Poly(ADP-ribose) polymerase-1-induced NAD(+) depletion promotes nuclear factor-κB transcriptional activity by preventing p65 de-acetylation.

NF-κB is a transcription factor that integrates pro-inflammatory and pro-survival responses in diverse cell types. The activity of NF-κB is regulated in part by acetylation of its p65 subunit at lysine 310, which is required for transcription complex formation. De-acetylation at this site is performed by sirtuin 1(SIRT1) and possibly other sirtuins in an NAD(+) dependent manner, such that SIRT1 inhibition promotes NF-κB transcriptional activity.

Identification of hypothalamic neuron-derived neurotrophic factor as a novel factor modulating appetite.

Disruption of finely coordinated neuropeptide signals in the hypothalamus can result in altered food intake and body weight. We identified neuron-derived neurotrophic factor (NENF) as a novel secreted protein through a large-scale screen aimed at identifying novel secreted hypothalamic proteins that regulate food intake. We observed robust Nenf expression in hypothalamic nuclei known to regulate food intake, and its expression was altered under the diet-induced obese (DIO) condition relative to the fed state.

Phosphoinositide 3-kinase couples NMDA receptors to superoxide release in excitotoxic neuronal death.

Sustained activation of neuronal N-methly D-aspartate (NMDA)-type glutamate receptors leads to excitotoxic cell death in stroke, trauma, and neurodegenerative disorders. Excitotoxic neuronal death results in part from superoxide produced by neuronal NADPH oxidase (NOX2), but how NMDA receptors are coupled to neuronal NOX2 activation is not well understood. Here, we identify a signaling pathway coupling NMDA receptor activation to NOX2 activation in primary neuron cultures.

Behavior of medically-derived 131I in the tidal Potomac River.

Iodine-131 (t1/2=8.04 d) is administered to patients for treatment of thyroid disorders, excreted by patients and discharged to surface waters via sewage effluent. Radionuclides generally behave like their stable analogs; therefore, medically-derived (131)I is useful as a transport-reaction tracer of anthropogenic inputs and the aquatic biogeochemistry of iodine.

Estrogen-related receptor β deletion modulates whole-body energy balance via estrogen-related receptor γ and attenuates neuropeptide Y gene expression.

Estrogen-related receptors (ERRs) α, β and γ are orphan nuclear hormone receptors with no known ligands. Little is known concerning the role of ERRβ in energy homeostasis, as complete ERRβ-null mice die mid-gestation. We generated two viable conditional ERRβ-null mouse models to address its metabolic function.

Biotensegrity: a unifying theory of biological architecture with applications to osteopathic practice, education, and research--a review and analysis.

Since its inception, osteopathic medicine has sought to identify the mechanical causes of disease and to understand the body's structure-function relationship. Research conducted during the past 25 years has demonstrated that the architectural principles of tensegrity can be applied to biological organisms (termed biotensegrity) and that these principles can demonstrate the mechanical structure-function relationship at all size scales in the human body. Further, biotensegrity at the cellular level allows the cell to mechanically sense its environment and convert mechanical signals into biochemical changes.

Rethinking health systems strengthening: key systems thinking tools and strategies for transformational change.

While reaching consensus on future plans to address current global health challenges is far from easy, there is broad agreement that reductionist approaches that suggest a limited set of targeted interventions to improve health around the world are inadequate. We argue that a comprehensive systems perspective should guide health practice, education, research and policy. We propose key 'systems thinking' tools and strategies that have the potential for transformational change in health systems.

Activation of neuronal NMDA receptors induces superoxide-mediated oxidative stress in neighboring neurons and astrocytes.

Excitotoxic neuronal death is mediated in part by NMDA receptor-induced activation of NOX2, an enzyme that produces superoxide and resultant oxidative stress. It is not known, however, whether the superoxide is generated in the intracellular space, producing oxidative stress in the neurons responding to NMDA receptor activation, or in the extracellular space, producing oxidative stress in neighboring cells. We evaluated these alternatives by preparing cortical neuron cultures from p47(phox-/-) mice, which are unable to form a functional NOX2 complex, and transfecting the cultures at low density with GFP-tagged p47(phox) to reconstitute NOX2 activity in widely scattered neurons.

Medically-derived 131I in municipal sewage effluent.

This work presents (131)I (t(½) = 8.04 d) concentrations in sewage effluent from the Stony Brook Water Pollution Control Plant (WPCP), a small plant serving a regional thyroid cancer treatment facility in Stony Brook, NY, USA. The concentrations detected in sewage effluent ranged from 1.

Recurrent/moderate hypoglycemia induces hippocampal dendritic injury, microglial activation, and cognitive impairment in diabetic rats.

Background: Recurrent/moderate (R/M) hypoglycemia is common in type 1 diabetes. Although mild or moderate hypoglycemia is not life-threatening, if recurrent, it may cause cognitive impairment. In the present study, we sought to determine whether R/M hypoglycemia leads to neuronal death, dendritic injury, or cognitive impairment.

An examination of the diagnostic efficiency of post-deployment mental health screens.

Objective: To conduct a blinded study to examine the diagnostic efficiency of the Department of Defense (DoD) Post-Deployment Health Reassessment (PDHRA) screens for major depressive disorder (MDD), posttraumatic stress disorder (PTSD), and alcohol abuse.

Method: Participants were 148 post-deployed soldiers who were completing the PDHRA protocol. Soldiers' mean age was 27.

Milk fat globule epidermal growth factor 8 (MFG-E8): a novel protein in the mammalian endometrium with putative roles in implantation and placentation.

