Efficient identification of trait-associated loss-of-function variants in the UK Biobank cohort by exome-sequencing based genotype imputation.

The large-scale open access whole-exome sequencing (WES) data of the UK Biobank ~200,000 participants is accelerating a new wave of genetic association studies aiming to identify rare and functional loss-of-function (LoF) variants associated with complex traits and diseases. We proposed to merge the WES genotypes and the genome-wide genotyping (GWAS) genotypes of 167,000 UKB homogeneous European participants into a combined reference panel, and then to impute 241,911 UKB homogeneous European participants who had the GWAS genotypes only. We then used the imputed data to replicate association identified in the discovery WES sample. The average imputation accuracy measure r2 is modest to high for LoF variants at all minor allele frequency intervals: 0.942 at MAF interval (0.01, 0.5), 0.807 at (1.0 × 10-3 , 0.01), 0.805 at (1.0 × 10-4 , 1.0 × 10-3 ), 0.664 at (1.0 × 10-5 , 1.0 × 10-4 ) and 0.410 at (0, 1.0 × 10-5 ). As applications, we studied associations of LoF variants with estimated heel BMD and four lipid traits. In addition to replicating dozens of previously reported genes, we also identified three novel associations, two genes PLIN1 and ANGPTL3 for high-density-lipoprotein cholesterol and one gene PDE3B for triglycerides. Our results highlighted the strength of WES based genotype imputation as well as provided useful imputed data within the UKB cohort.

The genetic architecture of age at menarche and its causal effects on other traits.

Age at menarche (AAM) is a sign of puberty of females. It is a heritable trait associated with various adult diseases. However, the genetic mechanism that determines AAM and links it to disease risk is poorly understood. Aiming to uncover the genetic basis for AAM, we conducted a joint association study in up to 438,089 women from 3 genome-wide association studies of European and East Asian ancestries. A series of bioinformatical analyses and causal inference were then followed to explore in-depth annotations at the associated loci and infer the causal relationship between AAM and other complex traits/diseases. This largest meta-analysis identified a total of 21 novel AAM associated loci at the genome wide significance level (P < 5.0 × 10-8), 4 of which were European ancestry-specific loci. Functional annotations prioritized 33 candidate genes at newly identified loci. Significant genetic correlations were observed between AAM and 67 complex traits. Further causal inference demonstrated the effects of AAM on 13 traits, including forced vital capacity (FVC), high blood pressure, age at first live birth, etc, indicating that earlier AAM causes lower FVC, worse lung function, hypertension and earlier age at first (last) live birth. Enrichment analysis identified 5 enriched tissues, including the hypothalamus middle, hypothalamo hypophyseal system, neurosecretory systems, hypothalamus and retina. Our findings may provide useful insights that elucidate the mechanisms determining AAM and the genetic interplay between AAM and some traits of women.

The fate and prospects of stem cell therapy in the treatment of hypoxic-ischemic encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) is a leading cause of long-term neurological disability in neonates and adults. Despite emerging advances in supportive care, like the most effective approach, hypothermia, poor prognosis has still been present in current clinical treatment for HIE. Stem cell therapy has been adopted for treating cerebral ischemia in preclinical and clinical trials, displaying its promising therapeutic value. At present, reported treatments for stroke employed stem cells to replace the lost neurons and integrate them into the existing host circuitry, promoting the release of growth factors to support and stimulate endogenous repair processes and so on. In this review, a meaningful overview to numerous studies published up to now was presented by introducing the preclinical and clinical research status of stem cell therapy for cerebral ischemia and hypoxia, discussing potential therapeutic mechanisms of stem cell transplantation for curing HI-induced brain injury, summarizing a series of approaches for marking transplanted cells and existing imaging systems for stem cell labelling and in vivo tracking and expounding the endogenous regeneration capability of stem cells in the newborn brain when subjected to an HI insult. Additionally, it is promising to combine stem therapy with neuromodulation through specific regulation of neural circuits. The crucial neural circuits across different brain areas related to functional recovery are of great significance for the application of neuromodulation strategies after the occurrence of neonatal hypoxic-ischemic encephalopathy (NHIE).

Causal Effects of Plasma Proteome on Osteoporosis and Osteoarthritis.

