Application of integrated transcriptomic, proteomic and metabolomic profiling for the delineation of mechanisms of drug induced cell stress.

High content omic techniques in combination with stable human in vitro cell culture systems have the potential to improve on current pre-clinical safety regimes by providing detailed mechanistic information of altered cellular processes. Here we investigated the added benefit of integrating transcriptomics, proteomics and metabolomics together with pharmacokinetics for drug testing regimes. Cultured human renal epithelial cells (RPTEC/TERT1) were exposed to the nephrotoxin Cyclosporine A (CsA) at therapeutic and supratherapeutic concentrations for 14days.

Antigen incorporated in virus-like particles is delivered to specific dendritic cell subsets that induce an effective antitumor immune response in vivo.

Virus-like particles (VLP) from rabbit hemorrhagic disease virus (RHDV) can be used as a scaffold to facilitate the delivery of antigens to induce cell-mediated immune responses. In this study, we investigated the immune response to lymphocytic choriomeningitis virus-derived peptide antigen (gp33) delivered by RHDV VLP. The gp33 peptides were incorporated into the VLP in 2 different forms, either recombinantly expressed inside the VLP (VLP-gp33r) or chemically coupled to the surface of the VLP (VLP-gp33c).

The unique cysteine knot regulates the pleotropic hormone leptin.

Leptin plays a key role in regulating energy intake/expenditure, metabolism and hypertension. It folds into a four-helix bundle that binds to the extracellular receptor to initiate signaling. Our work on leptin revealed a hidden complexity in the formation of a previously un-described, cysteine-knotted topology in leptin.

Substrate-specific reorganization of the conformational ensemble of CSK implicates novel modes of kinase function.

Protein kinases use ATP as a phosphoryl donor for the posttranslational modification of signaling targets. It is generally thought that the binding of this nucleotide induces conformational changes leading to closed, more compact forms of the kinase domain that ideally orient active-site residues for efficient catalysis. The kinase domain is oftentimes flanked by additional ligand binding domains that up- or down-regulate catalytic function.

Hygienic drainage for healthcare.

Peter Jennings, technical director for ACO Building Drainage, which specialises in the development of corrosion-resistant drainage systems and building products, looks at the key issues to consider when specifying and installing pipework and drainage for hygiene-critical environments such as hospitals and other healthcare facilities.

An overview of transcriptional regulation in response to toxicological insult.

The completion of the human genome project and the subsequent advent of DNA microarray and high-throughput sequencing technologies have led to a renaissance in molecular toxicology. Toxicogenomic data sets, from both in vivo and in vitro studies, are growing exponentially, providing a wealth of information on regulation of stress pathways at the transcriptome level. Through such studies, we are now beginning to appreciate the diversity and complexity of biological responses to xenobiotics.

APC(FZR1) prevents nondisjunction in mouse oocytes by controlling meiotic spindle assembly timing.

FZR1 is an anaphase-promoting complex (APC) activator best known for its role in the mitotic cell cycle at M-phase exit, in G1, and in maintaining genome integrity. Previous studies also established that it prevents meiotic resumption, equivalent to the G2/M transition. Here we report that mouse oocytes lacking FZR1 undergo passage through meiosis I that is accelerated by ~1 h, and this is due to an earlier onset of spindle assembly checkpoint (SAC) satisfaction and APC(CDC20) activity.

Oxidative stress induced by potassium bromate exposure results in altered tight junction protein expression in renal proximal tubule cells.

Potassium bromate (KBrO(3)) is an oxidising agent that has been widely used in the food and cosmetic industries. It has shown to be both a nephrotoxin and a renal carcinogen in in vivo and in vitro models. Here, we investigated the effects of KBrO(3) in the human and rat proximal tubular cell lines RPTEC/TERT1 and NRK-52E.

An automated CPR device compared with standard chest compressions for out-of-hospital resuscitation.

Background: Effective cardiopulmonary resuscitation and increased coronary perfusion pressures have been linked to improved survival from cardiac arrest. This study aimed to compare the rates of survival between conventional cardiopulmonary resuscitation (C-CPR) and automated CPR (A-CPR) using AutoPulse™ in adults following out-of-hospital cardiac arrest (OHCA).

Methods: This was a retrospective study using a matched case-control design across three regional study sites in Victoria, Australia.

Folding circular permutants of IL-1β: route selection driven by functional frustration.

Interleukin-1β (IL-1β) is the cytokine crucial to inflammatory and immune response. Two dominant routes are populated in the folding to native structure. These distinct routes are a result of the competition between early packing of the functional loops versus closure of the β-barrel to achieve efficient folding and have been observed both experimentally and computationally.

Explorative study of the sensitivity and specificity of the pronator quadratus fat pad sign as a predictor of subtle wrist fractures.

Objective: To investigate the value of post-traumatic pronator quadratus (PQ) fat pad sign as a reliable predictor of subtle wrist fractures.

Materials And Methods: This was a prospective study of 68 patients undergoing X-ray for traumatic wrist injuries and subsequent MRI. The reliability of a positive PQ fat pad sign on X-ray, defined as either raised, interrupted or obliterated, was evaluated in detection of subtle wrist fractures.

Characterization of Arabidopsis NEET reveals an ancient role for NEET proteins in iron metabolism.

