MR-BOIL: Causal inference in one-sample Mendelian randomization for binary outcome with integrated likelihood method.

Mendelian randomization is a statistical method for inferring the causal relationship between exposures and outcomes using an economics-derived instrumental variable approach. The research results are relatively complete when both exposures and outcomes are continuous variables. However, due to the noncollapsing nature of the logistic model, the existing methods inherited from the linear model for exploring binary outcome cannot take the effect of confounding factors into account, which leads to biased estimate of the causal effect. In this article, we propose an integrated likelihood method MR-BOIL to investigate causal relationships for binary outcomes by treating confounders as latent variables in one-sample Mendelian randomization. Under the assumption of a joint normal distribution of the confounders, we use expectation maximization algorithm to estimate the causal effect. Extensive simulations demonstrate that the estimator of MR-BOIL is asymptotically unbiased and that our method improves statistical power without inflating type I error rate. We then apply this method to analyze the data from Atherosclerosis Risk in Communications Study. The results show that MR-BOIL can better identify plausible causal relationships with high reliability, compared with the unreliable results of existing methods. MR-BOIL is implemented in R and the corresponding R code is provided for free download.

Individualized detection of TMPRSS2-ERG fusion status in prostate cancer: a rank-based qualitative transcriptome signature.

BACKGROUND: TMPRSS2-ERG (T2E) fusion is highly related to aggressive clinical features in prostate cancer (PC), which guides individual therapy. However, current fusion prediction tools lacked enough accuracy and biomarkers were unable to be applied to individuals across different platforms due to their quantitative nature. This study aims to identify a transcriptome signature to detect the T2E fusion status of PC at the individual level. METHODS: Based on 272 high-throughput mRNA expression profiles from the Sboner dataset, we developed a rank-based algorithm to identify a qualitative signature to detect T2E fusion in PC. The signature was validated in 1223 samples from three external datasets (Setlur, Clarissa, and TCGA). RESULTS: A signature, composed of five mRNAs coupled to ERG (five ERG-mRNA pairs, 5-ERG-mRPs), was developed to distinguish T2E fusion status in PC. 5-ERG-mRPs reached 84.56% accuracy in Sboner dataset, which was verified in Setlur dataset (n = 455, accuracy = 82.20%) and Clarissa dataset (n = 118, accuracy = 81.36%). Besides, for 495 samples from TCGA, two subtypes classified by 5-ERG-mRPs showed a higher level of significance in various T2E fusion features than subtypes obtained through current fusion prediction tools, such as STAR-Fusion. CONCLUSIONS: Overall, 5-ERG-mRPs can robustly detect T2E fusion in PC at the individual level, which can be used on any gene measurement platform without specific normalization procedures. Hence, 5-ERG-mRPs may serve as an auxiliary tool for PC patient management.

Synthetic viability induces resistance to immune checkpoint inhibitors in cancer cells.

BACKGROUND: Immune checkpoint inhibitors (ICI) have revolutionized the treatment for multiple cancers. However, most of patients encounter resistance. Synthetic viability (SV) between genes could induce resistance. In this study, we established SV signature to predict the efficacy of ICI treatment for melanoma. METHODS: We collected features and predicted SV gene pairs by random forest classifier. This work prioritized SV gene pairs based on CRISPR/Cas9 screens. SV gene pairs signature were constructed to predict the response to ICI for melanoma patients. RESULTS: This study predicted robust SV gene pairs based on 14 features. Filtered by CRISPR/Cas9 screens, we identified 1,861 SV gene pairs, which were also related with prognosis across multiple cancer types. Next, we constructed the six SV pairs signature to predict resistance to ICI for melanoma patients. This study applied the six SV pairs signature to divide melanoma patients into high-risk and low-risk. High-risk melanoma patients were associated with worse response after ICI treatment. Immune landscape analysis revealed that high-risk melanoma patients had lower natural killer cells and CD8+ T cells infiltration. CONCLUSIONS: In summary, the 14 features classifier accurately predicted robust SV gene pairs for cancer. The six SV pairs signature could predict resistance to ICI.

