Biochemical activity of reactive oxygen species scavengers do not predict retinal ganglion cell survival.
Retinal ganglion cells (RGCs) die as a result of axonal injury in a variety of optic neuropathies, including glaucoma. Reactive oxygen species (ROS) act as intracellular signaling molecules and initiate apoptosis in nerve growth factor-deprived sympathetic neurons and axotomized RGCs. Determination of the role of specific ROS relies on the use of small molecule or protein scavengers with various degrees of specificity. The pro- or anti-cell-death effect of several ROS generating and scavenging systems in cultured RGCs was correlated with their activity in cell-free assays. Neonatal rat retinas were dissociated and incubated with ROS-generating systems for hydroxyl radical, superoxide anion (O2-), and H2O2. Scavengers tested were catalase, polyethylene glycol-superoxide dismutase (PEG-SOD), manganese (III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP), 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), deferoxamine, and U-74389G. Viability of retrogradely labeled RGCs was determined with calcein-AM 24 hours after plating. O2- and H2O2 scavenging in cell-free assays was measured with dihydroethidium and Amplex Red (Invitrogen, Carlsbad, CA), respectively. Systematic differences were found between ROS scavenging in cell-free assays and the ability of scavengers to protect RGCs in cell culture. Furthermore, many ROS scavengers lost specificity and protected against various ROS, whereas others failed to protect against their unique ROS target. These activities stray from commonly recognized specificities of individual ROS scavengers or generating systems and are important in understanding ROS biology. In addition, antioxidant defense mechanisms used by RGCs and other retinal cells interfere with responses expected from ROS scavengers in well-defined systems. Last, H2O2 induced intramitochondrial O2-, whereas paraquat produced O2- outside of the mitochondria, and these areas of generation can mislead interpretations of ROS scavenger activity and effectiveness. There is discordance between ROS effects in cultured RGCs and cell-free assays, with several mechanisms accounting for this divergence. To identify the roles of ROS signaling in cell death accurately, several approaches should be used. These include using a panel of ROS scavengers and generators, testing the panel in primary neuronal cultures, and quantifying ROS with cell-free assays.


How Cells Respond to DNA Breaks in Mitosis.
DNA double-strand breaks (DSBs) are highly toxic lesions that can lead to chromosomal instability if they are not repaired correctly. DSBs are especially dangerous in mitosis when cells go through the complex process of equal chromosome segregation into daughter cells. When cells encounter DSBs in interphase, they are able to arrest the cell cycle until the breaks are repaired before entering mitosis. However, when DSBs occur during mitosis, cells no longer arrest but prioritize completion of cell division over repair of DNA damage. This review focuses on recent progress in our understanding of the mechanisms that allow mitotic cells to postpone DSB repair without accumulating massive chromosomal instability. Additionally, we review possible physiological consequences of failed DSB responses in mitosis.


Evaluation of a breast and colon cancer survivorship program.
This article describes a cancer survivorship program that addressed quality of life (QOL) changes related to chemotherapy. The program focused on adult breast and colon cancer survivors at a community oncology practice in the southeastern United States, and consisted of an educational visit designed to identify and address QOL changes that occurred as a result of chemotherapy. The QOL of Cancer Survivors (QOL-CS) survey administered before and after the visit analyzed QOL metrics, which were combined with program evaluation data to assess physical, psychosocial, social, and spiritual well-being changes that may have occurred as a result of program participation. Differences in QOL-CS scores did not represent statistically significant changes in QOL for program participants. However, program evaluation responses identified perceived changes in QOL as a result of participating in cancer treatment and a subsequent cancer survivorship program, which demonstrated clinical significance for program participants. Physical, psychosocial, social, and spiritual well-being measures were affected by program participation. Improvement in distress related to the initial cancer diagnosis and family distress were the most significant reported changes, and male gender and advanced age were associated with improved psychosocial well-being.


Genomic deletion of malic enzyme 2 confers collateral lethality in pancreatic cancer.
The genome of pancreatic ductal adenocarcinoma (PDAC) frequently contains deletions of tumour suppressor gene loci, most notably SMAD4, which is homozygously deleted in nearly one-third of cases. As loss of neighbouring housekeeping genes can confer collateral lethality, we sought to determine whether loss of the metabolic gene malic enzyme 2 (ME2) in the SMAD4 locus would create cancer-specific metabolic vulnerability upon targeting of its paralogous isoform ME3. The mitochondrial malic enzymes (ME2 and ME3) are oxidative decarboxylases that catalyse the conversion of malate to pyruvate and are essential for NADPH regeneration and reactive oxygen species homeostasis. Here we show that ME3 depletion selectively kills ME2-null PDAC cells in a manner consistent with an essential function for ME3 in ME2-null cancer cells. Mechanistically, integrated metabolomic and molecular investigation of cells deficient in mitochondrial malic enzymes revealed diminished NADPH production and consequent high levels of reactive oxygen species. These changes activate AMP activated protein kinase (AMPK), which in turn directly suppresses sterol regulatory element-binding protein 1 (SREBP1)-directed transcription of its direct targets including the BCAT2 branched-chain amino acid transaminase 2) gene. BCAT2 catalyses the transfer of the amino group from branched-chain amino acids to α-ketoglutarate (α-KG) thereby regenerating glutamate, which functions in part to support de novo nucleotide synthesis. Thus, mitochondrial malic enzyme deficiency, which results in impaired NADPH production, provides a prime 'collateral lethality' therapeutic strategy for the treatment of a substantial fraction of patients diagnosed with this intractable disease.