The two-sample Mendelian randomization (MR) study revealed a causal association of plasma proteins with osteoporosis (OP) and osteoarthritis (OA). Bone mineral density (BMD) is the gold standard for the clinical assessment of OP. Recent studies have shown that plasma proteins play an essential role in the regulation of bone development. However, the causal association of plasma proteins with BMD and OA remains unclear. We estimated the effects of 2889 plasma proteins on 2 BMD phenotypes and 6 OA phenotypes using two-sample MR analysis based on the genome-wide association study summary statistics. Then, we performed sensitivity analysis and reverse-direction MR analysis to evaluate the robustness of the MR analysis results, followed by gene ontology (GO) enrichment analysis and KEGG pathway analysis to explore the functional relevance of the identified plasma proteins. Overall, we observed a total of 257 protein-estimated heel BMD associations, 17 protein-total-body BMD associations, 2 protein-all-OA associations, and 2 protein-knee-OA associations at PFDR < 0.05. Reverse-direction MR analysis demonstrated that there was little evidence of the causal association of BMD and OA with plasma proteins. GO enrichment analysis and KEGG pathway analysis identified multiple pathways, which may be involved in the development of OP and OA. Our findings recognized plasma proteins that could be used to regulate changes in OP and OA, thus, providing new insights into protein-mediated mechanisms of bone development.

Screening Plasma Proteins for the Putative Drug Targets for Carpal Tunnel Syndrome.

Carpal tunnel syndrome (CTS) is one of the most common work-related musculoskeletal disorders. The present study sought to identify putative causal proteins for CTS. We conducted a two-sample Mendelian randomization (MR) analysis to evaluate the causal association between 2859 plasma proteins (N = 35,559) and CTS (N = 1,239,680) based on the published GWAS summary statistics. Then we replicated the significant associations using an independent plasma proteome GWAS (N = 10,708). Sensitivity analyses were conducted to validate the robustness of MR results. Multivariate MR and mediation analyses were conducted to evaluate the mediation effects of body mass index (BMI), type 2 diabetes (T2D), and arm tissue composition on the association between putative causal proteins and CTS. Colocalization analysis was used to examine whether the identified proteins and CTS shared causal variant(s). Finally, we evaluated druggability of the identified proteins. Ten plasma proteins were identified as putative causal markers for CTS, including sCD14, PVR, LTOR3, CTSS, SIGIRR, IFNL3, ASPN, TM11D, ASIP, and ITIH1. Sensitivity analyses and reverse MR analysis validated the robustness of their causal effects. Arm tissue composition, BMI, and T2D may play a fully/partial mediating role in the causal relationships of ASIP, TM11D, IFNL3, PVR, and LTOR3 with CTS. The association of ASPN and sCD14 with CTS were supported by colocalization analysis. Druggability assessment demonstrated that sCD14, CTSS, TM11D, and IFNL3 were potential drug therapeutic targets. The present study identified several potential plasma proteins that were causally associated with CTS risk, providing new insights into the pathogenesis of protein-mediated CTS and offering potential targets for new therapies.

Stable and Efficient Blue-Emitting CsPbBr3 Nanoplatelets with Potassium Bromide Surface Passivation.

Colloidal all-inorganic perovskites nanocrystals (NCs) have emerged as a promising material for display and lighting due to their excellent optical properties. However, blue emissive NCs usually suffer from low photoluminescence quantum yields (PLQYs) and poor stability, rendering them the bottleneck for full-color all-perovskite optoelectronic applications. Herein, a facile approach is reported to enhance the emission efficiency and stability of blue emissive perovskite nano-structures via surface passivation with potassium bromide. By adding potassium oleate and excess PbBr2 to the perovskite precursor solutions, potassium bromide-passivated (KBr-passivated) blue-emitting (≈450 nm) CsPbBr3 nanoplatelets (NPLs) is successfully synthesized with a respectably high PLQY of 87%. In sharp contrast to most reported perovskite NPLs, no shifting in emission wavelength is observed in these passivated NPLs even after prolonged exposures to intense irradiations and elevated temperature, clearly revealing their excellent photo- and thermal-stabilities. The enhancements are attributed to the formation of K-Br bonding on the surface which suppresses ion migration and formation of Br-vacancies, thus improving both the PL emission and stability of CsPbBr3 NPLs. Furthermore, all-perovskite white light-emitting diodes (WLEDs) are successfully constructed, suggesting that the proposed KBr-passivated strategy can promote the development of the perovskite family for a wider range of optoelectronic applications.