Association between homocysteine and nonalcoholic fatty liver disease: Mendelian randomisation study.

BACKGROUND: Many observational studies explore the relationship between homocysteine (Hcy) and nonalcoholic fatty liver disease (NAFLD), whereas the causality of this association remains uncertain, especially in European populations. We performed a bidirectional Mendelian randomisation study to elucidate the causal association between Hcy and NAFLD. Furthermore, we explored the relationship of Hcy with liver enzymes, including alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST). METHODS: Two-sample Mendelian randomisation study was conducted. Summary statistics for Hcy were obtained from a genome-wide association studies (GWAS) meta-analysis comprising 44,147 subjects. Summary-level data for NAFLD were acquired from a GWAS meta-analysis of 8434 cases and 770,180 noncases and another GWAS meta-analysis of 1483 cases and 17,781 noncases. Summary-level data for three liver enzymes were available from the UK Biobank. RESULTS: Genetic associations of Hcy concentrations with NAFLD and liver enzymes were observed. Genetically predicted higher Hcy concentrations were consistently associated with an increased NAFLD risk in two data sources. The combined odds ratio of NAFLD was 1.25 (95% confidence interval [CI], 1.05-1.45) per SD increase in Hcy concentrations. Genetically predicted higher Hcy concentrations showed significant association with ALP (Beta .69; 95% CI, 0.04-1.34), ALT (Beta 0.56; 95% CI, 0.15-0.97) and AST levels (Beta .57; 95% CI, 0.10-1.04). Genetic liability to NAFLD was not associated with Hcy concentrations. CONCLUSIONS: This study has clinical implications as it indicates that increased Hcy concentrations increase the relevant liver enzymes and may play a role in NAFLD risk in European populations.

Resting-state fMRI reveals changes within the anxiety and social avoidance circuitry of the brain in mice with psoriasis-like skin lesions.

Psoriasis is an autoimmune skin disease that often co-occurs with psychological morbidities such as anxiety and depression, and psychosocial issues also lead psoriasis patients to avoid other people. However, the precise mechanism underlying the comorbidity of psoriasis and anxiety is unknown. Also, whether the social avoidance phenomenon seen in human patients also exists in psoriasis-like animal models remains unknown. In the present study, anxiety-like behaviours and social avoidance-like behaviours were observed in an imiquimod-induced psoriasis-like C57-BL6 mouse model along with typical psoriasis-like dermatitis and itch-like behaviours. The 11.7T resting-state functional magnetic resonance imaging showed differences in brain regions between the model and control group, and voxel-based morphometry showed that the grey matter volume changed in the basal forebrain region, anterior commissure intrabulbar and striatum in the psoriasis-like mice. Seed-based resting state functional connectivity analysis revealed connectivity changes in the amygdala, periaqueductal gray, raphe nuclei and lateral septum. We conclude that the imiquimod-induced psoriasis-like C57-BL6 mouse model is well suited for mechanistic studies and for performing preclinical therapeutic trials for treating anxiety and pathological social avoidance in psoriasis patients.

Functional diversity of sodium channel variants in common eastern bumblebee, Bombus impatiens.

For the past decade, Colony Collapse Disorder has been reported worldwide. Insecticides containing pyrethroids may be responsible for a decline in bees, which are more sensitive to pyrethroids compared with other insects. Voltage-gated sodium channels (Nav ) are the major target sites of pyrethroids, and the sodium channel diversity is generated through extensive alternative splicing and RNA editing. In this study, we cloned and analyzed the function of variants of the Nav channel, BiNav , from Bombus impatiens. BiNav covers a 46 kb genome region including 30 exons. Sequence analysis of 56 clones showed that the clones can be grouped into 22 splice types with 11 optional exons (exons j, w, p, q, r, b, e, t, l/k, and z). Here, a special alternative exon w is identified, encoding a stretch of 31 amino acid resides in domain I between S3 and S4. RNA editing generates 18 amino acid changes in different positions in individual variants. Among 56 variants examined, only six variants generated sufficient sodium currents for functional characterization in Xenopus oocytes. In the presence of B. impatiens TipE and TEH1, the sodium current amplitude of BiNav 1-1 increased by fourfold, while TipE of other insect species had no effect on the expression. Abundant alternative splicing and RNA editing of BiNav suggests the molecular and functional pharmacology diversity of the Nav channel for bumblebees. This study provides a theoretical basis for the design of insecticides that specifically target pests without affecting beneficial insects.