Bioelectrical impedance assessment of wound healing.
Objective assessment of wound healing is fundamental to evaluate therapeutic and nutritional interventions and to identify complications. Despite availability of many techniques to monitor wounds, there is a need for a safe, practical, accurate, and effective method. A new method is localized bioelectrical impedance analysis (BIA) that noninvasively provides information describing cellular changes that occur during healing and signal complications to wound healing. This article describes the theory and application of localized BIA and provides examples of its use among patients with lower leg wounds. This promising method may afford clinicians a novel technique for routine monitoring of interventions and surveillance of wounds.


A survey of the Agrotis of Iran.
The present study reviews the genus Agrotis Ochsenheimer, 1816 (Lepidoptera: Noctuidae: Noctuinae) in Iran from a taxonomic and faunistic point of view. An identification key of external features is presented for 16 Iranian species and subspecies. A description of each taxon is presented based on external male and female genital characteristics. Diagnostic features and comparisons with the closest relatives are given for each species. Original combination and citation with the synonymy of each species or subspecies are expounded as well as their distribution and bionomy. Adult moths and male genitalia are illustrated.


Synaptic energy efficiency in retinal processing.
Recent work suggests that the visual system may represent early visual information in an energy efficient manner [Nature 381 (1996); Nature, 381 (1996) 607; Neural Comput. 3 (2001) 799; Curr. Opin. Neurobiol. 11 (2001) 475]. This paper applies the idea of energy efficient representations to understand retinal processing, and provides evidence that centre surround processing observed is efficient in terms of minimizing synaptic activity. In particular, it is shown that receptive fields at different retinal eccentricities and at different levels of noise, can be understood in terms of maximizing the transmission of visual information given a constraint on total synaptic strengths and hence energy consumption.


Microcloning and replica plating of mammalian cells.
A technique for cloning single mammalian cells has been developed by means of a microculture method (0.010 milliliters per culture). A technique of replica plating has also been developed for use with clones of single cells in microcultures; this technique permits the screening of desired properties of many clones simultaneously before the growth of stock cultures. With these techniques an investigator can with limited budget, space, and personnel perform research using tissue culture systems.


Prevalence and prognostic value of autonomic neuropathy assessed by Sudoscan® in transthyretin wild-type cardiac amyloidosis.
The prevalence of autonomic neuropathy (AN) is high in patients with hereditary transthyretin amyloidosis but remains unknown in transthyretin wild-type cardiac amyloidosis (ATTRwt-CA). This study aimed to determine the prevalence of AN in patients with ATTRwt-CA using Sudoscan®, a non-invasive method used to provide evidence of AN in clinical practice and based on measurement of electrochemical skin conductance at the hands and feet (fESC). A series of 62 non-diabetic patients with ATTRwt-CA was prospectively included over 2 years and compared with healthy elderly subjects, matched by age, gender, and body mass index. The presence of AN was defined as electrochemical skin conductance at the hands <60 μS and/or fESC <70 μS, and conductances were analysed according to clinical, biological, and echocardiographic data. Mean fESC was significantly lower in patients with ATTRwt-CA compared with elderly controls: 68.3 (64.1-72.5) vs. 76.9 (75.6-78.1) μS (P < 0.0001), respectively. Prevalence of fESC <70 μS was higher in ATTRwt-CA patients than in controls: 48.4% vs. 19.9%, P < 0.05. Univariate analysis showed that fESC, N-terminal pro-B-type natriuretic peptide, creatinine plasma levels, and echocardiographic global longitudinal strain were associated with decompensated cardiac failure and death. Multivariate analysis revealed that fESC was an independent prognostic factor, and Kaplan-Meier estimator evidenced a greater occurrence of cardiac decompensation and death in patients with fESC <70 μS, P = 0.046. Reduced fESC was observed in almost 50% of patients with ATTRwt-CA and was associated with a worse prognosis. Sudoscan® could easily be used to screen ATTRwt-CA patients for the presence of AN and identify patients at higher risk for a poor outcome.


p-Hydroxymercuribenzoic acid inhibits arachidonic acid esterification into two distinct pools and stimulates insulin release in intact rat islets.
Activation of an islet phospholipase A2 may contribute to glucose-induced insulin release. In order to simulate the accumulation of the resultant hydrolytic products (arachidonic acid, AA; its lipoxygenase-derived oxygenation product 12-hydroxyeicosatetraenoic acid; and lysophospholipids) without many of the other concomitants of beta cell activation, we studied the effects on intact rat islets of p-hydroxymercuribenzoic acid (PHMB), which inhibits the reacylation of lysophospholipids with AA in other cell types. PHMB inhibited in a dose-responsive fashion (-90% at 500 microM) the incorporation of [3H]AA into a "basal" pool or pools whose release and reuptake mechanisms appeared to be largely energy- and Ca++-independent (resistant to inhibition by mannoheptulose, antimycin A or CoCl2); reciprocally, islets prelabeled with [3H]AA accumulated an increased amount of [3H]-12-hydroxyeicosatetraenoic acid (twice basal at 200 microM PHMB and three times basal at 500 microM) when reacylation of any [3H]AA released basally at 1.7 mM glucose was inhibited. PHMB also blocked (by up to 99% at 500 microM) the incorporation of [3H]AA into a functionally defined, glucose-stimulated compartment of fatty acid (tightly coupled to the islet 12-lipoxygenase) whose release and reuptake required metabolic energy and Ca++. It was also demonstrated that PHMB inhibited the esterification of [3H]AA (at low or high glucose concentrations) into specific phospholipids in islet membranes. In parallel with these alterations in lipid metabolism, PHMB caused rapid, potent and reversible increments in insulin release with a threshold concentration (about 25 microM) identical to that inhibiting AA fluxes. PHMB both initiated release (at 1.7 mM glucose) and potentiated the effects of islet fuels (16.7 mM glucose or 15 mM alpha-ketoisocaproic acid). Thus, pharmacologic manipulation of the AA reuptake mechanism is a new approach to unmask potential roles in insulin release of phospholipid hydrolysis products from different lipid pools and in the absence or presence of phospholipase A2 activation.