Exome-Wide Sequencing Study Identified Genetic Variants Associated With Sarcopenic Obesity.

Sarcopenic obesity (SO) is an age-related disease characterized by the coexistence of excessive adiposity and low muscle mass or function. Although obesity and sarcopenia are heritable conditions, the genetic determinants of SO have not been fully understood. We conducted a large-scale exome-wide association analysis of SO in a sequenced sample of 2 887 cases and 113 284 controls and an imputed sample of 4 003 cases and 161 990 controls in the UK Biobank cohort. Single-variant association analysis identified one locus 1q41 (lead SNP rs1417066, LYPLAL1-AS1, odds ratio [OR] = 1.15, 95% confidence interval [CI] = [1.11-1.19], p = 1.75 × 10-14) that was significantly associated with SO at the exome-wide significance level (p < 1 × 10-8). Colocalization analysis in the Genotype-Tissue Expression expression quantitative trait locus database showed that LYPLAL1-AS1 was colocalized with SO in multiple musculoskeletal-related tissues. Gene-based burden test of rare loss-of-function variants identified 5 genes at the gene-wise significance level (p < 4.3 × 10-6): PDE3B (OR = 2.48, p = 1.10 × 10-6), MYOZ3 (OR = 25.49, p = 1.41 × 10-7), SLC15A3 (OR = 4.75, p = 6.82 × 10-7), RNF130 (OR = 25.83, p = 4.07 × 10-6), and TNK2 (OR = 4.25, p = 8.75 × 10-8). Overall, our study uncovered the genetic effects of both common and rare variants on SO susceptibility, expanded existing knowledge of the genetic architecture of SO, and improved understanding of the genetic mechanisms underlying SO.

Air-Stable Self-Driven UV Photodetectors on Controllable Lead-Free CsCu2I3 Microwire Arrays.

The rapid evolution of the Internet of Things has engendered increased requirements for low-cost, self-powered UV photodetectors. Herein, high-performance self-driven UV photodetectors are fabricated by designing asymmetric metal-semiconductor-metal structures on the high-quality large-area CsCu2I3 microwire arrays. The asymmetrical depletion region doubles the photocurrent and response speed compared to the symmetric structure device, leading to a high responsivity of 233 mA/W to 355 nm radiation. Notably, at 0 V bias, the asymmetric device produces an open-circuit voltage of 356 mV and drives to a short-circuit current of 372 pA; meanwhile, the switch ratio (Iph/Idark) reaches up to 103, indicating its excellent potential for detecting weak light. Furthermore, the device maintains stable responses throughout 10000 UV-light switch cycles, with negligible degradation even after 90-day storage in air. Our work establishes that CsCu2I3 is a good candidate for self-powered UV detection and thoroughly demonstrates its potential as a passive device.

Research progress in clinical trials of stem cell therapy for stroke and neurodegenerative diseases.

The incidence of stroke and neurodegenerative diseases is gradually increasing in modern society, but there is still no treatment that is effective enough. Stem cells are cells that can reproduce (self-renew) and differentiate into the body, which have shown significance in basic research, while doctors have also taken them into clinical trials to determine their efficacy and safety. Existing clinical trials mainly include middle-aged and elderly patients with stroke or Parkinson's disease (mostly 40-80 years old), mainly involving injection of mesenchymal stem cells and bone marrow mesenchymal stem cells through the veins and the putamen, with a dosage of mostly 106-108 cells. The neural and motor functions of the patients were restored after stem cell therapy, and the safety was found to be good during the follow-up period of 3 months to 5 years. Here, we review all clinical trials and the latest advances in stroke, Alzheimer's disease, and Parkinson's disease, with the hope that stem cell therapy will be used in the clinic in the future to achieve effective treatment rates and benefit patients.

Causal associations between type 1 diabetes and COVID-19 infection and prognosis: a two-sample Mendelian randomization study.

