An investigation to improve a nonlinear mixed-effects approach for EC50 estimation based on multi-donor dose-response data.

Dose-response relationships are important in assessing the efficacy and potency of compounds, which can usually be characterized by a 4-parameter logistic (4-PL) model estimating EC50, slope factor, lower asymptote, and upper asymptote. EC50, the concentration of a compound that induces a response halfway between the baseline and maximum, is a key quantity to evaluate compound potency. For multi-donor dose-response data, it is often of interest to estimate the overall EC50 (i.

Glucosylceramide synthase modulation ameliorates murine renal pathologies and promotes macrophage effector function in vitro.

While significant advances have been made in understanding renal pathophysiology, less is known about the role of glycosphingolipid (GSL) metabolism in driving organ dysfunction. Here, we used a small molecule inhibitor of glucosylceramide synthase to modulate GSL levels in three mouse models of distinct renal pathologies: Alport syndrome (Col4a3 KO), polycystic kidney disease (Nek8), and steroid-resistant nephrotic syndrome (Nphs2 cKO). At the tissue level, we identified a core immune-enriched transcriptional signature that was shared across models and enriched in human polycystic kidney disease.

Molecular subtypes explain lupus epigenomic heterogeneity unveiling new regulatory genetic risk variants.

The heterogeneity of systemic lupus erythematosus (SLE) can be explained by epigenetic alterations that disrupt transcriptional programs mediating environmental and genetic risk. This study evaluated the epigenetic contribution to SLE heterogeneity considering molecular and serological subtypes, genetics and transcriptional status, followed by drug target discovery. We performed a stratified epigenome-wide association studies of whole blood DNA methylation from 213 SLE patients and 221 controls.

A model-based clustering via mixture of hierarchical models with covariate adjustment for detecting differentially expressed genes from paired design.

The causes of many complex human diseases are still largely unknown. Genetics plays an important role in uncovering the molecular mechanisms of complex human diseases. A key step to characterize the genetics of a complex human disease is to unbiasedly identify disease-associated gene transcripts on a whole-genome scale.

An efficient mutagenesis system to improve the propamocarb tolerance in (Zimmermann) Zare & Gams.

(Zimmermann) Zare & Gams is used as an effective biopesticide for the control of sap-sucking insect pests on agricultural crops. However, low fungicide tolerance limits its large-scale field application. To improve the propamocarb tolerance in , a composite mutagenesis system was established by using UV-light (U), N-Methyl-N'-nitro-N-nitrosoguanidine (NTG) (N) and N ion-beam (I).

Increasing Enzyme Mannose-6-Phosphate Levels but Not Miglustat Coadministration Enhances the Efficacy of Enzyme Replacement Therapy in Pompe Mice.

Pompe disease is a rare glycogen storage disorder caused by a deficiency in the lysosomal enzyme acid -glucosidase, which leads to muscle weakness, cardiac and respiratory failure, and early mortality. Alglucosidase alfa, a recombinant human acid -glucosidase, was the first approved treatment of Pompe disease, but its uptake into skeletal muscle via the cation-independent mannose-6-phosphate (M6P) receptor (CIMPR) is limited. Avalglucosidase alfa has received marketing authorization in several countries for infantile-onset and/or late-onset Pompe disease.

Evaluation of Neurofilament Light Chain as a Biomarker of Neurodegeneration in X-Linked Childhood Cerebral Adrenoleukodystrophy.

Cerebral adrenoleukodystrophy (CALD) is a devastating, demyelinating neuroinflammatory manifestation found in up to 40% of young males with an inherited mutation in , the causative gene in adrenoleukodystrophy. The search for biomarkers which correlate to CALD disease burden and respond to intervention has long been sought after. We used the Olink Proximity Extension Assay (Uppsala, Sweden) to explore the cerebral spinal fluid (CSF) of young males with CALD followed by correlative analysis with plasma.

ETV2 regulates PARP-1 binding protein to induce ER stress-mediated death in tuberin-deficient cells.