Dopaminergic modulation of motor maps in rat motor cortex: an in vivo study.
While the primary motor cortex (M1) is know to receive dopaminergic projections, the functional role of these projections is poorly characterized. Here, it is hypothesized that dopaminergic signals modulate M1 excitability and somatotopy, two features of the M1 network relevant for movement execution and learning. To test this hypothesis, movement responses evoked by electrical stimulation using an electrode grid implanted epidurally over the caudal motor cortex (M1) were assessed before and after an intracortical injection of D1- (R-(+),8-chloro,7-hydroxy,2,3,4,5,-tetra-hydro,3-methyl,5-phenyl,1-H,3-benzazepine maleate, SCH 23390) or D2-receptor (raclopride) antagonists into the M1 forelimb area of rats. Stimulation mapping of M1 was repeated after 24 h. D2-inhibition reduced the size of the forelimb representation by 68.5% (P<0.001). Movements thresholds, i.e., minimal currents required to induce movement responses increased by 37.5% (P<0.001), and latencies increased by 35.9% (P<0.01). Twenty-4 h after the injections these effects were reversed. No changes were observed with D1-antagonist or vehicle. By enhancing intracortical excitability and signal transduction, D2-mediated dopaminergic signaling may affect movement execution, e.g. by enabling task-related muscle activation synergies, and learning.


A study on characteristics of atmospheric heavy metals in subway station.
In this study, we investigated the atmospheric heavy metal concentrations in the particulate matter inside the subway stations of Seoul. In particular, we examined the correlation between the heavy metals and studied the effect of the heavy metals on cell proliferation. In six selected subway stations in Seoul, particulate matter was captured at the platforms and 11 types of heavy metals were analyzed. The results showed that the mean concentration of iron was the highest out of the heavy metals in particulate matter, followed by copper, potassium, calcium, zinc, nickel, sodium, manganese, magnesium, chromium and cadmium in that order. The correlation analysis showed that the correlations between the heavy metals was highest in the following order: (Cu vs Zn) , (Ca vs Na) , (Ca vs Mn) , (Ni vs Cr) , (Na vs Mn) , (Cr vs Cd) , (Zn vs Cd) , (Cu vs Cd) , (Ni vs Cd) , (Cu vs Ni) , (K vs Zn) , (Cu vs K) , (Cu vs Cr) , (K vs Cd) , (Zn vs Cr) , (K vs Ni) , (Zn vs Ni) , (K vs Cr) , and (Fe vs Cu) . The correlation coefficient between zinc and copper was 0.937, indicating the highest correlation. Copper, zinc, nickel, chromium and cadmium, which are generated from artificial sources in general, showed correlations with many of the other metals and the correlation coefficients were also relatively high. The effect of the heavy metals on cell proliferation was also investigated in this study. Cultured cell was exposed to 10 mg/l or 100 mg/l of iron, copper, calcium, zinc, nickel, manganese, magnesium, chromium and cadmium for 24 hours. The cell proliferation in all the heavy metal-treated groups was not inhibited at 10 mg/l of the heavy metal concentration. The only exception to this was with the cadmium-treated group which showed a strong cell proliferation inhibition. This study provides the fundamental data for the understanding of simultaneous heavy metal exposure tendency at the time of particulate matter exposure in subway stations and the identification of heavy metal sources. Moreover, this study can be used as the fundamental data for the cell toxicity study of the subway-oriented heavy metal-containing particulate matter.


Keeping the leaves green above us.
The plant immune system relies to a great extent on the highly regulated expression of hundreds of defense genes encoding antimicrobial proteins, such as defensins, and antiherbivore proteins, such as lectins. The expression of many of these genes is controlled by a family of mediators known as jasmonates; these cyclic oxygenated fatty acid derivatives are reminiscent of prostaglandins. The roles of jasmonates also extend to the control of reproductive development. How are these complex events regulated? Nearly 20 members of the jasmonate family have been characterized. Some, like jasmonic acid, exist in unmodified forms, whereas others are conjugated to other lipids or to hydrophobic amino acids. Why do so many chemically different forms of these mediators exist, and do individual jasmonates have unique signaling properties or are they made to facilitate transport within and between cells? Key features of the jasmonate signal pathway have been identified and include the specific activation of E3-type ubiquitin ligases thought to target as-yet-undescribed transcriptional repressors for modification or destruction. Several classes of transcription factor are known to function in the jasmonate pathway, and, in some cases, these proteins provide nodes that integrate this network with other important defensive and developmental pathways. Progress in jasmonate research is now rapid, but large gaps in our knowledge exist. Aimed to keep pace with progress, the ensemble of jasmonate Connections Maps at the Signal Transduction Knowledge Environment describe (i) the canonical signaling pathway, (ii) the Arabidopsis signaling pathway, and (iii) the biogenesis and structures of the jasmonates themselves.