Risk factors of left ventricular diastolic dysfunction in maintenance hemodialysis patients.

OBJECTIVE: To investigate the risk factors of left ventricular diastolic dysfunction in maintenance hemodialysis (MHD) patients. METHOD: We retrospectively collected data from 363 hemodialysis patients who were on dialysis for at least 3 months at January 1, 2020. According to the echocardiogram results, these patients were divided into left ventricular diastolic dysfunction (LVDD) group and non-LVDD group. The differences in basic data, cardiac structure and functiona between the two groups were analyzed. Logistic regression analysis was used to analyze the risk factors of cardiac diastolic dysfunction in MHD patients. RESULTS: Compared with the non-LVDD group, patients in the LVDD group were older, with an increased proportion of coronary heart disease, more prone to chest tightness, shortness of breath. Simultaneously, they had a significantly increased (p < 0.05) proportion of cardiac structural abnormalities such as left ventricular hypertrophy, left heart enlargement and systolic dysfunction. Multivariate logistic regression analysis showed that the risk of LVDD was significantly increased in elderly MHD patients older than 60 years (OR = 3.86, 95%CI 1.429-10.429), and left ventricular hypertrophy was also significantly associated with LVDD (OR = 2.227, 95% CI 1.383-3.586). CONCLUSION: According to research, both age and left ventricular hypertrophy are risk factors for LVDD in MHD patients. It is recommended that early intervention for LVDD should be implemented to improve the quality of dialysis and reduce the incidence of cardiovascular events in MHD patients.

Polyglycerol Functionalized 10 B Enriched Boron Carbide Nanoparticle as an Effective Bimodal Anticancer Nanosensitizer for Boron Neutron Capture and Photothermal Therapies.

Boron neutron capture therapy (BNCT) is a non-invasive cancer treatment with little adverse effect utilizing nuclear fission of 10 B upon neutron irradiation. While neutron source has been developed from a nuclear reactor to a compact accelerator, only two kinds of drugs, boronophenylalanine and sodium borocaptate, have been clinically used for decades despite their low tumor specificity and/or retentivity. To overcome these challenges, various boron-containing nanomaterials, or "nanosensitizers", have been designed based on micelles, (bio)polymers and inorganic nanoparticles. Among them, inorganic nanoparticles such as boron carbide can include a much higher 10 B content, but successful in vivo applications are very limited. Additionally, recent reports on the photothermal effect of boron carbide are motivating for the addition of another modality of photothermal therapy. In this study, 10 B enriched boron carbide (10 B4 C) nanoparticle is functionalized with polyglycerol (PG), giving 10 B4 C-PG with enough dispersibility in a physiological environment. Pharmacokinetic experiments show that 10 B4 C-PG fulfills the following three requirements for BNCT; 1) low intrinsic toxicity, 2) 10 B in tumor/tumor tissue (wt/wt) ≥ 20 ppm, and 3) 10 B concentrations in tumor/blood ≥ 3. In vivo study reveals that neutron irradiation after intravenous administration of 10 B4 C-PG suppresses cancer growth significantly and eradicates cancer with the help of near-infrared light irradiation.

Effect of Protein Corona on Mitochondrial Targeting Ability and Cytotoxicity of Triphenylphosphonium Conjugated with Polyglycerol-Functionalized Nanodiamond.

