Contribution of CRISPRable DNA to human complex traits

CRISPR-Cas is a powerful genome editing tool for various species and human cell lines, widely used in many research areas including studying the mechanisms, targets, and gene therapies of human diseases. Recent developments have even allowed high-throughput genetic screening using the CRISPR system. However, due to the practical and ethical limitations in human gene editing research, little is known about whether CRISPR-editable DNA segments could influence human complex traits or diseases. Here, we investigated the human genomic regions condensed with different CRISPR Cas enzymes’ protospacer-adjacent motifs (PAMs). We found that Cas enzymes with GC-rich PAMs could interfere more with the genomic regions that harbor enriched heritability for human complex traits and diseases. The results linked GC content across the genome to the functional genomic elements in the heritability enrichment of human complex traits. We provide a genetic overview of the effects of high-throughput genome editing on human complex traits

Automatic optimum order assignment in IIR adaptive filters

金沢大学理工研究域　電子情報学

A retrospective analysis of factors associated with the length of hospital stay in COVID-19 patients treated with Nirmatrelvir / Ritonavir

Objectives: This study reviewed factors influencing the length of hospital stay in adult inpatients with confirmed Coronavirus disease (COVID-19) who were treated with Nirmatrelvir/Ritonavir.Methods: We did a retrospective analysis of data from a cohort of inpatients with confirmed diagnosis of Omicron variant of SARS-CoV-2 infection who were treated with Nirmatrelvir/Ritonavir. We included patients who were treated from 13th March 2022 to 6th May 2022 in various in-patient treatment units in Quanzhou, Fujian Province, China. The primary study outcome was the length of hospital stay. Secondary study outcome was viral elimination defined as negative for ORF1ab and N genes [cycle threshold (Ct) value ≥35 in real-time PCR], according to local guidelines. Hazard ratios (HR) of event outcomes were analyzed using Multivariate Cox regression models.Results: We studied 31 inpatients with high risk for severe COVID-19 who were treated with Nirmatrelvir/Ritonavir. We found that inpatients with shorter length of hospital stay (≤17 days) were mostly females with lower body mass index (BMI) and Charlson Comorbidity Index (CCI) index. Their treatment regimen with Nirmatrelvir/Ritonavir was started within 5 days of diagnosis (p < 0.05). Multivariate Cox regression indicated that inpatients starting treatment of Nirmatrelvir/Ritonavir within 5 days had a shorter length of hospital stay (HR 3.573, p = 0.004) and had a faster clearance of viral load (HR 2.755, p = 0.043).Conclusion: This study assumes relevance during the Omicron BA.2 epidemic as our findings suggest that early treatment with Nirmatrelvir/Ritonavir within 5 days of diagnosis (≤5 days) was highly effective in shortening the length of hospital stay and faster viral load clearance

Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma

Published in final edited form as: Sci Transl Med. 2017 May 10; 9(389). https://doi.org/10.1126/scitranslmed.aal2668.Multiple myeloma (MM) is a frequently incurable hematological cancer in which overactivity of MYC plays a central role, notably through up-regulation of ribosome biogenesis and translation. To better understand the oncogenic program driven by MYC and investigate its potential as a therapeutic target, we screened a chemically diverse small-molecule library for anti-MM activity. The most potent hits identified were rocaglate scaffold inhibitors of translation initiation. Expression profiling of MM cells revealed reversion of the oncogenic MYC-driven transcriptional program by CMLD010509, the most promising rocaglate. Proteome-wide reversion correlated with selective depletion of short-lived proteins that are key to MM growth and survival, most notably MYC, MDM2, CCND1, MAF, and MCL-1. The efficacy of CMLD010509 in mouse models of MM confirmed the therapeutic relevance of these findings in vivo and supports the feasibility of targeting the oncogenic MYC-driven translation program in MM with rocaglates

Development and evaluation of a risk prediction model for diabetes mellitus type 2 patients with vision-threatening diabetic retinopathy

ObjectiveThis study aims to develop and evaluate a non-imaging clinical data-based nomogram for predicting the risk of vision-threatening diabetic retinopathy (VTDR) in diabetes mellitus type 2 (T2DM) patients.MethodsBased on the baseline data of the Guangdong Shaoguan Diabetes Cohort Study conducted by the Zhongshan Ophthalmic Center (ZOC) in 2019, 2294 complete data of T2DM patients were randomly divided into a training set (n=1605) and a testing set (n=689). Independent risk factors were selected through univariate and multivariate logistic regression analysis on the training dataset, and a nomogram was constructed for predicting the risk of VTDR in T2DM patients. The model was evaluated using receiver operating characteristic (ROC) curves and area under the curve (AUC) in the training and testing datasets to assess discrimination, and Hosmer-Lemeshow test and calibration curves to assess calibration.ResultsThe results of the multivariate logistic regression analysis showed that Age (OR = 0.954, 95% CI: 0.940-0.969, p = 0.000), BMI (OR = 0.942, 95% CI: 0.902-0.984, p = 0.007), systolic blood pressure (SBP) (OR =1.014, 95% CI: 1.007-1.022, p = 0.000), diabetes duration (10-15y: OR =3.126, 95% CI: 2.087-4.682, p = 0.000; >15y: OR =3.750, 95% CI: 2.362-5.954, p = 0.000), and glycated hemoglobin (HbA1C) (OR = 1.325, 95% CI: 1.221-1.438, p = 0.000) were independent risk factors for T2DM patients with VTDR. A nomogram was constructed using these variables. The model discrimination results showed an AUC of 0.7193 for the training set and 0.6897 for the testing set. The Hosmer-Lemeshow test results showed a high consistency between the predicted and observed probabilities for both the training set (Chi-square=2.2029, P=0.9742) and the testing set (Chi-square=7.6628, P=0.4671).ConclusionThe introduction of Age, BMI, SBP, Duration, and HbA1C as variables helps to stratify the risk of T2DM patients with VTDR