Lymphangioleiomyomatosis (LAM) is a rare progressive disease, characterized by mutations in the tuberous sclerosis complex genes ( or ) and hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1). Here, we report that E26 transformation-specific (ETS) variant transcription factor 2 (ETV2) is a critical regulator of -deficient cell survival. ETV2 nuclear localization in -deficient cells is mTORC1-independent and is enhanced by spleen tyrosine kinase (Syk) inhibition.

powerEQTL: an R package and shiny application for sample size and power calculation of bulk tissue and single-cell eQTL analysis.

Summary: Genome-wide association studies (GWAS) have revealed thousands of genetic loci for common diseases. One of the main challenges in the post-GWAS era is to understand the causality of the genetic variants. Expression quantitative trait locus (eQTL) analysis is an effective way to address this question by examining the relationship between gene expression and genetic variation in a sufficiently powered cohort.

Drug Repurposing to Treat Glucocorticoid Resistance in Asthma.

Corticosteroid resistance causes significant morbidity in asthma, and drug repurposing may identify timely and cost-effective adjunctive treatments for corticosteroid resistance. In 95 subjects from the Childhood Asthma Management Program (CAMP) and 19 subjects from the Severe Asthma Research Program (SARP), corticosteroid response was measured by the change in percent predicted forced expiratory volume in one second (FEV). In each cohort, differential gene expression analysis was performed comparing poor (resistant) responders, defined as those with zero to negative change in FEV, to good responders, followed by Connectivity Map (CMap) analysis to identify inversely associated (i.

MTOR suppresses autophagy-mediated production of IL25 in allergic airway inflammation.

Introduction: Airway epithelial cells are recognised as an essential controller for the initiation and perpetuation of asthmatic inflammation, yet the detailed mechanisms remain largely unknown. This study aims to investigate the roles and mechanisms of the mechanistic target of rapamycin (MTOR)-autophagy axis in airway epithelial injury in asthma.

Methods: We examined the MTOR-autophagy signalling in airway epithelium from asthmatic patients or allergic mice induced by ovalbumin or house dust mites, or in human bronchial epithelial (HBE) cells.

The association of telomere length and telomerase activity with adverse outcomes in older patients with non-ST-elevation acute coronary syndrome.

Background: Non-ST elevation acute coronary syndrome (NSTEACS) occurs more frequently in older patients with an increased occurrence of recurrent cardiac events following the index presentation. Telomeres are structures consisting of repeated DNA sequences as associated shelterin proteins at the ends of chromosomes. We aim to determine whether telomere length (TL) and telomerase activity (TA) predicted poor outcomes in older patients presenting with NSTEACS undergoing invasive care.

Model-based clustering for identifying disease-associated SNPs in case-control genome-wide association studies.

Genome-wide association studies (GWASs) aim to detect genetic risk factors for complex human diseases by identifying disease-associated single-nucleotide polymorphisms (SNPs). The traditional SNP-wise approach along with multiple testing adjustment is over-conservative and lack of power in many GWASs. In this article, we proposed a model-based clustering method that transforms the challenging high-dimension-small-sample-size problem to low-dimension-large-sample-size problem and borrows information across SNPs by grouping SNPs into three clusters.

The association between vitamin D status and clinical events in high-risk older patients with non-ST elevation acute coronary syndrome undergoing invasive management.

There is a higher incidence of vitamin D deficiency in older adults. This may play a plausible mechanistic role in the occurrence of increased adverse events after non-ST elevation acute coronary syndrome (NSTEACS). This study investigated whether total vitamin D levels at the time of presentation predicted adverse outcomes in older adults undergoing invasive management of NSTEACS.

DNA methylation is associated with inhaled corticosteroid response in persistent childhood asthmatics.

Background: Response to inhaled corticosteroids is highly variable, and the association between DNA methylation and treatment response is not known.

Objective: To examine the association between peripheral blood DNA methylation and inhaled corticosteroid response in children with persistent asthma.

Methods: Epigenome-wide DNA methylation was analysed in individuals on inhaled corticosteroids in three independent and ethnically diverse cohorts-Childhood Asthma Management Program (CAMP); Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE); and Genetic Epidemiology of Asthma in Costa Rica Study (GACRS).

An Investigation about Gene Modules Associated with hDPSC Differentiation for Adolescents.

