Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias.

The epidermal growth factor receptor (EGFR) is frequently mutated in human cancer1,2, and is an important therapeutic target. EGFR inhibitors have been successful in lung cancer, where mutations in the intracellular tyrosine kinase domain activate the receptor1, but not in glioblastoma multiforme (GBM)3, where mutations occur exclusively in the extracellular region. Here we show that common extracellular GBM mutations prevent EGFR from discriminating between its activating ligands4. Different growth factor ligands stabilize distinct EGFR dimer structures5 that signal with different kinetics to specify or bias outcome5,6. EGF itself induces strong symmetric dimers that signal transiently to promote proliferation. Epiregulin (EREG) induces much weaker asymmetric dimers that drive sustained signalling and differentiation5. GBM mutations reduce the ability of EGFR to distinguish EREG from EGF in cellular assays, and allow EGFR to form strong (EGF-like) dimers in response to EREG and other low-affinity ligands. Using X-ray crystallography, we further show that the R84K GBM mutation symmetrizes EREG-driven extracellular dimers so that they resemble dimers normally seen with EGF. By contrast, a second GBM mutation, A265V, remodels key dimerization contacts to strengthen asymmetric EREG-driven dimers. Our results argue for an important role of altered ligand discrimination by EGFR in GBM, with potential implications for therapeutic targeting.

A statistical framework to identify cell types whose genetically regulated proportions are associated with complex diseases.

Finding disease-relevant tissues and cell types can facilitate the identification and investigation of functional genes and variants. In particular, cell type proportions can serve as potential disease predictive biomarkers. In this manuscript, we introduce a novel statistical framework, cell-type Wide Association Study (cWAS), that integrates genetic data with transcriptomics data to identify cell types whose genetically regulated proportions (GRPs) are disease/trait-associated. On simulated and real GWAS data, cWAS showed good statistical power with newly identified significant GRP associations in disease-associated tissues. More specifically, GRPs of endothelial and myofibroblasts in lung tissue were associated with Idiopathic Pulmonary Fibrosis and Chronic Obstructive Pulmonary Disease, respectively. For breast cancer, the GRP of blood CD8+ T cells was negatively associated with breast cancer (BC) risk as well as survival. Overall, cWAS is a powerful tool to reveal cell types associated with complex diseases mediated by GRPs.

Loureirin B improves H/R-induced hepatic ischemia-reperfusion injury by downregulating ALOX5 to regulate mitochondrial homeostasis.

This study was conceived to explore the role and the mechanism of Loureirin B (LB) in hepatic IRI. The viability of LB-treated AML-12 cells was assessed using CCK-8 assay and inflammatory cytokines were detected using ELISA. The activities of ROS and oxidative stress markers MDA, SOD, and GSH-Px were detected using DCFH-DA and corresponding assay kits. The cell apoptosis and caspase3 activity were estimated with flow cytometry and caspase3 assay kits. The expressions of arachidonate 5-lipoxygenase (ALOX5) and apoptosis- and mitochondrial dynamics-related proteins were detected using western blot. The interaction between LB and ALOX5 was analyzed with molecular docking. The transfection efficacy of oe-ALOX5 was examined with RT-qPCR and western blot. Mitochondrial membrane potential was detected with JC-1 staining and immunofluorescence (IF) assay was employed to estimate mitochondrial fusion and fission. The present work found that LB revived the viability, inhibited inflammatory response, suppressed oxidative stress, repressed the apoptosis, and maintained mitochondrial homeostasis in H/R-induced AML-12 cells, which were all reversed by ALOX5 overexpression. Collectively, LB regulated mitochondrial homeostasis by downregulating ALOX5, thereby improving hepatic IRI.

SUPERGNOVA: local genetic correlation analysis reveals heterogeneous etiologic sharing of complex traits.

Local genetic correlation quantifies the genetic similarity of complex traits in specific genomic regions. However, accurate estimation of local genetic correlation remains challenging, due to linkage disequilibrium in local genomic regions and sample overlap across studies. We introduce SUPERGNOVA, a statistical framework to estimate local genetic correlations using summary statistics from genome-wide association studies. We demonstrate that SUPERGNOVA outperforms existing methods through simulations and analyses of 30 complex traits. In particular, we show that the positive yet paradoxical genetic correlation between autism spectrum disorder and cognitive performance could be explained by two etiologically distinct genetic signatures with bidirectional local genetic correlations.

Transcriptome-wide association analysis of brain structures yields insights into pleiotropy with complex neuropsychiatric traits.

Structural variations of the human brain are heritable and highly polygenic traits, with hundreds of associated genes identified in recent genome-wide association studies (GWAS). Transcriptome-wide association studies (TWAS) can both prioritize these GWAS findings and also identify additional gene-trait associations. Here we perform cross-tissue TWAS analysis of 211 structural neuroimaging and discover 278 associated genes exceeding Bonferroni significance threshold of 1.04 × 10-8. The TWAS-significant genes for brain structures have been linked to a wide range of complex traits in different domains. Through TWAS gene-based polygenic risk scores (PRS) prediction, we find that TWAS PRS gains substantial power in association analysis compared to conventional variant-based GWAS PRS, and up to 6.97% of phenotypic variance (p-value = 7.56 × 10-31) can be explained in independent testing data sets. In conclusion, our study illustrates that TWAS can be a powerful supplement to traditional GWAS in imaging genetics studies for gene discovery-validation, genetic co-architecture analysis, and polygenic risk prediction.

