Differential responses of pancreatic β-cells to ROS and RNS.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) direct the activation of distinct signaling pathways that determine cell fate. In this study, the pathways activated and the mechanisms by which ROS and RNS control the viability of pancreatic β-cells were examined. Although both nitric oxide and hydrogen peroxide (H₂O₂) induce DNA damage, reduce cell viability, and activate AMPK, the mechanisms of AMPK activation and cell death induction differ between each reactive species.

Effect of the bacterium Serratia marcescens SCBI on the longevity and reproduction of the nematode Caenorhabditis briggsae KT0001.

Background: Extensive research effort has advanced our understanding of Caenorhabditis as a model system, but its natural association with bacteria remains to be explored in an ecological context. Explored associations vary vastly from mutualistic to parasitic. Serratia marcescens has been shown to be pathogenic to Caenorhabditis with a fitness cost.

Integration of cellular bioenergetics with mitochondrial quality control and autophagy.

Bioenergetic dysfunction is emerging as a cornerstone for establishing a framework for understanding the pathophysiology of cardiovascular disease, diabetes,cancer and neurodegeneration. Recent advances in cellular bioenergetics have shown that many cells maintain a substantial bioenergetic reserve capacity, which is a prospective index of ‘ healthy ’ mitochondrial populations.The bioenergetics of the cell are likely regulated by energy requirements and substrate availability.

Relationship between fractional anisotropy of cerebral white matter and metabolite concentrations measured using (1)H magnetic resonance spectroscopy in healthy adults.

Fractional anisotropy (FA) of water diffusion in cerebral white matter (WM), derived from diffusion tensor imaging (DTI), is a sensitive index of microscopic WM integrity. Physiological and metabolic factors that explain intersubject variability in FA values were evaluated in two cohorts of healthy adults of different age spans (N=65, range: 28-50years; and N=25, age=66.6±6.

Automated regional behavioral analysis for human brain images.

Behavioral categories of functional imaging experiments along with standardized brain coordinates of associated activations were used to develop a method to automate regional behavioral analysis of human brain images. Behavioral and coordinate data were taken from the BrainMap database (http://www.brainmap.

Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients.

Background: Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB.

Methods And Findings: Three recent systematic reviews were used to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB.

Telaprevir: a hepatitis C NS3/4A protease inhibitor.

Background: Telaprevir is a hepatitis C NS3/4A protease inhibitor approved by the US Food and Drug Administration as part of combination therapy for the management of chronic hepatitis C virus (HCV) genotype 1 infection.

Objective: The article reviews published literature on telaprevir, including its chemistry, mechanism of action, resistance, pharmacodynamic and pharmacokinetic properties, drug interactions, therapeutic efficacy, HIV/HCV coinfection, pharmacogenomics, adverse events, pharmacoeconomics, and dosing and administration.

Methods: English-language literature was included.

Prevalence of and risk factors for resistance to second-line drugs in people with multidrug-resistant tuberculosis in eight countries: a prospective cohort study.

Background: The prevalence of extensively drug-resistant (XDR) tuberculosis is increasing due to the expanded use of second-line drugs in people with multidrug-resistant (MDR) disease. We prospectively assessed resistance to second-line antituberculosis drugs in eight countries.

Methods: From Jan 1, 2005, to Dec 31, 2008, we enrolled consecutive adults with locally confirmed pulmonary MDR tuberculosis at the start of second-line treatment in Estonia, Latvia, Peru, Philippines, Russia, South Africa, South Korea, and Thailand.

MicroRNA miR-214 regulates ovarian cancer cell stemness by targeting p53/Nanog.

Previous studies have shown aberrant expression of miR-214 in human malignancy. Elevated miR-214 is associated with chemoresistance and metastasis. In this study, we identified miR-214 regulation of ovarian cancer stem cell (OCSC) properties by targeting p53/Nanog axis.

A phase I trial of dasatinib, an SRC-family kinase inhibitor, in combination with paclitaxel and carboplatin in patients with advanced or recurrent ovarian cancer.

Purpose: We conducted a phase I study of dasatinib, an oral SRC-family tyrosine kinase inhibitor, in combination with paclitaxel and carboplatin in the treatment of advanced and recurrent epithelial ovarian cancer.

Experimental Design: The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included defining toxicity, response rate (RR), pharmacokinetics, and pharmacodynamics.

Characterizing the efficacy of fermented wheat germ extract against ovarian cancer and defining the genomic basis of its activity.

Objective: Most women with advanced-stage epithelial ovarian cancer (OVCA) ultimately develop chemoresistant recurrent disease. Therefore, a great need to develop new, more active, and less toxic agents and/or to optimize the efficacy of existing agents exists.

Methods: In this study, we investigated the activity of Avemar, a natural, nontoxic, fermented wheat germ extract (FWGE), against a range of OVCA cell lines, both alone and in combination with cisplatin chemotherapy and delineated the molecular signaling pathways that underlie FWGE activity at a genome-wide level.

Erythrocyte storage increases rates of NO and nitrite scavenging: implications for transfusion-related toxicity.

Storage of erythrocytes in blood banks is associated with biochemical and morphological changes to RBCs (red blood cells). It has been suggested that these changes have potential negative clinical effects characterized by inflammation and microcirculatory dysfunction which add to other transfusion-related toxicities. However, the mechanisms linking RBC storage and toxicity remain unclear.

Desferrioxamine inhibits protein tyrosine nitration: mechanisms and implications.

