overall survival (OS). Snail1 is the target gene of miR-34c-5p, as predicted by an online database, which is further verified by a dual-luciferase reporter assay. The expression level of Snail1 in NSCLC cells is markedly reduced following miR-34c-5p overexpression, leading to the inactivation of the Snail1 downstream TGF-β/Smad3 signaling pathway. The TGF-β signaling-specific inhibitor LY2157299 reverses the enhanced EMT, proliferation, migration, and invasion abilities induced by the miR-34c-5p inhibitor. Furthermore, tail vein injection of miR-34c-5p agomir inhibits xenografted tumor metastasis. Overall, this study concludes that miR-34c-5p, induced by ING5 overexpression, is a tumor suppressor that targets Snail1 and mediates the inhibitory effects of ING5 on the EMT and invasion of NSCLC cells. These results provide a novel mechanism mediating the antitumor effects of ING5.

Abstract Background The incidence of early-onset colorectal cancer (EOCRC; patients < 50 years old) has been rising rapidly, whereas the EOCRC genetic susceptibility remains incompletely investigated. Here, we aimed to systematically identify specific susceptible genetic variants for EOCRC. Methods Two parallel GWASs were conducted in 17,789 CRC cases (including 1490 EOCRC cases) and 19,951 healthy controls. A polygenic risk score (PRS) model was built based on identified EOCRC-specific susceptibility variants by using the UK Biobank cohort. We also interpreted the potential biological mechanisms of the prioritized risk variant. Results We identified 49 independent susceptibility loci that were significantly associated with the susceptibility to EOCRC and the diagnosed age of CRC (both P < 5.0×10−4), replicating 3 previous CRC GWAS loci. There are 88 assigned susceptibility genes involved in chromatin assembly and DNA replication pathways, mainly associating with precancerous polyps. Additionally, we assessed the genetic effect of the identified variants by developing a PRS model. Compared to the individuals in the low genetic risk group, the individuals in the high genetic risk group have increased EOCRC risk, and these results were replicated in the UKB cohort with a 1.63-fold risk (95% CI: 1.32–2.02, P = 7.67×10−6). The addition of the identified EOCRC risk loci significantly increased the prediction accuracy of the PRS model, compared to the PRS model derived from the previous GWAS-identified loci. Mechanistically, we also elucidated that rs12794623 may contribute to the early stage of CRC carcinogenesis via allele-specific regulating the expression of POLA2. Conclusions These findings will broaden the understanding of the etiology of EOCRC and may facilitate the early screening and individualized prevention. Graphical Abstract

Abstract Treatment options specifically for patients with locally advanced pancreatic adenocarcinoma (LAPC) are scare and chemotherapy alone delivers limited efficacy. Immunotherapy and radiotherapy are potential effective treatments for LAPC, and both of them may synergize with chemotherapy. Therefore, in this prospective cohort study, we compared the efficacy and safety of nab-paclitaxel plus gemcitabine combined with anti-programmed cell death (PD-1) immunotherapy and radiotherapy (hereafter, combination treatment) versus nab-paclitaxel plus gemcitabine (chemotherapy alone) in the treatment of LAPC. In the combination group, participants received conventional fractionated radiotherapy with doses ranging from 54 to 63 Gy in 28 fractions, intravenous camrelizumab 200 mg once every 3 weeks, and intravenous nab-paclitaxel plus gemcitabine on day 1 and 8 of a 21-day cycle for eight cycles until disease progression, death or unacceptable toxicity. In the chemotherapy group, participants received intravenous nab-paclitaxel plus gemcitabine on day 1 and 8 of a 21-day cycle for eight cycles. From April, 2020 to December, 2021, 96 participants with LAPC were prospectively enrolled with 32 received combination treatment and 64 received chemotherapy alone at a single center. The combination treatment yielded significantly longer median overall-survival (22.3 months vs. 18.6 months, P = 0.031) and progression-free survival (12.0 months vs. 10.5 months, P = 0.043) than chemotherapy alone did. And the incidence of severe adverse events was not significantly different between the combination group and chemotherapy group (P = 0.856). In conclusion, nab-paclitaxel plus gemcitabine combined with anti-PD-1 immunotherapy and radiotherapy was effective and safe for LAPC patients, and it warrants further investigation in larger randomized trials.