A convenient polyculture system that controls a shrimp viral disease with a high transmission rate.

Developing ecological approaches for disease control is critical for future sustainable aquaculture development. White spot syndrome (WSS), caused by white spot syndrome virus (WSSV), is the most severe disease in cultured shrimp production. Culturing specific pathogen-free (SPF) broodstock is an effective and widely used strategy for controlling WSS. However, most small-scale farmers, who predominate shrimp aquaculture in developing countries, cannot cultivate SPF shrimp, as they do not have the required infrastructure and skills. Thus, these producers are more vulnerable to WSS outbreaks than industrial farms. Here we developed a shrimp polyculture system that prevents WSS outbreaks by introducing specific fish species. The system is easy to implement and requires no special biosecurity measures. The promotion of this system in China demonstrated that it allowed small-scale farmers to improve their livelihood through shrimp cultivation by controlling WSS outbreaks and increasing the production of ponds.

Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection.

Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15-1.36; P = 1.8 × 10-7), including sepsis (HR 2.68; 95% CI = 2.25-3.19; P = 3.1 × 10-28), pneumonia (HR 1.76; 95% CI = 1.53-2.03; P = 2.3 × 10-15), digestive system infections (HR 1.51; 95% CI = 1.32-1.73; P = 2.2 × 10-9) and genitourinary infections (HR 1.25; 95% CI = 1.11-1.41; P = 3.7 × 10-4). A genome-wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.

Local delivery of sunitinib and Ce6 via redox-responsive zwitterionic hydrogels effectively prevents osteosarcoma recurrence.

Surgery combined with adjuvant or neoadjuvant chemotherapy is still the standard treatment for osteosarcoma. However, the high risk of tumor recurrence and side effects of chemotherapy usually lead to high mortality for cancer patients. Herein, the multi-targeted receptor tyrosine kinase (RTK) inhibitor sunitinib (Sun) and photodynamic therapy (PDT) drug chlorin e6 (Ce6) were locally delivered to the postoperative tumor site via a zwitterionic hydrogel. This hydrogel exhibited excellent biocompatibility and redox responsiveness. In vitro study demonstrated that Sun/Ce6@Gel induced 143B human osteosarcoma cell apoptosis via downregulating the expression of Bcl-2 and upregulating the expression levels of Bax and caspase-3. Similarly, the in vivo study showed that Sun/Ce6@Gel provided sustained drug release under redox conditions, and then synergistically induced tumor apoptosis to prevent tumor recurrence without systemic toxicity. Therefore, local implantation of Sun/Ce6@Gel may be a promising topical therapeutic method for prevention of the recurrence of osteosarcoma after surgery.

Hematopoietic mosaic chromosomal alterations and risk for infection among 767,891 individuals without blood cancer.

Age is the dominant risk factor for infectious diseases, but the mechanisms linking the two are incompletely understood1,2. Age-related mosaic chromosomal alterations (mCAs) detected from blood-derived DNA genotyping, are structural somatic variants associated with aberrant leukocyte cell counts, hematological malignancy, and mortality3-11. Whether mCAs represent independent risk factors for infection is unknown. Here we use genome-wide genotyping of blood DNA to show that mCAs predispose to diverse infectious diseases. We analyzed mCAs from 767,891 individuals without hematological cancer at DNA acquisition across four countries. Expanded mCA (cell fraction >10%) prevalence approached 4% by 60 years of age and was associated with diverse incident infections, including sepsis, pneumonia, and coronavirus disease 2019 (COVID-19) hospitalization. A genome-wide association study of expanded mCAs identified 63 significant loci. Germline genetic alleles associated with expanded mCAs were enriched at transcriptional regulatory sites for immune cells. Our results link mCAs with impaired immunity and predisposition to infections. Furthermore, these findings may also have important implications for the ongoing COVID-19 pandemic, particularly in prioritizing individual preventive strategies and evaluating immunization responses.

Hematopoietic mosaic chromosomal alterations and risk for infection among 767,891 individuals without blood cancer.

Age is the dominant risk factor for infectious diseases, but the mechanisms linking the two are incompletely understood1,2. Age-related mosaic chromosomal alterations (mCAs) detected from blood-derived DNA genotyping, are structural somatic variants associated with aberrant leukocyte cell counts, hematological malignancy, and mortality3-11. Whether mCAs represent independent risk factors for infection is unknown. Here we use genome-wide genotyping of blood DNA to show that mCAs predispose to diverse infectious diseases. We analyzed mCAs from 767,891 individuals without hematological cancer at DNA acquisition across four countries. Expanded mCA (cell fraction >10%) prevalence approached 4% by 60 years of age and was associated with diverse incident infections, including sepsis, pneumonia, and coronavirus disease 2019 (COVID-19) hospitalization. A genome-wide association study of expanded mCAs identified 63 significant loci. Germline genetic alleles associated with expanded mCAs were enriched at transcriptional regulatory sites for immune cells. Our results link mCAs with impaired immunity and predisposition to infections. Furthermore, these findings may also have important implications for the ongoing COVID-19 pandemic, particularly in prioritizing individual preventive strategies and evaluating immunization responses.