Screening for Atrial Fibrillation With Electrocardiography: US Preventive Services Task Force Recommendation Statement.
Atrial fibrillation is the most common type of cardiac arrhythmia (irregular heartbeat), and its prevalence increases with age, affecting about 3% of men and 2% of women aged 65 to 69 years and about 10% of adults 85 years and older. Atrial fibrillation is a major risk factor for ischemic stroke, increasing risk of stroke by as much as 5-fold. Approximately 20% of patients who have a stroke associated with atrial fibrillation are first diagnosed with atrial fibrillation at the time of stroke or shortly thereafter. To issue a new US Preventive Services Task Force (USPSTF) recommendation on screening for atrial fibrillation with electrocardiography (ECG). The USPSTF reviewed the evidence on the benefits and harms of screening for atrial fibrillation with ECG in adults 65 years and older, the effectiveness of screening with ECG for detecting previously undiagnosed atrial fibrillation compared with usual care, and the benefits and harms of anticoagulant or antiplatelet therapy for the treatment of screen-detected atrial fibrillation in older adults. Most older adults with previously undiagnosed atrial fibrillation have a stroke risk above the threshold for anticoagulant therapy and would be eligible for treatment. Anticoagulant therapy is effective for stroke prevention in symptomatic persons with atrial fibrillation and high stroke risk. However, the USPSTF found inadequate evidence to determine whether screening with ECG and subsequent treatment in asymptomatic adults is more effective than usual care. At the same time, the harms of diagnostic follow-up and treatment prompted by abnormal ECG results are well established and include misdiagnosis and invasive testing. Given these uncertainties, it is not possible to determine the net benefit of screening with ECG. The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for atrial fibrillation with ECG. (I statement).


Recent experience with diaphragmatic hernia and ECMO.
In the past 4 years at the Medical College of Georgia, a total of 74 patients underwent extracorporeal membrane oxygenation (ECMO) with 62 (84%) survivors. Forty-seven of these infants had meconium aspiration syndrome and 11 had diaphragmatic hernia. The use of ECMO, when indicated, after reduction and repair of the diaphragmatic hernia, results in normal oxygen delivery, allows time for pulmonary maturation, and increases survival. A total of 27 referrals for diaphragmatic hernia were studied. Six infants had surgical repair and did not require ECMO. Eleven patients, after surgical repair, were treated with ECMO and seven survived. More importantly 10 patients died before the use of ECMO. Six infants died either before or during transport from referring hospitals and four died while in the delivery room or neonatal unit before ECMO. Of these 10 infants, eight were potential candidates for ECMO. Thirteen of the twenty-seven (48%) infants survived. Seven of eleven (64%) infants who received the benefit of ECMO survived. Eight infants who met the criteria for ECMO died before its use. Had ECMO been used in those eight infants, our data suggests that at least four may have survived. The data from this report support the concept that infants undergoing surgical repair of diaphragmatic hernia, when ECMO is not available, should be referred to an ECMO center in the early postoperative period. Furthermore infants with prenatal diagnosis of diaphragmatic hernia should be delivered at a center where surgical as well as ECMO expertise are available.


Evolutionary diversification of SPANX-N sperm protein gene structure and expression.
The sperm protein associated with nucleus in the X chromosome (SPANX) genes cluster at Xq27 in two subfamilies, SPANX-A/D and SPANX-N. SPANX-A/D is specific for hominoids and is fairly well characterized. The SPANX-N gave rise to SPANX-A/D in the hominoid lineage approximately 7 MYA. Given the proposed role of SPANX genes in spermatogenesis, we have extended studies to SPANX-N gene evolution, variation, regulation of expression, and intra-sperm localization. By immunofluorescence analysis, SPANX-N proteins are localized in post-meiotic spermatids exclusively, like SPANX-A/D. But in contrast to SPANX-A/D, SPANX-N are found in all ejaculated spermatozoa rather than only in a subpopulation, are localized in the acrosome rather than in the nuclear envelope, and are expressed at a low level in several nongametogenic adult tissues as well as many cancers. Presence of a binding site for CTCF and its testis-specific paralogue BORIS in the SPANX promoters suggests, by analogy to MAGE-A1 and NY-ESO-1, that their activation in spermatogenesis is mediated by the programmed replacement of CTCF by BORIS. Based on the relative density of CpG, the more extended expression of SPANX-N compared to SPANX-A/D in nongametogenic tissues is likely attributed to differences in promoter methylation. Our findings suggest that the recent duplication of SPANX genes in hominoids was accompanied by different localization of SPANX-N proteins in post-meiotic sperm and additional expression in several nongonadal tissues. This suggests a corresponding functional diversification of SPANX gene families in hominoids. SPANX proteins thus provide unique targets to investigate their roles in the function of spermatozoa, selected malignancies, and for SPANX-N, in other tissues as well.


GLUT 1 receptor expression and circulating levels of fasting glucose in high grade serous ovarian cancer.
In recent years, the poorly remarkable goals achieved in terms of patients' important outcomes for ovarian cancer have fueled our interest toward the study of its metabolic roots. Within this research pipeline, we assessed the association between the expression of the glucose transporter GLUT1, as expressed at the tumor tissue level, and circulating pre-surgical levels of fasting glucose in a case series including data from 40 patients with high FIGO stage serous ovarian cancer. Patients who provided data to the current analysis were randomly selected from a larger cohort. To our purposes, the procedures related to serum and tissue collection, storage and biomarker assessment were highly standardized and centralized at the institutional laboratories. The GLUT1 antibody SPM498 SPRING (REF. E13810) was used at a 1:500 dilution in 2 µm slides. Staining for GLUT1 was observed at the cell membrane level in all the cases assessed, but strong staining was described in 29 (72.5%) of them. The agreement between the two independent reviewers was 100%. Strong GLUT1 staining was inversely associated with circulating levels of fasting glucose, with a particularly striking difference for patients in the lowest fasting glucose tertile (p = 0.044). These results support the biological plausibility of the association of interest. If confirmed in larger studies, our findings may help clarify the potentials of biomarkers related to energy metabolism in terms of prognosis definition, treatment assignment, and outcome interpretation for patients with high FIGO stage serous ovarian cancer.