INTRODUCTION: It has been suggested that type 1 diabetes was associated with increased COVID-19 morbidity and mortality. However, their causal relationship is still unclear. Herein, we performed a two-sample Mendelian randomization (MR) to investigate the causal effect of type 1 diabetes on COVID-19 infection and prognosis. RESEARCH DESIGN AND METHODS: The summary statistics of type 1 diabetes were obtained from two published genome-wide association studies of European population, one as a discovery sample including 15 573 cases and 158 408 controls, and the other data as a replication sample consisting of 5913 cases and 8828 controls. We first performed a two-sample MR analysis to evaluate the causal effect of type 1 diabetes on COVID-19 infection and prognosis. Then, reverse MR analysis was conducted to determine whether reverse causality exists. RESULTS: MR analysis results showed that the genetically predicted type 1 diabetes was associated with higher risk of severe COVID-19 (OR=1.073, 95% CI: 1.034 to 1.114, pFDR=1.15×10-3) and COVID-19 death (OR=1.075, 95% CI: 1.033 to 1.119, pFDR=1.15×10-3). Analysis of replication dataset showed similar results, namely a positive association between type 1 diabetes and severe COVID-19 (OR=1.055, 95% CI: 1.029 to 1.081, pFDR=1.59×10-4), and a positively correlated association with COVID-19 death (OR=1.053, 95% CI: 1.026 to 1.081, pFDR=3.50×10-4). No causal association was observed between type 1 diabetes and COVID-19 positive, hospitalized COVID-19, the time to the end of COVID-19 symptoms in the colchicine treatment group and placebo treatment group. Reverse MR analysis showed no reverse causality. CONCLUSIONS: Type 1 diabetes had a causal effect on severe COVID-19 and death after COVID-19 infection. Further mechanistic studies are needed to explore the relationship between type 1 diabetes and COVID-19 infection and prognosis.

Downregulating EVA1C exerts the potential to promote neuron growth after neonatal hypoxic-ischemic encephalopathy injury associated with alternative splicing.

Neonatal hypoxic-ischemic encephalopathy (NHIE) is one of the major diseases in newborns during the perinatal stage, which globally is the main reason for children's morbidity and mortality. However, the mechanism of NHIE still remains poorly clear. In this study, the 7-day-old rats were subjected to hypoxic-ischemia (HI), then brain damage was detected. Afterward, the expression of eva-1 homolog C (EVA1C) was measured in vitro by establishing the oxygen-glucose deprivation (OGD) model in SHSY5Y cells and human fetal neurons. Subsequently, the potential function and mechanism of EVA1C were explored by silencing EVA1C and alternative splicing prediction. As a result, obvious neurobehavioral impairment and brain infarction were detected through Zea-Longa score and TTC staining; meanwhile, neuron injury was tested by HE and Nissl staining post HI. Moreover, it was found that the expression of EVA1C was notably upregulated in SHSY5Y cells and human fetal neurons after OGD. In addition, cell survival and growth were increased after silencing EVA1C, which might be associated with alternative splicing. In conclusion, EVA1C interference exhibited potential in promoting neuron survival and growth, associated with exon skipping with the alternative splicing site in 34613318:34687258, which may provide the basis for the therapeutic target and mechanism research of NHIE.

The alternative 3' splice site of GPNMB may promote neuronal survival after neonatal hypoxic-ischemic encephalopathy injury.

This study aimed to decipher the effect of glycoprotein nonmetastatic melanoma protein B (GPNMB) on neonatal hypoxic-ischemic encephalopathy (NHIE) and its potential molecular mechanism. The hypoxic-ischemic (HI) model was established in 7-day-old rats, and then, Zea-Longa scores and Nissl staining were performed to measure brain damage post-HI. In addition, gene sequencing was used to detect the differential expression genes (DEGs), and then, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases were used to determine the function of DEGs. Furthermore, an oxygen-glucose deprivation (OGD) model was developed in SY5Y cells and human fetal neurons, and then, the level of GPNMB was verified by quantitative real-time polymerase chain reaction. In addition, methyl thiazolyl tetrazolium and cell counting kit-8 assays were applied after GPNMB interference. Finally, the alternative splicing of GPNMB expression was analyzed using Splice Grapher software. The results indicated that HI induced marked neurological impairment and neuron injury in rats. Also, GPNMB was the most obviously upregulated gene in DEGs. Additionally, GPNMB was upregulated significantly in SY5Y and fetal neurons after OGD, and GPNMB-si promoted an increase in cell viability and number. Moreover, we found that the GPNMB alternative splicing type was the Alternative 3' splice site, with the alternative splicing site in 143382985:143404102. Herein, GPNMB promotes a crucial regulatory mechanism with alternative splicing for neuronal survival after NHIE.

The differentially expressed proteins related to clinical viral encephalitis revealed by proteomics.