Objectives: MFG-E8 is a novel endometrial protein with conserved functions in tissue remodeling and angiogenesis in non-uterine tissues. Our aims were: 1. To examine the presence of MFG-E8 protein in the human endometrium during the window of implantation, in human endometrial cell lines, in human placental tissue at different gestational ages, and in murine implantation sites during early gestation; and 2.

Protecting patients from an unsafe system: the etiology and recovery of intraoperative deviations in care.

Objective: To understand the etiology and resolution of unanticipated events in the operating room (OR).

Background: The majority of surgical adverse events occur intraoperatively. The OR represents a complex, high-risk system.

Proteomics-based, multivariate random forest method for prediction of protein separation behavior during cation-exchange chromatography.

The most significant cost of recombinant protein production lies in the optimization of the downstream purification methods, mainly due to a lack of knowledge of the separation behavior of the host cell proteins (HCP). To reduce the effort required for purification process development, this work was aimed at modeling the separation behavior of a complex mixture of proteins in cation-exchange chromatography (CEX). With the emergence of molecular pharming as a viable option for the production of recombinant pharmaceutical proteins, the HCP mixture chosen was an extract of corn germ.

Aberrant substrate engagement of the ER translocon triggers degradation by the Hrd1 ubiquitin ligase.

Little is known about quality control of proteins that aberrantly or persistently engage the endoplasmic reticulum (ER)-localized translocon en route to membrane localization or the secretory pathway. Hrd1 and Doa10, the primary ubiquitin ligases that function in ER-associated degradation (ERAD) in yeast, target distinct subsets of misfolded or otherwise abnormal proteins based primarily on degradation signal (degron) location. We report the surprising observation that fusing Deg1, a cytoplasmic degron normally recognized by Doa10, to the Sec62 membrane protein rendered the protein a Hrd1 substrate.

(1,3)-β-D-glucan as a prognostic marker of treatment response in invasive candidiasis.

Background: (1,3)-β-D-glucan (BG) is a biomarker for invasive candidiasis (IC). The usefulness of BG level as a prognostic marker of treatment outcome is not well characterized.

Methods: Two hundred fifty-seven patients with proven IC were enrolled in an anidulafungin study.

Predictors of lymph node count in colorectal cancer resections: data from US nationwide prospective cohort studies.

Objective: To identify factors that influence the total and negative lymph node counts in colorectal cancer resection specimens independent of pathologists and surgeons.

Design: We used multivariate negative binomial regression. Covariates included age, sex, body mass index, family history of colorectal carcinoma, year of diagnosis, hospital setting, tumor location, resected colorectal length (specimen length), tumor size, circumferential growth, TNM stage, lymphocytic reactions and other pathological features, and tumor molecular features (microsatellite instability, CpG island methylator phenotype, long interspersed nucleotide element 1 [LINE-1] methylation, and BRAF, KRAS, and PIK3CA mutations).

Characterization of a high-affinity human antibody with a disulfide bridge in the third complementarity-determining region of the heavy chain.

Disulfide bridges are common in the antigen-binding site from sharks (new antigen receptor) and camels (single variable heavy-chain domain, VHH), in which they confer both structural diversity and domain stability. In human antibodies, cysteine residues in the third complementarity-determining region of the heavy chain (CDR-H3) are rare but naturally encoded in the IGHD germline genes. Here, by panning a phage display library designed based on human germline genes and synthetic CDR-H3 regions against a human cytokine, we identified an antibody (M3) containing two cysteine residues in the CDR-H3.

Endoscopic pyloric balloon dilatation obviates the need for pyloroplasty at esophagectomy.

Background: Because the rate of acquired pyloric stenosis (APS) from truncal vagotomy is 15%, many surgeons perform pyloroplasty or pyloromyotomy at the time of esophagectomy. Endoscopic pyloric balloon dilatation (EPBD) is another method to manage APS. This study evaluated a cohort treated with preoperative EPBD.

Prevention of traumatic brain injury-induced neuron death by intranasal delivery of nicotinamide adenine dinucleotide.

Traumatic brain injury (TBI) is one of the most devastating injuries experienced by military personnel, as well as the general population, and can result in acute and chronic complications such as cognitive impairments. Since there are currently no effective tools for the treatment of TBI, it is of great importance to determine the mechanisms of neuronal death that characterize this insult. Several studies have indicated that TBI-induced neuronal death arises in part due to excessive activation of poly(ADP-ribose) polymerase-1 (PARP-1), which results in nicotinamide adenine dinucleotide (NAD⁺) depletion and subsequent energy failure.

Microglial activation induced by brain trauma is suppressed by post-injury treatment with a PARP inhibitor.

Background: Traumatic brain injury (TBI) induces activation of microglia. Activated microglia can in turn increase secondary injury and impair recovery. This innate immune response requires hours to days to become fully manifest, thus providing a clinically relevant window of opportunity for therapeutic intervention.

Anger and postcombat mental health: validation of a brief anger measure with U.S. soldiers postdeployed from Iraq and Afghanistan.

The involvement of anger in the psychological adjustment of current war veterans, particularly in conjunction with combat-related posttraumatic stress disorder (PTSD), warrants greater research focus than it has received. The present study concerns a brief anger measure, Dimensions of Anger Reactions (DAR), intended for use in large sample studies and as a screening tool. The concurrent validity, discriminant validity, and incremental validity of the instrument were examined in conjunction with behavioral health data for 3,528 treatment-seeking soldiers who had been in combat in Iraq and Afghanistan.

Genetic construct design and recombinant protein expression for structural biology.

Obtaining diffraction quality crystals is frequently an iterative process which traditionally has involved screening large numbers of crystallization conditions. Due to advances in high-throughput gene engineering, recombinant expression, and purification, the protein of interest has now become one of the many variables routinely investigated during crystallization trials. As such, construct design is a critical step in the path toward successful crystallization.