A Pathway-Based Kernel Boosting Method for Sample Classification Using Genomic Data.

The analysis of cancer genomic data has long suffered "the curse of dimensionality." Sample sizes for most cancer genomic studies are a few hundreds at most while there are tens of thousands of genomic features studied. Various methods have been proposed to leverage prior biological knowledge, such as pathways, to more effectively analyze cancer genomic data. Most of the methods focus on testing marginal significance of the associations between pathways and clinical phenotypes. They can identify informative pathways but do not involve predictive modeling. In this article, we propose a Pathway-based Kernel Boosting (PKB) method for integrating gene pathway information for sample classification, where we use kernel functions calculated from each pathway as base learners and learn the weights through iterative optimization of the classification loss function. We apply PKB and several competing methods to three cancer studies with pathological and clinical information, including tumor grade, stage, tumor sites and metastasis status. Our results show that PKB outperforms other methods and identifies pathways relevant to the outcome variables.

A statistical framework for cross-tissue transcriptome-wide association analysis.

Transcriptome-wide association analysis is a powerful approach to studying the genetic architecture of complex traits. A key component of this approach is to build a model to impute gene expression levels from genotypes by using samples with matched genotypes and gene expression data in a given tissue. However, it is challenging to develop robust and accurate imputation models with a limited sample size for any single tissue. Here, we first introduce a multi-task learning method to jointly impute gene expression in 44 human tissues. Compared with single-tissue methods, our approach achieved an average of 39% improvement in imputation accuracy and generated effective imputation models for an average of 120% more genes. We describe a summary-statistic-based testing framework that combines multiple single-tissue associations into a powerful metric to quantify the overall gene-trait association. We applied our method, called UTMOST (unified test for molecular signatures), to multiple genome-wide-association results and demonstrate its advantages over single-tissue strategies.

The barbed suture of deep fascia walks away and pierces through skin far from the incision - a case report.

Barbed suture has been widely used in surgeries. However, this technique may raise many problems. Here, we report that the barbed suture of deep fascia walks away and pierces through skin far from the incision in a 61-year-old male 6 weeks after total hip arthroplasty.

Exposing the transverse acetabular ligament in the presence of large floor osteophytes in primary total hip arthroplasty.

BACKGROUND/OBJECTIVE: The transverse acetabular ligament (TAL) can be used to position the acetabular cup and may help to improve the accuracy of primary total hip arthroplasty (THA). However, because the TAL may be covered by osteophytes, the ability to find the TAL varies greatly in the reported literature. In the present study, we introduce 2 methods and make a comparison between them to identify the easier procedure for finding an osteophyte-covered TAL. METHODS: During primary THA operations conducted from January 2012 to June 2015, a total of 100 patients (100 hips) were confirmed to have an osteophyte-covered TAL following the exposure of the acetabulum and removal of all soft tissues covering the TAL. These 100 patients were enrolled in this study. 2 methods were used to identify the TAL: the use of a bone chisel or a small reamer, and patients were allocated randomly to 1 of these 2 methods. The proportion of patients in whom TAL was identified was compared between the 2 methods using the chi-square test. RESULTS: The percentage of patients in whom the TAL was found using a bone chisel was 54.1% (26/48), whereas the percentage was 94.2% (49/52) in patients for whom a small reamer was used. The difference between the 2 methods was statistically significant (chi-square test, p<0.05). CONCLUSIONS: The TAL can be found more easily with a small reamer than with a bone chisel.

Downregulation of IL-10 secretion by Treg cells in osteoarthritis is associated with a reduction in Tim-3 expression.

Knee osteoarthritis (OA) is the most common cause of musculoskeletal pain and disability in the knee. Though traditionally thought a mechanical wear-and-tear disease, in recent years, knee OA as a low-grade, chronic inflammatory disease has been increasingly recognized. In this study, we examined the Treg responses in non-obese knee OA patients at different stages. Significantly elevated frequencies of CD4(+)CD25(+)Foxp3(+) Tregs were found in OA patients, while on the other hand, lower IL-10 secretion from Tregs in OA patients was observed. Importantly, this decrease in IL-10 was associated with reduced Tim-3 expression on Tregs. Although both Tim-3(-) and Tim3(+) Tregs could secrete IL-10, the majority of IL-10 was observed in Tim-3(+) Tregs. Reduction of Tim-3(+) Tregs in OA patients resulted in less IL-10-producing Tregs. Interestingly, the OA patients in more advanced stages showed further reductions in IL-10 and Tim-3 expression. In conclusion, our results revealed an immunoregulatory disorder in OA independent of obesity, and demonstrated a potential mechanism in establishing the proinflammatory status of OA patients.