Functionalization of nanoparticles (NPs) with targeting moieties has a high potential to advance precision nanomedicine. However, the targeting moieties on a NP surface are known to be masked by a protein corona in biofluids, lowering the targeting efficiency. Although it has been demonstrated at the cellular level, little is known about the influence of the protein corona on the subcellular targeting. Herein, we adopted triphenylphosphonium (TPP) as a mitochondrial targeting moiety and investigated the effects of protein coronas from fetal bovine serum and human plasma on its targeting ability and cytotoxicity. Specifically, we introduced TPP in low (l) and high (h) densities on the surface of nanodiamond (ND) functionalized with polyglycerol (PG). Despite the "corona-free" PG interface, we found that the TPP moiety attracted proteins to form a corona layer with clear linearity between the TPP density and the protein amount. By performing investigations on human cervix epithelium (HeLa) and human lung epithelial carcinoma (A549) cells, we further demonstrated that (1) the protein corona alleviated the cytotoxicity of both ND-PG-TPP-l and -h, (2) a smaller amount of proteins on the surface of ND-PG-TPP-l did not affect its mitochondrial targeting ability, and (3) a larger amount of proteins on the surface of ND-PG-TPP-h diminished its targeting specificity by restricting the NDs inside the endosome and lysosome compartments. Our findings will provide in-depth insights into the design of NPs with active targeting moiety for more precise and safer delivery at the subcellular level.

Radical Dehydroxylative Alkylation of Tertiary Alcohols by Ti Catalysis.

Deoxygenative radical C-C bond-forming reactions of alcohols are a long-standing challenge in synthetic chemistry, and the current methods rely on multistep procedures. Herein, we report a direct dehydroxylative radical alkylation reaction of tertiary alcohols. This new protocol shows the feasibility of generating tertiary carbon radicals from alcohols and offers an approach for the facile and precise construction of all-carbon quaternary centers. The reaction proceeds with a broad substrate scope of alcohols and activated alkenes. It can tolerate a wide range of electrophilic coupling partners, including allylic carboxylates, aryl and vinyl electrophiles, and primary alkyl chlorides/bromides, making the method complementary to the cross-coupling procedures. The method is highly selective for the alkylation of tertiary alcohols, leaving secondary/primary alcohols (benzyl alcohols included) and phenols intact. The synthetic utility of the method is highlighted by its 10-g-scale reaction and the late-stage modification of complex molecules. A combination of experiments and density functional theory calculations establishes a plausible mechanism implicating a tertiary carbon radical generated via Ti-catalyzed homolysis of the C-OH bond.

TaGS5-3A, a grain size gene selected during wheat improvement for larger kernel and yield.

Grain size is a dominant component of grain weight in cereals. Earlier studies have shown that OsGS5 plays a major role in regulating both grain size and weight in rice via promotion of cell division. In this study, we isolated TaGS5 homoeologues in wheat and mapped them on chromosomes 3A, 3B and 3D. Temporal and spatial expression analysis showed that TaGS5 homoeologues were preferentially expressed in young spikes and developing grains. Two alleles of TaGS5-3A, TaGS5-3A-T and TaGS5-3A-G were identified in wheat accessions, and a functional marker was developed to discriminate them. Association analysis revealed that TaGS5-3A-T was significantly correlated with larger grain size and higher thousand kernel weight. Biochemical assays showed that TaGS5-3A-T possesses a higher enzymatic activity than TaGS5-3A-G. Transgenic rice lines overexpressing TaGS5-3A-T also exhibited larger grain size and higher thousand kernel weight than TaGS5-3A-G lines, and the transcript levels of cell cycle-related genes in TaGS5-3A-T lines were higher than those in TaGS5-3A-G lines. Furthermore, systematic evolution analysis in diploid, tetraploid and hexaploid wheat showed that TaGS5-3A underwent strong artificial selection during wheat polyploidization events and the frequency changes of two alleles demonstrated that TaGS5-3A-T was favoured in global modern wheat cultivars. These results suggest that TaGS5-3A is a positive regulator of grain size and its favoured allele TaGS5-3A-T exhibits a larger potential application in wheat high-yield breeding.

Global selection on sucrose synthase haplotypes during a century of wheat breeding.