Using the "reverse Warburg effect" to identify high-risk breast cancer patients: stromal MCT4 predicts poor clinical outcome in triple-negative breast cancers.
We have recently proposed a new model of cancer metabolism to explain the role of aerobic glycolysis and L-lactate production in fueling tumor growth and metastasis. In this model, cancer cells secrete hydrogen peroxide (H2O2), initiating oxidative stress and aerobic glycolysis in the tumor stroma. This, in turn, drives L-lactate secretion from cancer-associated fibroblasts. Secreted L-lactate then fuels oxidative mitochondrial metabolism (OXPHOS) in epithelial cancer cells, by acting as a paracrine onco-metabolite. We have previously termed this type of two-compartment tumor metabolism the "Reverse Warburg Effect," as aerobic glycolysis takes place in stromal fibroblasts, rather than epithelial cancer cells. Here, we used MCT4 immuno-staining of human breast cancer tissue microarrays (TMAs; > 180 triple-negative patients) to directly assess the prognostic value of the "Reverse Warburg Effect." MCT4 expression is a functional marker of hypoxia, oxidative stress, aerobic glycolysis, and L-lactate efflux. Remarkably, high stromal MCT4 levels (score = 2) were specifically associated with decreased overall survival (< 18% survival at 10 y post-diagnosis). In contrast, patients with absent stromal MCT4 expression (score = 0), had 10-y survival rates of ~97% (p-value < 10 (-32) ). High stromal levels of MCT4 were strictly correlated with a loss of stromal Cav-1 (p-value < 10 (-14) ), a known marker of early tumor recurrence and metastasis. In fact, the combined use of stromal Cav-1 and stromal MCT4 allowed us to more precisely identify high-risk triple-negative breast cancer patients, consistent with the goal of individualized risk-assessment and personalized cancer treatment. However, epithelial MCT4 staining had no prognostic value, indicating that the "conventional" Warburg effect does not predict clinical outcome. Thus, the "Reverse Warburg Effect" or "parasitic" energy-transfer is a key determinant of poor overall patient survival. As MCT4 is a druggable-target, MCT4 inhibitors should be developed for the treatment of aggressive breast cancers, and possibly other types of human cancers. Similarly, we discuss how stromal MCT4 could be used as a biomarker for identifying high-risk cancer patients that could likely benefit from treatment with FDA-approved drugs or existing MCT-inhibitors (such as, AR-C155858, AR-C117977, and AZD-3965).


Nucleostemin as a possible progenitor marker of corneal epithelial cells.
Nucleostemin, a nuclear protein involved in the regulation of cell cycle and proliferation, is a candidate marker for various stem cells. We examined the expression of nucleostemin as a marker of differentiation and senescence in corneal epithelial progenitor cells. Nucleostemin expression in normal mouse corneal epithelium was examined by RT-PCR, as well as in cultured mouse corneal epithelial cells by immunohistochemistry. Co-expression with the progenitor markers p63 and Bmi-1, cytokeratin 14 and 19, the proliferating marker Ki67, differentiation markers cytokeratin 12 and involucrin, and with the senescent marker SA-beta-gal were examined by immunohistochemistry. Correlation of cellular size and nucleostemin expression was also examined. Nucleostemin expression was detected in mouse corneal epithelium by RT-PCR. Immunohistochemistry revealed that nucleostemin was expressed predominantly in basal and suprabasal cells of the whole cornea. The expression of nucleostemin was not associated with the expression of Ki67, K14, and K19, but with the expression of Bmi-1 and particularly with p63. Nucleostemin was not co-expressed with SA-beta-gal in same cell. Nucleostemin can be used as a progenitor marker analogous to p63.


Predictors of treatment response for depression and inadequate social support--the ENRICHD randomized clinical trial.
To determine whether the 'dose' of treatment exposure, delivery of specific components of cognitive behavior therapy (CBT), patient adherence and/or use of antidepressants predict favorable depression and social support outcomes after 6 months of cognitive behavioral treatment. Secondary analyses of the intervention arm of the Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial involving persons with acute myocardial infarction (MI): n = 641 for the depression outcomes and n = 523 for the social support outcomes. The outcome measures were, for depression: the Beck Depression Inventory (BDI) and Hamilton Rating Scale for Depression (HAM-D); for social support: the ENRICHD Social Support Instrument (ESSI) and Perceived Social Support Scale (PSSS). Better depression outcomes (measured by the BDI) were receiving a high number of depression-specific intervention components, p < 0.01, and completing a high proportion of homework assignments, p < 0.02. Better depression outcomes (measured by the HAM-D) were receiving a high number of the social communication and assertiveness components of the intervention, p < 0.01, and completing a high proportion of homework assignments, p < 0.01. Better social support outcomes (measured by the ESSI and PSSS) were predicted by membership in a racial or ethnic minority group, p < 0.02 and p < 0.01, respectively; and by completing a higher number of homework assignments, p < 0.01 and p < 0.05, respectively. Delivery of the social communication and assertiveness components of the intervention was an independent predictor of a worse social support outcome, p < 0.01 (measured by the PSSS). The standard components of CBT for depression are useful in treating comorbid depression in post-MI patients. Working on communication skills may help to improve depression but not necessarily social support outcomes in this patient population, while adherence to cognitive-behavioral homework assignments is important for both outcomes. Other components of the ENRICHD intervention that were designed to improve social support had no discernible effects on outcomes. Intervention refinements may be needed in order to achieve better results in future post-MI clinical trials. A greater emphasis on CBT homework adherence could improve both depression and social support outcomes.