To screen out the prospective biomarkers of viral encephalitis (VE), analyze the biological process and signaling pathways involved by differentially expressed proteins (DEPs). A total of 11 cerebrospinal fluid (CSF) samples with VE and 5 with non-nervous system infection were used to perform label-free proteomic techniques. Then, the bioinformatic analysis of DEPs was applied by Interproscan software. Moreover, 73 CSF samples in the VE group and 53 in the control group were used to verify the changes of some DEPs by enzyme-linked immunosorbent assay (ELISA). Thirty-nine DEPs were identified, including 18 upregulated DEPs and 21 downregulated DEPs. DEPs were mainly enriched in cell adhesion molecules by Kyoto Encyclopedia of Genes and Genomes analysis pathway analysis. The DEPs related to axon tissue were obviously downregulated and the most significant downregulated proteins were neurexin 3, neurofascin, and neuroligin 2 (NLGN2). Moreover, the protein expression of NLGN2 in the VE group was significantly higher than that in the control group by ELISA. The correlation analysis of NLGN2 in the VE group revealed that there was a weak positive correlation with CSF protein and a weak negative correlation with CSF chloride. The clinical VE may be closely related to NLGN2 and the cell adhesion molecule pathway.

Mendelian Randomization Analysis Reveals Causal Effects of Plasma Proteome on Body Composition Traits.

CONTEXT: Observational studies have demonstrated associations between plasma proteins and obesity, but evidence of causal relationship remains to be studied. OBJECTIVE: We aimed to evaluate the causal relationship between plasma proteins and body composition. METHODS: We conducted a 2-sample Mendelian randomization (MR) analysis based on the genome-wide association study (GWAS) summary statistics of 23 body composition traits and 2656 plasma proteins. We then performed hierarchical cluster analysis to evaluate the structure and pattern of the identified causal associations, and we performed gene ontology enrichment analysis to explore the functional relevance of the identified proteins. RESULTS: We identified 430 putatively causal effects of 96 plasma proteins on 22 body composition traits (except obesity status) with strong MR evidence (P < 2.53 × 10 - 6, at a Bonferroni-corrected threshold). The top 3 causal associations are follistatin (FST) on trunk fat-free mass (Beta = -0.63, SE = 0.04, P = 2.00 × 10-63), insulin-like growth factor-binding protein 1 (IGFBP1) on trunk fat-free mass (Beta = -0.54, SE = 0.03, P = 1.79 × 10-57) and r-spondin-3 (RSPO3) on WHR (waist circumference/hip circumference) (Beta = 0.01, SE = 4.47 × 10-4, P = 5.45 × 10-60), respectively. Further clustering analysis and pathway analysis demonstrated that the pattern of causal effect to fat mass and fat-free mass may be different. CONCLUSION: Our findings may provide evidence for causal relationships from plasma proteins to various body composition traits and provide basis for further targeted functional studies.

Population pharmacokinetics of intravenous colistin sulfate and dosage optimization in critically ill patients.

Aims: To explore the population pharmacokinetics of colistin sulfate and to optimize the dosing strategy for critically ill patients. Methods: The study enrolled critically ill adult patients who received colistin sulfate intravenously for more than 72 h with at least one measurement of plasma concentration. Colistin concentrations in plasma or urine samples were measured by ultraperformance liquid chromatography tandem mass spectrometry (LC-MS/MS). The population pharmacokinetics (PPK) model for colistin sulfate was developed using the Phoenix NLME program. Monte Carlo simulation was conducted to evaluate the probability of target attainment (PTA) for optimizing dosing regimens. Results: A total of 98 plasma concentrations from 20 patients were recorded for PPK modeling. The data were adequately described by a two-compartment model with linear elimination. During modeling, creatinine clearance (CrCL) and alanine aminotransferase (ALT) were identified as covariates of the clearance (CL) and volume of peripheral compartment distribution (V2), respectively. In addition, colistin sulfate was predominantly cleared by the nonrenal pathway with a median urinary recovery of 10.05% with large inter-individual variability. Monte Carlo simulations revealed a greater creatinine clearance associated with a higher risk of sub-therapeutic exposure to colistin sulfate. The target PTA (≥90%) of dosage regimens recommended by the label sheet was achievable only in patients infected by pathogens with MIC ≤0.5 mg/L or with renal impairments. Conclusion: Our study showed that the dose of intravenous colistin sulfate was best adjusted by CrCL and ALT. Importantly, the recommended dosing regimen of 1.0-1.5 million units daily was insufficient for patients with normal renal functions (CrCL ≥80 ml/min) or those infected by pathogens with MIC ≥1.0 mg/L. The dosage of colistin sulfate should be adjusted according to renal function and drug exposure.