Spike number per unit area, number of grains per spike, and thousand kernel weight (TKW) are important yield components. In China, increases in wheat (Triticum aestivum) yields are mainly due to increases in grain number per spike and TKW. TKW mainly depends on starch content, as starch accounts for about 70% of the grain endosperm. Sucrose synthase catalysis is the first step in the conversion of sucrose to starch, that is, the conversion of sucrose to fructose and UDP-glucose by the wheat sucrose synthase genes (TaSus1 and TaSus2) that are located on chromosomes 7A/7B/7D and 2A/2B/2D, respectively. A total of 1,520 wheat accessions were genotyped at the six loci. Two, two, five, and two haplotypes were identified at the TaSus2-2A, TaSus2-2B, TaSus1-7A, and TaSus1-7B loci, respectively. Their main variations were detected within the introns. Significant differences between the haplotypes correlated with TKW differences among 348 modern Chinese cultivars from the core collection. Frequency changes for favored haplotypes showed gradual increases in cultivars released since beginning of the last century in China, Europe, and North America. Geographic distributions and time changes of favored haplotypes were characterized in six major wheat production regions worldwide. Strong selection bottlenecks to haplotype variations occurred at polyploidization and domestication and during breeding of wheat. Genetic-effect differences between haplotypes at the same locus influence the selection time and intensity. This work shows that the endosperm starch synthesis pathway is a major target of indirect selection in global wheat breeding for higher yield.

A haplotype block associated with thousand-kernel weight on chromosome 5DS in common wheat (Triticum aestivum L.).

Spike number per unit area, number of grains per spike, and thousand-kernel weight (TKW) are important yield components for wheat (Triticum aestivum L.). TKW has the highest heritability among the three components. We validated 27 simple sequence repeat (SSR) loci associated with TKW in an F(2:5) breeding population grown in four environments. A cfd7(8265bp) marker on chromosome 5DS showed the strongest association with TKW and had a significantly positive effect on TKW compared to allele cfd7(8259bp), with mean increases of 5.17, 3.63, 4.11, and 5.16 g in the four environments. Markers cfd67 and cfd40 flanking cfd78 also showed significantly positive associations with TKW with increases of 5.11, 3.29, 4.31, and 4.50 g for cfd67(205), and 4.98, 3.49, 4.06, and 4.84 g for cfd40(187) compared with cfd67(203) and cfd40(190) in the four environments, respectively. A major quantitative trait locus for TKW spanning 2.94 cM on chromosome 5DS was detected by association mapping. Strong linkage disequilibrium (LD) (r(2) > 0.2) was detected among the three linked markers, which formed three haplotype blocks in the F(2:5) breeding population. Mean TKW differences between HapB-I and HapB-II were 5.80, 4.41, 4.02, and 5.06 g in the four environments, respectively. Moreover, significant LD was detected only between cfd78 and cfd67 and between cfd67 and cfd40 in a germplasm collection. This study provides a base for cloning genes related to TKW on chromosome 5DS.

Homologous haplotypes, expression, genetic effects and geographic distribution of the wheat yield gene TaGW2.