Race/Ethnicity, Underlying Medical Conditions, Homelessness, and Hospitalization Status of Adult Patients with COVID-19 at an Urban Safety-Net Medical Center - Boston, Massachusetts, 2020.
As of July 5, 2020, approximately 2.8 million coronavirus disease 2019 (COVID-19) cases and 130,000 COVID-19-associated deaths had been reported in the United States (1). Populations historically affected by health disparities, including certain racial and ethnic minority populations, have been disproportionally affected by and hospitalized with COVID-19 (2-4). Data also suggest a higher prevalence of infection with SARS-CoV-2, the virus that causes COVID-19, among persons experiencing homelessness (5). Safety-net hospitals,† such as Boston Medical Center (BMC), which provide health care to persons regardless of their insurance status or ability to pay, treat higher proportions of these populations and might experience challenges during the COVID-19 pandemic. This report describes the characteristics and clinical outcomes of adult patients with laboratory-confirmed COVID-19 treated at BMC during March 1-May 18, 2020. During this time, 2,729 patients with SARS-CoV-2 infection were treated at BMC and categorized into one of the following mutually exclusive clinical severity designations: exclusive outpatient management (1,543; 56.5%), non-intensive care unit (ICU) hospitalization (900; 33.0%), ICU hospitalization without invasive mechanical ventilation (69; 2.5%), ICU hospitalization with mechanical ventilation (119; 4.4%), and death (98; 3.6%). The cohort comprised 44.6% non-Hispanic black (black) patients and 30.1% Hispanic or Latino (Hispanic) patients. Persons experiencing homelessness accounted for 16.4% of patients. Most patients who died were aged ≥60 years (81.6%). Clinical severity differed by age, race/ethnicity, underlying medical conditions, and homelessness. A higher proportion of Hispanic patients were hospitalized (46.5%) than were black (39.5%) or non-Hispanic white (white) (34.4%) patients, a finding most pronounced among those aged <60 years. A higher proportion of non-ICU inpatients were experiencing homelessness (24.3%), compared with homeless patients who were admitted to the ICU without mechanical ventilation (15.9%), with mechanical ventilation (15.1%), or who died (15.3%). Patient characteristics associated with illness and clinical severity, such as age, race/ethnicity, homelessness, and underlying medical conditions can inform tailored strategies that might improve outcomes and mitigate strain on the health care system from COVID-19.


The effects of a ketogenic diet on exercise metabolism and physical performance in off-road cyclists.
The main objective of this research was to determine the effects of a long-term ketogenic diet, rich in polyunsaturated fatty acids, on aerobic performance and exercise metabolism in off-road cyclists. Additionally, the effects of this diet on body mass and body composition were evaluated, as well as those that occurred in the lipid and lipoprotein profiles due to the dietary intervention. The research material included eight male subjects, aged 28.3 ± 3.9 years, with at least five years of training experience that competed in off-road cycling. Each cyclist performed a continuous exercise protocol on a cycloergometer with varied intensity, after a mixed and ketogenic diet in a crossover design. The ketogenic diet stimulated favorable changes in body mass and body composition, as well as in the lipid and lipoprotein profiles. Important findings of the present study include a significant increase in the relative values of maximal oxygen uptake (VO2max) and oxygen uptake at lactate threshold (VO2 LT) after the ketogenic diet, which can be explained by reductions in body mass and fat mass and/or the greater oxygen uptake necessary to obtain the same energy yield as on a mixed diet, due to increased fat oxidation or by enhanced sympathetic activation. The max work load and the work load at lactate threshold were significantly higher after the mixed diet. The values of the respiratory exchange ratio (RER) were significantly lower at rest and during particular stages of the exercise protocol following the ketogenic diet. The heart rate (HR) and oxygen uptake were significantly higher at rest and during the first three stages of exercise after the ketogenic diet, while the reverse was true during the last stage of the exercise protocol conducted with maximal intensity. Creatine kinase (CK) and lactate dehydrogenase (LDH) activity were significantly lower at rest and during particular stages of the 105-min exercise protocol following the low carbohydrate ketogenic diet. The alterations in insulin and cortisol concentrations due to the dietary intervention confirm the concept that the glucostatic mechanism controls the hormonal and metabolic responses to exercise.


Hot-starting software containers for STAR aligner.
Using software containers has become standard practice to reproducibly deploy and execute biomedical workflows on the cloud. However, some applications that contain time-consuming initialization steps will produce unnecessary costs for repeated executions. We demonstrate that hot-starting from containers that have been frozen after the application has already begun execution can speed up bioinformatics workflows by avoiding repetitive initialization steps. We use an open-source tool called Checkpoint and Restore in Userspace (CRIU) to save the state of the containers as a collection of checkpoint files on disk after it has read in the indices. The resulting checkpoint files are migrated to the host, and CRIU is used to regenerate the containers in that ready-to-run hot-start state. As a proof-of-concept example, we create a hot-start container for the spliced transcripts alignment to a reference (STAR) aligner and deploy this container to align RNA sequencing data. We compare the performance of the alignment step with and without checkpoints on cloud platforms using local and network disks. We demonstrate that hot-starting Docker containers from snapshots taken after repetitive initialization steps are completed significantly speeds up the execution of the STAR aligner on all experimental platforms, including Amazon Web Services, Microsoft Azure, and local virtual machines. Our method can be potentially employed in other bioinformatics applications in which a checkpoint can be inserted after a repetitive initialization phase.