Enhanced Optoelectronic Performance Induced by Ion Migration in Lead-Free CsCu2I3 Single-Crystal Microrods.

Lead-free perovskite has attracted great attention in realizing high-performance optoelectronic devices due to their excellent atmospheric stability and nontoxic characteristics. Although a pronounced ion migration effect has been observed in this new class of materials, its potential in enhancing the overall device performance is yet to be fully explored. In this work, we studied the effect of ion migrations on the carrier transport behavior and found that the recoverable migration process can contribute to enhancing the on/off ratio in a lead-free CsCu2I3 single-crystal microrod-based photodetector. In detail, we synthesized CsCu2I3 single-crystal microrods via an in-plane self-assembly supersaturated crystallization approach. These microrods with well-defined morphologies were then used to construct ultraviolet (UV)-band photodetectors, which outperform most reported lead-free perovskite photodetectors based on individual single crystals. Simultaneously, ion migration can result in asymmetric band bending in the two-terminal device, as confirmed by surface potential profiling with Kelvin probe force microscopy (KPFM). Such an effect can be harnessed to increase the on/off ratio by almost an order of magnitude. Furthermore, the lead-free CsCu2I3 single crystal exhibits excellent thermal and air stabilities. These findings demonstrate that the CsCu2I3 single-crystal microrods can be used in stable and efficient photodetection, and the ion migration effect can potentially be utilized for improving the optoelectronic performance of lead-free devices.

Mendelian randomization analysis identified causal Association of Childhood Obesity with adult major depressive disorder.

BACKGROUND: Childhood obesity is associated with adult major depressive disorder (MDD), but their causality is not clear. METHODS: We performed a two-sample Mendelian randomization (MR) analysis to explore the causality of childhood body mass index (BMI) and childhood obesity on MDD, followed by a multivariable MR (MVMR) analysis to investigate the potential role of adult BMI in mediating such effect. We accessed genome-wide association summary statistics of childhood BMI, childhood obesity, adult BMI and adult MDD from the Early Growth Genetics consortium (nBMI  = 47 541, nobesity  = 24 160), the Genetic Investigation of Anthropometric Traits consortium (nadult_BMI  = âˆ¼700 000) and the Psychiatric Genomics consortium (nMDD  = 500 199), respectively. The MR-PRESSO test was performed to remove SNPs with potential pleiotropic effect. The MR analysis was performed by inverse-variance weighted test. Further sensitivity analyses, including the MR-Egger intercept test and leave-one-out analysis, were performed to evaluate the reliability of the results. RESULTS: Our study found that childhood obesity might increase the odds of developing MDD in adults (OR = 1.03, 95% CI: 1.01-1.06, p = 2.6 × 10-3 ). Children with higher BMI were more likely to develop MDD in adulthood, with an OR of 1.12 per standard deviation score (SDS) increase in BMI (95% CI: 1.07-1.17, p = 4.4 × 10-7 ). Sensitivity analyses verified the reliability of the causality between childhood BMI/obesity and MDD. Further MVMR results revealed that the impact of childhood BMI on MDD risk was predominantly mediated by adult BMI. CONCLUSION: Our findings provided evidence of a causal relationship between childhood BMI/obesity and adult MDD, thus providing new insights into the prevention of MDD.

Molecular alterations differentiate microinvasive carcinoma from ductal carcinoma in situ and invasive breast carcinoma: retrospective analysis of a large single-center series.