BACKGROUND: TaGW2-6A, cloned in earlier research, strongly influences wheat grain width and TKW. Here, we mainly analyzed haplotypes of TaGW2-6B and their effects on TKW and interaction with haplotypes at TaGW2-6A. RESULTS: About 2.9 kb of the promoter sequences of TaGW2-6B and TaGW2-6D were cloned in 34 bread wheat cultivars. Eleven SNPs were detected in the promoter region of TaGW2-6B, forming 4 haplotypes, but no divergence was detected in the TaGW2-6D promoter or coding region. Three molecular markers including CAPS, dCAPS and ACAS, were developed to distinguish the TaGW2-6B haplotypes. Haplotype association analysis indicated that TaGW2-6B has a stronger influence than TaGW2-6A on TKW, and Hap-6B-1 was a favored haplotype increasing grain width and weight that had undergone strong positive selection in global wheat breeding. However, clear geographic distribution differences for TaGW2-6A haplotypes were found; Hap-6A-A was favored in Chinese, Australian and Russian cultivars, whereas Hap-6A-G was preferred in European, American and CIMMYT cultivars. This difference might be caused by a flowering and maturity time difference between the two haplotypes. Hap-6A-A is the earlier type. Haplotype interaction analysis between TaGW2-6A and TaGW2-6B showed additive effects between the favored haplotypes. Hap-6A-A/Hap-6B-1 was the best combination to increase TKW. Relative expression analysis of the three TaGW2 homoeologous genes in 22 cultivars revealed that TaGW2-6A underwent the highest expression. TaGW2-6D was the least expressed during grain development and TaGW2-6B was intermediate. Diversity of the three genes was negatively correlated with their effect on TKW. CONCLUSIONS: Genetic effects, expression patterns and historic changes of haplotypes at three homoeologous genes of TaGW2 influencing yield were dissected in wheat cultivars. Strong and constant selection to favored haplotypes has been found in global wheat breeding during the past century. This research also provides a valuable case for understanding interaction of genes that control complex traits in polyploid species.

TEF-7A, a transcript elongation factor gene, influences yield-related traits in bread wheat (Triticum aestivum L.).

In this study, TaTEF-7A, a member of the transcript elongation factor gene family, and its flanking sequences were isolated. TaTEF-7A was located on chromosome 7A and was flanked by markers Xwmc83 and XP3156.3. Subcellular localization revealed that TaTEF-7A protein was localized in the nucleus. This gene was expressed in all organs, but the highest expression occurred in young spikes and developing seeds. Overexpression of TaTEF-7A in Arabidopsis thaliana produced pleiotropic effects on vegetative and reproductive development that enhanced grain length, silique number, and silique length. No diversity was found in the coding region of TaTEF-7A, but 16 single nucleotide polymorphisms and Indels were detected in the promoter regions of different cultivars. Markers based on sequence variations in the promoter regions (InDel-629 and InDel-604) were developed, and three haplotypes were identified based on those markers. Haplotype-trait association analysis of the Chinese wheat mini core collection revealed that TaTEF-7A was significantly associated with grain number per spike. Phenotyping of near-isogenic lines (NILs) confirmed that TaTEF-7A increases potential grain yield and yield-related traits. Frequency changes in favoured haplotypes gradually increased in cultivars released in China from the 1940s. Geographic distributions of favoured haplotypes were characterized in six major wheat production regions worldwide. The presence of Hap-7A-3, the favoured haplotype, showed a positive correlation with yield in a global set of breeding lines. These results suggest that TaTEF-7A is a functional regulatory factor for grain number per spike and provide a basis for marker-assisted selection.

Role of vascular endothelial growth factor D in lung adenocarcinoma immunotherapy response.

OBJECTIVE: To identify key genes associated with tumor-associated macrophages (TAMs), tumor immunotherapy, in the prognosis of lung adenocarcinoma (LUAD). METHODS: The mRNA expression profiles of LUAD samples were obtained from The Cancer Genome Atlas (TCGA) database. The "CIBERSORT" R package was employed to calculate the proportion of innate immune cell infiltration in both tumor and adjacent normal tissues. TAM-associated genes in LUAD were identified to construct a prognostic risk model using weighted gene correlation network analysis (WGCNA), Least Absolute Shrinkage and Selection Operator (LASSO), and multivariate Cox regression analyses (COX). The IMvigor210 cohort was utilized to validate the roles of these genes as predictors of immunotherapy response. Tissue microarrays, immunofluorescence staining, and mRNA level detection methods were used to determine the correlation of risk factors in LUAD tissues. RESULTS: CIBERSORT analysis revealed significant differences in innate immune cells between tumor and adjacent tissues. Seventy-four differential genes linked to these cells were identified from WGCNA. Four hub genes (endothelin receptor type B, vascular endothelial growth factor D (VEGFD), latent transforming growth factor beta binding protein 4 (LTBP4), and fibroblast growth factor receptor 4 (FGFR4)) in the TAM prognostic model were identified as independent prognostic risk factors (P < 0.05). VEGFD expression was identified as a low-risk factor for LUAD prognosis prediction (P < 0.05). Moreover, low-risk patients exhibited higher sensitivity to anti-PD-L1 therapy compared to high-risk patients (P < 0.05). VEGFD levels were negatively correlated with programmed cell death 1 (PD-1) levels (r = -0.363; P < 0.05), suggesting that VEGFD may serve as a predictor for anti-PD-1 treatment. CONCLUSIONS: VEGFD is associated with innate immunity in LUAD, it can predict LUAD prognosis, and therefor may be a potential predictor for anti-PD-1 treatment in patients with LUAD.