Tissues are exposed to exogenous and endogenous nitrogen dioxide ((·)NO(2)), which is the terminal agent in protein tyrosine nitration. Besides iron chelation, the hydroxamic acid (HA) desferrioxamine (DFO) shows multiple functionalities including nitration inhibition. To investigate mechanisms whereby DFO affects 3-nitrotyrosine (3-NT) formation, we utilized gas-phase (·)NO(2) exposures, to limit introduction of other reactive species, and a lung surface model wherein red cell membranes (RCM) were immobilized under a defined aqueous film.

Natural knowledge as a propaedeutic to self-betterment: Francis Bacon and the transformation of natural history.

This paper establishes the 'emblematic' use of natural history as a propaedeutic to self-betterment in the Renaissance; in particular, in the natural histories of Gessner and Topsell, but also in the works of Erasmus and Rabelais. Subsequently, it investigates how Francis Bacon's conception of natural history is envisaged in relation to them. The paper contends that, where humanist natural historians understood the use of natural knowledge as a preliminary to individual improvement, Bacon conceived self-betterment foremost as a means to Christian charity, or social-betterment.

Methylsulfonyl benzothiazole (MSBT): a selective protein thiol blocking reagent.

A new thiol blocking reagent, methylsulfonyl benzothiazole, was discovered. This reagent showed good selectivity and high reactivity for protein thiols.

Volumetric MRI differences in treatment naïve and chronically treated adolescents with ADHD-combined type.

Objective: The purpose of this study was to determine whether there are differences in the volume of specific brain regions using magnetic resonance imaging (MRI) between children and adolescents with ADHD and controls and whether such differences are related to the participants' history of stimulant treatment.

Method: A total of 16 healthy controls, 16 children, and adolescents with ADHD-combined (ADHD-C) type with a history of stimulant treatment, and 13 children and adolescents with ADHD-C type treatment naïve participated.

Results: Total frontal, prefrontal, and caudate volumes were larger for children and adolescents with ADHD compared with controls with no differences based on medication history with larger right gray and white matter prefrontal volumes in the ADHD groups.

The effects of poloxamer-188 on left ventricular function in chronic heart failure after myocardial infarction.

Background: Poloxamer-188 (P-188) is a biological membrane sealant that prevents the unregulated entry of Ca into cardiomyocytes and has been shown to have the ability to act as a membrane-repair agent in isolated cardiac myocytes. The purpose of this study was to determine if treatment with P-188 would improve left ventricular (LV) function in a rat chronic heart failure (CHF) model.

Methods: We ligated the left coronary artery of adult male Sprague-Dawley rats to induce a myocardial infarction (MI).

In vitro analysis of ovarian cancer response to cisplatin, carboplatin, and paclitaxel identifies common pathways that are also associated with overall patient survival.

Background: Carboplatin and cisplatin, alone or in combination with paclitaxel, have similar efficacies against ovarian cancer (OVCA) yet exhibit different toxicity profiles. We characterised the common and unique cellular pathways that underlie OVCA response to these drugs and analyse whether they have a role in OVCA survival.

Methods: Ovarian cancer cell lines (n=36) were treated with carboplatin, cisplatin, paclitaxel, or carboplatin-paclitaxel (CPTX).

Electrophysiological and functional connectivity of the human supplementary motor area.

Neuro-imaging methods for detecting functional and structural inter-regional connectivity are in a rapid phase of development. While reports of regional connectivity patterns based on individual methods are becoming common, studies comparing the results of two or more connectivity-mapping methods remain rare. In this study, we applied transcranial magnetic stimulation during PET imaging (TMS/PET), a stimulation-based method, and meta-analytic connectivity modeling (MACM), a task-based method to map the connectivity patterns of the supplementary motor area (SMA).

P-selectin Expression Tracks Cerebral Atrophy in Mexican-Americans.

Background And Purpose: We hypothesized that the P-selectin (SELP) gene, localized to a region on chromosome 1q24, pleiotropically contributes to increased blood pressure and cerebral atrophy. We tested this hypothesis by performing genetic correlation analyses for 13 mRNA gene expression measures from P-selectin and 11 other genes located in 1q24 region and three magnetic resonance imaging derived indices of cerebral integrity.

Methods: The subject pool consisted of 369 (219F; aged 28-85, average = 47.

The O-glycan pathway is associated with in vitro sensitivity to gemcitabine and overall survival from ovarian cancer.

Ovarian cancer (OVCA) is the most lethal gynecological malignancy. The high mortality rate associated with this disease is due in large part to the development of resistance to chemotherapy; however, the biological basis of this remains unclear. Gemcitabine is frequently used for the treatment of patients with platinum-resistant OVCA.

Identification of common variants associated with human hippocampal and intracranial volumes.

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies.

Environmental heme-based sensor proteins: implications for understanding bacterial pathogenesis.

Significance: Heme is an important prosthetic group required in a wide array of functions, including respiration, photosynthesis, metabolism, O(2) transport, xenobiotic detoxification, and peroxide production and destruction, and is an essential cofactor in proteins such as catalases, peroxidases, and members of the cytochrome P450 superfamily. Importantly, bacterial heme-based sensor proteins exploit the redox chemistry of heme to sense environmental gases and the intracellular redox state of the cell.

Recent Advances: The bacterial proteins FixL (Rhizobium ssp.

BCL2 antagonist of cell death kinases, phosphatases, and ovarian cancer sensitivity to cisplatin.

Objective: The BCL2 family proteins are critical mediators of cellular apoptosis and, as such, have been implicated as determinants of cancer cell chemo-sensitivity. Recently, it has been demonstrated that the phosphorylation status of the BCL2 antagonist of cell death (BAD) protein may influence ovarian cancer (OVCA) cell sensitivity to cisplatin. Here, we sought to evaluate how kinase and phosphatase components of the BAD apoptosis pathway influence OVCA chemo-sensitivity.