Microinvasive carcinoma (MIC) of the breast is a rare lesion. The clinicopathologic features and biologic behavior of MIC are unclear. Whether MIC is a distinct entity or an interim stage in the progression from ductal carcinoma in situ (DCIS) to invasive breast carcinoma (IBC) remains to be determined. A retrospective review of clinicopathologic features and analysis of the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), and Ki-67 in patients with MIC (90 cases), DCIS (268 cases) and IBC (1504 cases) was performed. Most MICs (93.3%) exhibited an intermediate to high nuclear grade, and this proportion was larger than that of DCIS (62.7%, P < 0.001) or IBC (85.4%, P = 0.036). The incidence of sentinel lymph node metastasis in MIC (12.5%) was higher than that of DCIS (1.6%, P < 0.001), but much lower than that of IBC (39.7%, P < 0.001). MICs had higher expression of HER-2 and lower expression of ER and PR compared to DCIS and IBC; and MIC was more likely to present with a HER-2+ subtype. Furthermore, DCIS exhibited greater HER-2 overexpression or gene amplification (P < 0.001) levels and lower proliferation index of Ki-67 (P < 0.001) compared to IBC. Our results suggest that the clinicopathologic and molecular phenotype of MIC are different from DCIS and IBC. Thus, MIC may be a distinct entity rather than an interim stage in the progression from DCIS to IBC. The prognosis of MIC and the biologic behavior of this uncommon subset need to be further explored.

Causal Relationship Between Gut Microbiota and Autoimmune Diseases: A Two-Sample Mendelian Randomization Study.

Background: Growing evidence has shown that alterations in gut microbiota composition are associated with multiple autoimmune diseases (ADs). However, it is unclear whether these associations reflect a causal relationship. Objective: To reveal the causal association between gut microbiota and AD, we conducted a two-sample Mendelian randomization (MR) analysis. Materials and Methods: We assessed genome-wide association study (GWAS) summary statistics for gut microbiota and six common ADs, namely, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, type 1 diabetes (T1D), and celiac disease (CeD), from published GWASs. Two-sample MR analyses were first performed to identify causal bacterial taxa for ADs in discovery samples. Significant bacterial taxa were further replicated in independent replication outcome samples. A series of sensitivity analyses was performed to validate the robustness of the results. Finally, a reverse MR analysis was performed to evaluate the possibility of reverse causation. Results: Combining the results from the discovery and replication stages, we identified one causal bacterial genus, Bifidobacterium. A higher relative abundance of the Bifidobacterium genus was associated with a higher risk of T1D [odds ratio (OR): 1.605; 95% CI, 1.339-1.922; PFDR = 4.19 × 10-7] and CeD (OR: 1.401; 95% CI, 1.139-1.722; PFDR = 2.03 × 10-3), respectively. Further sensitivity analyses validated the robustness of the above associations. The results of reverse MR analysis showed no evidence of reverse causality from T1D and CeD to the Bifidobacterium genus. Conclusion: This study implied a causal relationship between the Bifidobacterium genus and T1D and CeD, thus providing novel insights into the gut microbiota-mediated development mechanism of ADs.

Gut Microbiota and Psychiatric Disorders: A Two-Sample Mendelian Randomization Study.

Evidence supports the observational associations of gut microbiota with a variety of psychiatric disorders, but the causal nature of such associations remains obscure. Aiming to comprehensively investigate their causal relationship and to identify specific causal microbe taxa for psychiatric diseases, we conducted a two-sample Mendelian randomization (MR) analysis of gut microbiome with 15 psychiatric diseases. Specifically, the microbiome genome-wide association study (GWAS) in 18,473 individuals from the MiBioGen study was used as exposure sample, and the GWAS for 15 psychiatric diseases was used as outcome samples. One-hundred ninety bacterial taxa from six levels were available for analysis. At a multiple-testing corrected significance level (phylum P < 5.56 × 10-3, class P < 3.33 × 10-3, order P < 2.63 × 10-3, family P < 1.67 × 10-3, genus P < 4.90 × 10-4, and species P < 3.33 × 10-3), the following eight causal associations from seven bacterial features (one phylum + three classes + one order + one family + one species) were identified: family Prevotellaceae with autism spectrum disorder (P = 5.31 × 10-4), class Betaproteobacteria with bipolar disorder (P = 1.53 × 10-3), class Actinobacteria with schizophrenia (P = 1.33 × 10-3), class Bacteroidia and order Bacteroidales with Tourette syndrome (P = 2.51 × 10-3 and 2.51 × 10-3), phylum Actinobacteria and class Actinobacteria with extroversion (P = 8.22 × 10-4 and 1.09 × 10-3), and species Clostridium innocuum with neuroticism (P = 8.92 × 10-4). Sensitivity analysis showed no evidence of reverse causality, pleiotropy, and heterogeneity. Our findings offered novel insights into the gut microbiota-mediated development mechanism of psychiatric disorders.