Challenges in dengue research: A computational perspective.
The dengue virus is now the most widespread arbovirus affecting human populations, causing significant economic and social impact in South America and South-East Asia. Increasing urbanization and globalization, coupled with insufficient resources for control, misguided policies or lack of political will, and expansion of its mosquito vectors are some of the reasons why interventions have so far failed to curb this major public health problem. Computational approaches have elucidated on dengue's population dynamics with the aim to provide not only a better understanding of the evolution and epidemiology of the virus but also robust intervention strategies. It is clear, however, that these have been insufficient to address key aspects of dengue's biology, many of which will play a crucial role for the success of future control programmes, including vaccination. Within a multiscale perspective on this biological system, with the aim of linking evolutionary, ecological and epidemiological thinking, as well as to expand on classic modelling assumptions, we here propose, discuss and exemplify a few major computational avenues-real-time computational analysis of genetic data, phylodynamic modelling frameworks, within-host model frameworks and GPU-accelerated computing. We argue that these emerging approaches should offer valuable research opportunities over the coming years, as previously applied and demonstrated in the context of other pathogens.


Encephaloduroarteriosynangiosis and encephalomyoarteriosynangiosis for treatment of moyamoya syndrome in pediatric patients with sickle cell disease.
OBJECT Pediatric patients with sickle cell disease (SCD) and moyamoya syndrome (MMS) are at significant risk for cerebrovascular accidents despite chronic transfusion therapy. Encephaloduroarteriosynangiosis (EDAS) and encephalomyoarteriosynangiosis (EMAS) are additional therapeutic options for these patients. To date, the incidence of complications after and efficacy of EDAS and EMAS in stroke prevention in this population have been described in several institutional case series reports, but no randomized prospective trials have been reported. METHODS The authors retrospectively reviewed the cases of all pediatric patients at the University of Alabama at Birmingham with a history of homozygous hemoglobin S (HbS) and sickle cell/β-thalassemia (SB0 thalassemia) and on chronic transfusion therapy, including 14 patients with MMS who underwent EDAS or EMAS. RESULTS Sixty-two patients with SCD and on chronic transfusion therapy were identified. After exclusion of patients on chronic transfusion therapy for indications other than stroke prevention, 48 patients (77.4%) remained. Of those patients, 14 (29.1%) underwent EDAS or EMAS. Nine (18.8%) and 25 (52.1%) patients were on chronic transfusion therapy for primary or secondary stroke prevention, respectively, but did not undergo EDAS or EMAS. The 14 patients with SCD and radiological evidence of MMS and on chronic transfusion therapy for primary or secondary stroke prevention underwent 21 EDAS or EMAS procedures for progressive vascular disease (92.9% of patients), stroke (71.4%), and/or seizure (7.1%). The mean (± SD) time from initiation of chronic transfusion therapy to EDAS or EMAS was 76.8 ± 58.8 months. Complications included 1 perioperative stroke, 1 symptomatic subdural hygroma, 1 postoperative seizure, and 1 case of intraoperative cerebral edema that required subsequent cranioplasty. Before EDAS or EMAS, the stroke rate was calculated to be 1 stroke per 7.8 patient-years. One additional stroke occurred during the follow-up period (mean follow-up time 33.7 ± 19.6 months), resulting in a post-EDAS/EMAS stroke rate of 1 stroke per 39.3 patient-years, a 5-fold reduction compared with that in the pre-EDAS/EMAS period. The patients' mean pre-EDAS/EMAS HbS level of 29.5% ± 6.4% was comparable to the mean post-EDAS/EMAS HbS level of 25.5% ± 6.1% (p = 0.104). CONCLUSIONS The results of this retrospective case series in a large cohort of pediatric patients with SCD and MMS suggest that EDAS/EMAS provides a stroke-prevention benefit with an acceptably low morbidity rate. Given the combined experience with EDAS and EMAS for this indication at this and other institutions, a prospective clinical trial to assess their efficacy compared with that of chronic transfusion therapy alone is warranted.


Vogesella lacus sp. nov., isolated from a soft-shell turtle culture pond.
A non-pigmented, Gram-negative, aerobic, rod-shaped bacterium, strain GR13(T), was isolated using nutrient agar from a water sample from a pond used for the culture of soft-shell turtles (Trionyx sinensis), Pingtung County, Taiwan. 16S rRNA gene sequence studies indicated that the novel strain formed a monophyletic branch at the periphery of the evolutionary radiation occupied by the genus Vogesella. Its closest neighbours were Vogesella indigofera ATCC 19706(T) and Vogesella perlucida DS-28(T) (both with 97.4 % gene sequence similarity). The novel isolate could be distinguished from these species by several phenotypic characteristics. The predominant fatty acids were summed feature 3 (C(16 : 1)omega7c and/or C(15 : 0) iso 2-OH; 60 %), C(16 : 0) (13.6 %) and C(18 : 1)omega7c (12.5 %). The DNA G+C content of strain GR13(T) was 63 mol%. The DNA-DNA hybridization values for the novel strain with V. indigofera and V. perlucida were <25 %. On the basis of the 16S rRNA gene sequence analysis and the chemotaxonomic and physiological data, it is concluded that strain GR13(T) represents a novel species in the genus Vogesella, for which the name Vogesella lacus sp. nov. is proposed. The type strain is GR13(T) (=BCRC 17836(T)=LMG 24504(T)).


