Ezrin Inhibition Overcomes Acquired Resistance to Vemurafenib in BRAFV600E-Mutated Colon Cancer and Melanoma Cells In Vitro.

Despite the advancements in targeted therapy for BRAFV600E-mutated metastatic colorectal cancer (mCRC), the development of resistance to BRAFV600E inhibition limits the response rate and durability of the treatment. Better understanding of the resistance mechanisms to BRAF inhibitors will facilitate the design of novel pharmacological strategies for BRAF-mutated mCRC. The aim of this study was to identify novel protein candidates involved in acquired resistance to BRAFV600E inhibitor vemurafenib in BRAFV600E-mutated colon cancer cells using an integrated proteomics approach.

Engineering of increased L-Threonine production in bacteria by combinatorial cloning and machine learning.

The goal of this study is to develop a general strategy for bacterial engineering using an integrated synthetic biology and machine learning (ML) approach. This strategy was developed in the context of increasing L-threonine production in ATCC 21277. A set of 16 genes was initially selected based on metabolic pathway relevance to threonine biosynthesis and used for combinatorial cloning to construct a set of 385 strains to generate training data (i.

Exploring Toxin Genes of Myanmar Russell's Viper, , through De Novo Venom Gland Transcriptomics.

The Russell's viper () is a medically important venomous snake in Myanmar. Next-generation sequencing (NGS) shows potential to investigate the venom complexity, giving deeper insights into snakebite pathogenesis and possible drug discoveries. mRNA from venom gland tissue was extracted and sequenced on the Illumina HiSeq platform and de novo assembled by Trinity.

RNA-Sequencing of Snake Venom Glands.

Next-generation sequencing (NGS), particularly RNA-sequencing (RNA-Seq) technique, allows detection and quantification of different RNA transcripts in a tissue sample, and in our case toxin transcripts from snake venom glands. Using this approach, novel toxin transcripts can be detected and abundancies of different isoforms of each toxin measured. The analytical pipeline can be briefly outlined as follows.

Is there a Function for a Sex Pheromone Precursor?

Functional coupling and comparative genomics analysis have been applied to study functional associations of orthologs of enterococcal cAD1 sex pheromone (P13268) known to be responsible for biofilm formation, conjugative plasmid transfer and spreading of bacterial antibiotics resistance. cAD1 peptide pheromone is released from the membrane lipoprotein with the peptide precursor encoded by a gene cad (tr|C2JQE7). Our analysis of genomic neighbourhood of cad and motifs of the encoded polypeptide and its orthologs suggests a close functional association between cAD1 and ApbE protein (Q82Z24), a FMN insertion and trafficking facilitator.

Roles of RbcX in Carboxysome Biosynthesis in the Cyanobacterium PCC7942.

Rubisco is the essential enzyme mediating the fixation of atmospheric CO during photosynthesis. In cyanobacteria, Rubisco enzymes are densely packed and encapsulated in a specialized organelle known as the carboxysome. Well-defined Rubisco assembly and carboxysome formation are pivotal for efficient CO fixation.

Peripheral blood RNA gene expression in children with pneumococcal meningitis: a prospective case-control study.

Introduction: Invasive pneumococcal disease (IPD), caused by is a leading cause of pneumonia, meningitis and septicaemia worldwide, with increased morbidity and mortality in HIV-infected children.

Objectives: We aimed to compare peripheral blood expression profiles between HIV-infected and uninfected children with pneumococcal meningitis and controls, and between survivors and non-survivors, in order to provide insight into the host inflammatory response leading to poorer outcomes.

Design And Setting: Prospective case-control observational study in a tertiary hospital in Malawi.

Analysis of snake venom metalloproteinases from Myanmar Russell's viper transcriptome.

Snake venom metalloproteinases (SVMPs) are the key enzymes in Russell's viper (RV) venom which target all important components of haemostasis, such as clotting factors, platelets, endothelial cells and basement membrane. The structural diversity of SVMPs contributes to the broad spectrum of biological activities. The aim of the study was to investigate the SVMP transcript profile to gain better insights into the characteristic clinical manifestations of the Myanmar Russell's viper (MRV) bites that distinguish it from the RVs of other habitats.