The NEET family is a newly discovered group of proteins involved in a diverse array of biological processes, including autophagy, apoptosis, aging, diabetes, and reactive oxygen homeostasis. They form a novel structure, the NEET fold, in which two protomers intertwine to form a two-domain motif, a cap, and a unique redox-active labile 2Fe-2S cluster binding domain. To accelerate the functional study of NEET proteins, as well as to examine whether they have an evolutionarily conserved role, we identified and characterized a plant NEET protein.

Comparative analysis of perturbed molecular pathways identified in in vitro and in vivo toxicology studies.

The development of in vitro toxicological testing strategies are hampered by the difficulty in extrapolation to the intact organism. Academic toxicological literature contains a wealth of mechanistically rich information, especially arising from omic studies, which could potentially be utilized to uncover commonalities between in vitro and in vivo observations on the cellular level. Using a literature mining strategy, we identified 1221 unique human genes as being associated to nephrotoxicity, hepatotoxicity, or CNS toxicity, either linked to in vitro, in vivo, or both experimental conditions.

Glucose reintroduction triggers the activation of Nrf2 during experimental ischemia reperfusion.

Reperfusion results in a rapid reintroduction of oxygen, glucose, and other restricted components to an ischemic tissue. It brings with it not only the necessary components for cell survival but also a burst of oxidative stress and cellular damage. In this study, our primary aims were to investigate glucose as a determining factor for the activation of the transcription factor NF-E2-related factor 2 (Nrf2) upon reperfusion and the expression of downstream anti-oxidant NADPH-dependent reductases.

NADPH inhibits [2Fe-2S] cluster protein transfer from diabetes drug target MitoNEET to an apo-acceptor protein.

MitoNEET (mNT) is the founding member of the recently discovered CDGSH family of [2Fe-2S] proteins capable of [2Fe-2S] cluster transfer to apo-acceptor proteins. It is a target of the thiazolidinedione (TZD) class of anti-diabetes drugs whose binding modulate both electron transfer and cluster transfer properties. The [2Fe-2S] cluster in mNT is destabilized upon binding of NADPH, which leads to loss of the [2Fe-2S] cluster to the solution environment.

Peptidyl-prolyl isomerase Pin1 controls down-regulation of conventional protein kinase C isozymes.

The down-regulation or cellular depletion of protein kinase C (PKC) attendant to prolonged activation by phorbol esters is a widely described property of this key family of signaling enzymes. However, neither the mechanism of down-regulation nor whether this mechanism occurs following stimulation by physiological agonists is known. Here we show that the peptidyl-prolyl isomerase Pin1 provides a timer for the lifetime of conventional PKC isozymes, converting the enzymes into a species that can be dephosphorylated and ubiquitinated following activation induced by either phorbol esters or natural agonists.

Strand swapping regulates the iron-sulfur cluster in the diabetes drug target mitoNEET.

MitoNEET is a recently identified diabetes drug target that coordinates a transferable 2Fe-2S cluster, and additionally contains an unusual strand swap. In this manuscript, we use a dual basin structure-based model to predict and characterize the folding and functionality of strand swapping in mitoNEET. We demonstrate that a strand unswapped conformation is kinetically accessible and that multiple levels of control are employed to regulate the conformational dynamics of the system.

β-Bulge triggers route-switching on the functional landscape of interleukin-1β.

Proteins fold into three-dimensional structures in a funneled energy landscape. This landscape is also used for functional activity. Frustration in this landscape can arise from the competing evolutionary pressures of biological function and reliable folding.

Theoretical studies of Pt-Ti nanoparticles for potential use as PEMFC electrocatalysts.

A theoretical investigation is presented of alloying platinum with titanium to form binary Pt-Ti nanoalloys as an alternative to the expensive pure platinum catalysts commonly used for Proton Exchange Membrane Fuel Cell cathode electrocatalysts. Density Functional Theory calculations are performed to investigate compositional effects on structural properties as well as Oxygen Reduction Reaction kinetics and poisoning effects. High symmetry A(32)-B(6) clusters are studied to investigate structural properties.

Carcinogens induce loss of the primary cilium in human renal proximal tubular epithelial cells independently of effects on the cell cycle.

The primary cilium is an immotile sensory and signaling organelle found on the majority of mammalian cell types. Of the multitude of roles that the primary cilium performs, perhaps some of the most important include maintenance of differentiation, quiescence, and cellular polarity. Given that the progression of cancer requires disruption of all of these processes, we have investigated the effects of several carcinogens on the primary cilium of the RPTEC/TERT1 human proximal tubular epithelial cell line.

Morphine and ketamine is superior to morphine alone for out-of-hospital trauma analgesia: a randomized controlled trial.

Study Objective: We assess the efficacy of intravenous ketamine compared with intravenous morphine in reducing pain in adults with significant out-of-hospital traumatic pain.

Methods: This study was an out-of-hospital, prospective, randomized, controlled, open-label study. Patients with trauma and a verbal pain score of greater than 5 after 5 mg intravenous morphine were eligible for enrollment.

Contemplative/emotion training reduces negative emotional behavior and promotes prosocial responses.

Contemplative practices are believed to alleviate psychological problems, cultivate prosocial behavior and promote self-awareness. In addition, psychological science has developed tools and models for understanding the mind and promoting well-being. Additional effort is needed to combine frameworks and techniques from these traditions to improve emotional experience and socioemotional behavior.