Dental pulp stem cells (DPSCs) have the property of self-renewal and multidirectional differentiation so that they have the potential for future regenerative therapy of various diseases. The latest breakthrough in the biology of stem cells and the development of regenerative biology provides an effective strategy for regenerative therapy. However, in the medium promoting differentiation during long-term passage, DPSCs would lose their differentiation capability.

First-in-class immune-modulating small molecule Icaritin in advanced hepatocellular carcinoma: preliminary results of safety, durable survival and immune biomarkers.

Background: With poor prognosis and limited treatment options for advanced hepatocellular carcinoma (HCC), development of novel therapeutic agents is urgently needed. This single-arm phase I study sought to assess the safety and preliminary efficacy of icaritin in human as a potential oral immunotherapy in addition to the immune-checkpoint inhibitors.

Methods: Eligible advanced HCC patients with Child-Pugh Class A or B were administered with a fixed oral dose of icaritin at either 600 or 800 mg b.

Novel Data Transformations for RNA-seq Differential Expression Analysis.

We propose eight data transformations (r, r2, rv, rv2, l, l2, lv, and lv2) for RNA-seq data analysis aiming to make the transformed sample mean to be representative of the distribution center since it is not always possible to transform count data to satisfy the normality assumption. Simulation studies showed that for data sets with small (e.g.

Pilot study of DNA methylation, molecular aging markers and measures of health and well-being in aging.

Relations of DNA methylation markers to other biological aging markers and to psychosocial, behavioral, and health measures remain unclear. The sample included 23 participants (n = 11 cases with psychiatric diagnoses and n = 12 controls without current or lifetime psychiatric disorder), balanced by age and sex. Genomic DNA was extracted from blood samples; the following were performed: genome-wide DNA methylation assay using Illumina 850k methylationEPIC; PCR assays for relative telomere length (RTL) and mitochondrial DNA copy number (mtCN).

Urine podoplanin heralds the onset of ischemia-reperfusion injury of the kidney.

Ischemia-reperfusion injury represents one of the most common causes of acute kidney injury, a serious and often deadly condition that affects up to 20% of all hospitalized patients in the United States. However, the current standard assay used universally for the diagnosis of acute kidney injury, serum creatinine, does not detect renal damage early in its course. Serendipitously, we found that the immunofluorescent signal of the constitutive podocyte marker podoplanin fades in the glomerulus and intensifies in the tubulointerstitial compartment of the kidney shortly after ischemia-reperfusion injury in 8- to 10-wk-old male C57Bl/6j mice.

New Statistical Methods for Constructing Robust Differential Correlation Networks to characterize the interactions among microRNAs.

The interplay among microRNAs (miRNAs) plays an important role in the developments of complex human diseases. Co-expression networks can characterize the interactions among miRNAs. Differential correlation network is a powerful tool to investigate the differences of co-expression networks between cases and controls.

Coronary artery lesion phenotype in frail older patients with non-ST-elevation acute coronary syndrome undergoing invasive care.

Aims: The association of frailty with coronary plaque phenotype among older patients with non-ST-elevation acute coronary syndrome (NSTEACS) is not known. The aim of this study was to evaluate the association of frailty with coronary plaque phenotype among older patients with NSTEACS.

Methods And Results: Older patients with NSTEACS who underwent invasive angiography were recruited.

Cognitive Decline in Older Patients With Non- ST Elevation Acute Coronary Syndrome.

Background Dementia is a growing health burden of an aging population. This study aims to evaluate the prevalence of cognitive impairment and the predictors of cognitive decline at 1 year in older patients with non-ST-elevation acute coronary syndrome undergoing invasive care. Methods and Results Older patients with non-ST-elevation acute coronary syndrome were recruited into the ICON1 study.

DNA methylation is associated with improvement in lung function on inhaled corticosteroids in pediatric asthmatics.

Asthma is the most common chronic disease in children. Inhaled corticosteroids (ICS) are the first-line treatment for asthma control, but up to one-third of children have a poor treatment response. The mechanism of ICS resistance is poorly understood, and the role of DNA methylation in ICS treatment response is not known.