Cascading social-ecological benefits of biodiversity for agriculture.

Cultivated species diversity can provide numerous benefits to agricultural systems. Many ecological theories have been proposed to understand the relationships between plant species diversity and trophic interactions. However, extending such theories to socioeconomic systems has been rare for agriculture. Here, we establish ten hypotheses (e.g., the natural enemy hypothesis, resource concentration hypothesis, insurance hypothesis, and aggregation hypothesis) about the relationships between cultivated species diversity (i.e., crop diversification, co-cultures of crops and domestic animals, and co-cultures of crops and edible fungi) and trophic cascades of crops, invertebrate herbivores and natural enemies in cropping systems. We then explore the socioeconomic advantages (e.g., yield, economic and environmental performance) of these trophic cascades. Finally, we propose a multi-perspective framework to promote the cascading social-ecological benefits of species diversity for agricultural sustainability. Integrating the benefits of trophic cascades into agricultural socioeconomic systems requires policies and legislation that support multi-species co-culture practices and the willingness of consumers to pay for these practices through higher prices for agricultural products.

The microbiomic signature of hemorrhoids and comparison with associated microbiomes.

Hemorrhoids are a common ailment that can cause significant disruptions to one's daily life. While some researchers have speculated about a potential link between hemorrhoid development and gut microbes, there is currently insufficient evidence to support this claim. In this study, we collected samples from 60 hemorrhoid patients and analyzed the composition and characteristics of microbiomes in hemorrhoids. PCoA results revealed distinct differences between the microbiomes of hemorrhoids, skin-originated microbiomes, and gut microbes, highlighting the complex nature of hemorrhoidal microbiomes. The distribution characteristics of Staphylococcus suggest that the skin microbiome influences the microbiome of hemorrhoids. Additionally, we observed higher levels of Prevotella in two cases of thrombosed hemorrhoids compared to non-thrombosed hemorrhoids. This finding suggests that Prevotella may play a crucial role in the development of thrombosed hemorrhoids.

Unraveling Immune Heterogeneity across Pan-Cancer and Deep Insights in Lung Adenocarcinoma based on Alternative Splicing.

Alternative splicing (AS) participates in tumor development and tumor microenvironment formation. However, the landscape of immune infiltrating AS events (IIASE) in pan-cancer and mechanisms of AS in lung adenocarcinoma (LUAD) have not been comprehensively characterized. We systematically profiled the IIASE landscape of pan-cancer using data from The Cancer Genome Atlas (TCGA), analyzing both commonalities and specific characteristics among different cancer types. We found that AS events tend to occur specifically in one cancer type rather than in multiple cancer types. AS events were used to classify 512 LUAD samples into two subtypes by unsupervised clustering: aberrant splicing subtype (ABS) and immune infiltrating subtype (IIS). The two subtypes showed significant differences in clinicopathology, prognosis, transcriptomics, genomics and immune microenvironment. We constructed a classification signature comprising 10 genes involved in 14 AS events using Logistic regression. The robustness of the signature was validated in three independent datasets using survival analysis. To explore AS mechanisms in LUAD, we constructed subtype-specific co-expression networks using Pearson correlation analysis. AS event of AKT3 regulated by splicing factor ENOX1 was associated with poor prognosis in LUAD. Overall, we outline AS events associated with immune infiltration in pan-cancer and this study provides insights into AS mechanisms in LUAD patient classification.