Statistical analysis of human microarray data shows that dietary intervention with n-3 fatty acids, flavonoids and resveratrol enriches for immune response and disease pathways.

n-3 Fatty acids, flavonoids and resveratrol are well publicised for their beneficial effects on human health and wellbeing. Identifying common, underlying biological mechanisms targeted by these functional foods would therefore be informative for the public health sector for advising on nutritional health and disease, food and drug product development and consumer interest. The aim of this study was to explore the potential effects of gene expression changes associated with n-3 fatty acids EPA and DHA, flavonoids and resveratrol on modifying biological systems and disease pathways.

Gene Expression Meta-Analysis of Potential Metastatic Breast Cancer Markers.

Background: Breast cancer metastasis is a highly prevalent cause of death for European females. DNA microarray analysis has established that primary tumors, which remain localized, differ in gene expression from those that metastasize. Crossanalysis of these studies allow to revile the differences that may be used as predictive in the disease prognosis and therapy.

On the heterogeneity of human populations as reflected by mortality dynamics.

The heterogeneity of populations is used to explain the variability of mortality rates across the lifespan and their deviations from an exponential growth at young and very old ages. A mathematical model that combines the heterogeneity with the assumption that the mortality of each constituent subpopulation increases exponentially with age, has been shown to successfully reproduce the entire mortality pattern across the lifespan and its evolution over time. In this work we aim to show that the heterogeneity is not only a convenient consideration for fitting mortality data but is indeed the actual structure of the population as reflected by the mortality dynamics over age and time.

A systems biology approach to defining regulatory mechanisms for cartilage and tendon cell phenotypes.

Phenotypic plasticity of adult somatic cells has provided emerging avenues for the development of regenerative therapeutics. In musculoskeletal biology the mechanistic regulatory networks of genes governing the phenotypic plasticity of cartilage and tendon cells has not been considered systematically. Additionally, a lack of strategies to effectively reproduce in vitro functional models of cartilage and tendon is retarding progress in this field.

An integrative in silico system for predicting dysregulated genes in the human epileptic focus: Application to SLC transporters.

Objective: Many different gene families are currently being investigated for their potential role in epilepsy and in the response to antiepileptic drugs. A common research challenge is identifying the members of a gene family that are most significantly dysregulated within the human epileptic focus, before taking them forward for resource-intensive functional studies. Published data about transcriptomic changes within the human epileptic focus remains incomplete.

NUDT2 Disruption Elevates Diadenosine Tetraphosphate (Ap4A) and Down-Regulates Immune Response and Cancer Promotion Genes.

Regulation of gene expression is one of several roles proposed for the stress-induced nucleotide diadenosine tetraphosphate (Ap4A). We have examined this directly by a comparative RNA-Seq analysis of KBM-7 chronic myelogenous leukemia cells and KBM-7 cells in which the NUDT2 Ap4A hydrolase gene had been disrupted (NuKO cells), causing a 175-fold increase in intracellular Ap4A. 6,288 differentially expressed genes were identified with P < 0.

Rapid evolution of microbe-mediated protection against pathogens in a worm host.

Microbes can defend their host against virulent infections, but direct evidence for the adaptive origin of microbe-mediated protection is lacking. Using experimental evolution of a novel, tripartite interaction, we demonstrate that mildly pathogenic bacteria (Enterococcus faecalis) living in worms (Caenorhabditis elegans) rapidly evolved to defend their animal hosts against infection by a more virulent pathogen (Staphylococcus aureus), crossing the parasitism-mutualism continuum. Host protection evolved in all six, independently selected populations in response to within-host bacterial interactions and without direct selection for host health.

In silico, in vitro and in vivo analysis identifies a potential role for steroid hormone regulation of FOXD3 in endometriosis-associated genes.

Study Question: Can bioinformatics analysis of publically available microarray datasets be utilized in identifying potentially important transcription factors (TF) in the hormonal regulation of the endometrium?

Summary Answer: Systems integration and analysis of existing complex (published) datasets, predicted a role for the novel transcription factor, Forkhead Box D3 (FOXD3) in healthy endometrium and in endometriosis, which was followed by the demonstration of decreased levels of the protein upon decidualisation of normal human endometrial stromal cells in vitro and differential endometrial expression in the stroma in endometriosis.

What Is Known Already: The reported endometriosis-associated endometrial aberrations are most pronounced in the progesterone-dominant secretory phase and progesterone resistance is a proposed causative factor.