Biosensors fabricated by laser-induced metallization on DLP composite resin

With the growing emphasis on medical testing, people are seeking more technologies to detect indexes of the human body quickly and at a low cost. The electrochemical biosensors became a research hotspot due to their excellent properties. In this study, dicopper hydroxide phosphate (Cu2(OH)PO4) was incorporated in resin, and the resin sheets were prepared by digital light processing (DLP). The copper base points were activated on the resin sheet surface by Nd: YAG laser and then covered by the electroless copper plating and the electroless silver plating. The laser could effectively activate copper base points on the resin surface. Furthermore, silver electrodes on the detection chips could distinguish glucose solutions of different concentrations well. Finally, a novel detection kit with a three-electrode chip was designed for rapid health testing at home or in medical institutions in the future

Genetic Incorporation of Unnatural Amino Acids into Proteins in Mycobacterium tuberculosis

New tools are needed to study the intracellular pathogen Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), to facilitate new drug discovery and vaccine development. We have developed methodology to genetically incorporate unnatural amino acids into proteins in Mycobacterium smegmatis, BCG and Mtb, grown both extracellularly in culture and inside host cells. Orthogonal mutant tRNATyr/tyrosyl-tRNA synthetase pairs derived from Methanococcus jannaschii and evolved in Escherichia coli incorporate a variety of unnatural amino acids (including photocrosslinking, chemically reactive, heavy atom containing, and immunogenic amino acids) into proteins in response to the amber nonsense codon. By taking advantage of the fidelity and suppression efficiency of the MjtRNA/pIpaRS pair in mycobacteria, we are also able to use p-iodophenylalanine to induce the expression of proteins in mycobacteria both extracellularly in culture and inside of mammalian host cells. This provides a new approach to regulate the expression of reporter genes or mycobacteria endogenous genes of interest. The establishment of the unnatural amino acid expression system in Mtb, an intracellular pathogen, should facilitate studies of TB biology and vaccine development

Genetic Landscape of the ACE2 Coronavirus Receptor

Background:SARS-CoV-2, the causal agent of COVID-19, enters human cells using the ACE2 (angiotensin-converting enzyme 2) protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart and respiratory and gastrointestinal tracts, playing important regulatory roles in the cardiovascular and other biological systems. However, the genetic basis of the ACE2 protein levels is not well understood.Methods:We have conducted the largest genome-wide association meta-analysis of plasma ACE2 levels in >28 000 individuals of the SCALLOP Consortium (Systematic and Combined Analysis of Olink Proteins). We summarize the cross-sectional epidemiological correlates of circulating ACE2. Using the summary statistics–based high-definition likelihood method, we estimate relevant genetic correlations with cardiometabolic phenotypes, COVID-19, and other human complex traits and diseases. We perform causal inference of soluble ACE2 on vascular disease outcomes and COVID-19 severity using mendelian randomization. We also perform in silico functional analysis by integrating with other types of omics data.Results:We identified 10 loci, including 8 novel, capturing 30% of the heritability of the protein. We detected that plasma ACE2 was genetically correlated with vascular diseases, severe COVID-19, and a wide range of human complex diseases and medications. An X-chromosome cis–protein quantitative trait loci–based mendelian randomization analysis suggested a causal effect of elevated ACE2 levels on COVID-19 severity (odds ratio, 1.63 [95% CI, 1.10–2.42]; P=0.01), hospitalization (odds ratio, 1.52 [95% CI, 1.05–2.21]; P=0.03), and infection (odds ratio, 1.60 [95% CI, 1.08–2.37]; P=0.02). Tissue- and cell type–specific transcriptomic and epigenomic analysis revealed that the ACE2 regulatory variants were enriched for DNA methylation sites in blood immune cells.Conclusions:Human plasma ACE2 shares a genetic basis with cardiovascular disease, COVID-19, and other related diseases. The genetic architecture of the ACE2 protein is mapped, providing a useful resource for further biological and clinical studies on this coronavirus receptor