Study Design, Size, Duration: The study was initially an 'in silico' study, with confirmatory 'wet lab' data from western blotting (WB), qPCR and Immunohistochemistry (IHC) on endometrial biopsies obtained from 142 women undergoing gynaecological surgery.

On predicting regulatory genes by analysis of functional networks in C. elegans.

Background: Connectivity networks, which reflect multiple interactions between genes and proteins, possess not only a descriptive but also a predictive value, as new connections can be extrapolated and tested by means of computational analysis. Integration of different types of connectivity data (such as co-expression and genetic interactions) in one network has proven to benefit 'guilt by association' analysis. However predictive values of connectives of different types, that had their specific functional meaning and topological characteristics were not obvious, and have been addressed in this analysis.

Life without oxygen: gene regulatory responses of the crucian carp (Carassius carassius) heart subjected to chronic anoxia.

Crucian carp are unusual among vertebrates in surviving extended periods in the complete absence of molecular oxygen. During this time cardiac output is maintained though these mechanisms are not well understood. Using a high-density cDNA microarray, we have defined the genome-wide gene expression responses of cardiac tissue after exposing the fish at two temperatures (8 and 13 °C) to one and seven days of anoxia, followed by seven days after restoration to normoxia.

Pathway analysis of genetic factors associated with spontaneous preterm birth and pre-labor preterm rupture of membranes.

Background: Pre-term birth (PTB) remains the leading cause of infant mortality and morbidity. Its etiology is multifactorial, with a strong genetic component. Genetic predisposition for the two subtypes, spontaneous PTB with intact membranes (sPTB) and preterm prelabor rapture of membranes (PPROM), and differences between them, have not yet been systematically summarised.

Label-free mass spectrometric profiling of urinary proteins and metabolites from paediatric idiopathic nephrotic syndrome.

Idiopathic nephrotic syndrome (INS) is caused by renal diseases that increase the permeability of the glomerular filtration barrier without evidence of a specific systemic cause. The aim of the present work was to reveal inherent molecular features of INS in children using combined urinary proteomics and metabolomics profiling. In this study, label-free mass spectrometric analysis of urinary proteins and small molecule metabolites was carried out in 12 patients with INS versus 12 sex- and age-matched control subjects with normal renal function.

The heparin-binding protein interactome in pancreatic diseases.

Background: The cellular microenvironment plays an important role in the regulation of homoeostasis and is a source of potential biomarkers and drug targets. In a genome-wide analysis the extracellular proteins that bind to heparin (HBPs) have been shown to form highly modular and interconnected extracellular protein regulatory networks. Using a systems biology approach, we have investigated the role of HBP networks in the normal pancreas and pancreatic digestive diseases.

PNUTS/PP1 regulates RNAPII-mediated gene expression and is necessary for developmental growth.

In multicellular organisms, tight regulation of gene expression ensures appropriate tissue and organismal growth throughout development. Reversible phosphorylation of the RNA Polymerase II (RNAPII) C-terminal domain (CTD) is critical for the regulation of gene expression states, but how phosphorylation is actively modified in a developmental context remains poorly understood. Protein phosphatase 1 (PP1) is one of several enzymes that has been reported to dephosphorylate the RNAPII CTD.

Inhibition of pre-B cell colony-enhancing factor (PBEF/NAMPT/visfatin) decreases the ability of human neutrophils to generate reactive oxidants but does not impair bacterial killing.

NAMPT, also known as PBEF and visfatin, can act extracellularly as a cytokine-like molecule or intracellularly as a NAMPT, regulating NAD biosynthesis in the NAD salvage pathway. Inhibitors of NAMPT have anti-inflammatory and anticancer activity and are finding use as therapeutic agents. In view of the importance of NAD metabolism in neutrophil function, we determined the effects of NAMPT inhibition on a variety of neutrophil functions associated with their role in host protection against infections.

Mathematical modelling in developmental biology.

In recent decades, molecular and cellular biology has benefited from numerous fascinating developments in experimental technique, generating an overwhelming amount of data on various biological objects and processes. This, in turn, has led biologists to look for appropriate tools to facilitate systematic analysis of data. Thus, the need for mathematical techniques, which can be used to aid the classification and understanding of this ever-growing body of experimental data, is more profound now than ever before.