Transporter taxonomy - a comparison of different transport protein classification schemes.
Currently, there are more than 800 well characterized human membrane transport proteins (including channels and transporters) and there are estimates that about 10% (approx. 2000) of all human genes are related to transport. Membrane transport proteins are of interest as potential drug targets, for drug delivery, and as a cause of side effects and drug–drug interactions. In light of the development of Open PHACTS, which provides an open pharmacological space, we analyzed selected membrane transport protein classification schemes (Transporter Classification Database, ChEMBL, IUPHAR/BPS Guide to Pharmacology, and Gene Ontology) for their ability to serve as a basis for pharmacology driven protein classification. A comparison of these membrane transport protein classification schemes by using a set of clinically relevant transporters as use-case reveals the strengths and weaknesses of the different taxonomy approaches.


Why hydroxy-proline improves the catalytic power of the peptidoglycan N-deacetylase enzyme: insight from theory.
Nature exploits different strategies for enhancing the catalytic activity of enzymes, often resorting to producing beneficial mutations. The case of post-translational proline hydroxylation mutation in the active site of polysaccharide deacetylase (PDA) Bc1960 from Bacillus cereus is an interesting example of how small chemical modifications can cause significant improvements in enzymatic activity. In the present study the deacetylation mechanism promoted by both OH-proline (2Hyp) and standard proline (Pro) containing PDA is investigated using density functional theory. Although the mechanism presented for the two examined enzymes is in agreement with protease catalysis in metalloenzymes, the analysis along the potential energy surface (PES) reveals that the intermediate and product benefit energetically from the presence of the hydroxyl group on the proline. Our calculations provide evidence that for PDA-2Hyp, the hydrogen bond network established by the -OH group on the Cα of the proline with its closest neighbors stabilizes the transition states and, consequently, the reaction takes advantage of this. These results further contribute towards explaining the different catalytic activity experimentally observed for the polysaccharide deacetylase enzymes.


Genetic architecture of open angle glaucoma and related determinants.
Although the vertical cup-disc ratio (VCDR) and intraocular pressure (IOP) are important determinants of open angle glaucoma (OAG), it is unclear to what extent the genetic origin of these traits overlap with those of OAG. We evaluated whether the same genes that determine VCDR and IOP also predict OAG. Genetic risk scores were constructed from single nucleotide polymorphisms (SNPs) using genome wide association data of 9326 participants from the Rotterdam Study cohorts (mean ± SD age: 64.6 ± 9.1 years). These risk scores were used to calculate the explained variance of VCDR and IOP in an independent cohort (Erasmus Rucphen Family study) consisting of 1646 participants (mean ± SD age: 46.8 ± 14.1 years) and the OAG risk in a subset of the Rotterdam Study cohorts. To evaluate false positive findings, we generated two new variables containing randomly sampled values to serve as a negative control. The explained variance of VCDR increased when increasing the number of SNPs included in the risk score, suggesting a polygenic model. We found no clear evidence for a similar model for IOP, suggesting that a small number of SNPs determine the susceptibility to IOP. The SNPs related to IOP in terms of p values contributed little to VCDR. The risk scores associated with VCDR were also associated significantly with OAG. This suggests a common polygenic background for VCDR and OAG CONCLUSIONS: We found evidence for a polygenic model underlying one of the major traits of OAG, VCDR, and OAG itself. The IOP did not show any evidence for such a model.


Electronic structure of pyrochlore Cd(2)Re(2)O(7).
Detailed band structure calculations have been performed for Cd(2)Re(2)O(7) in high-, middle- and low-temperature (T) phases. The calculations are based on the observed lattice structures from x-ray diffraction measurements. The spin-orbit interaction is incorporated self-consistently in both the generalized gradient approximation (GGA) and the GGA plus Hubbard U (GGA+U) approaches. It is found that the on-site U has negligible effects on the Re 5d band structures; therefore both the GGA and GGA+U Re 5d band energies agree well with the observed O K-edge x-ray absorption spectroscopy (XAS) spectrum, whereas the Cd 4d band energy observed from photoemission spectroscopy can only be correctly reproduced by GGA+U calculations, indicating the relatively itinerant Re 5d and localized Cd 4d electrons. On the other hand, the spin-orbit coupling gives rise to nontrivial spin and orbital magnetic moments for the middle- T phase. Most unexpectedly, we found that the low- T phase exhibits quasi-two-dimensional Fermi surfaces. The calculated carrier numbers for the three phases are, at least qualitatively, consistent with the measured Hall coefficient.


Group-Personalized Regression Models for Predicting Mental Health Scores From Objective Mobile Phone Data Streams: Observational Study.
Objective behavioral markers of mental illness, often recorded through smartphones or wearable devices, have the potential to transform how mental health services are delivered and to help users monitor their own health. Linking objective markers to illness is commonly performed using population-level models, which assume that everyone is the same. The reality is that there are large levels of natural interindividual variability, both in terms of response to illness and in usual behavioral patterns, as well as intraindividual variability that these models do not consider. The objective of this study was to demonstrate the utility of splitting the population into subsets of individuals that exhibit similar relationships between their objective markers and their mental states. Using these subsets, "group-personalized" models can be built for individuals based on other individuals to whom they are most similar. We collected geolocation data from 59 participants who were part of the Automated Monitoring of Symptom Severity study at the University of Oxford. This was an observational data collection study. Participants were diagnosed with bipolar disorder (n=20); borderline personality disorder (n=17); or were healthy controls (n=22). Geolocation data were collected using a custom Android app installed on participants' smartphones, and participants weekly reported their symptoms of depression using the 16-item quick inventory of depressive symptomatology questionnaire. Population-level models were built to estimate levels of depression using features derived from the geolocation data recorded from participants, and it was hypothesized that results could be improved by splitting individuals into subgroups with similar relationships between their behavioral features and depressive symptoms. We developed a new model using a Dirichlet process prior for splitting individuals into groups, with a Bayesian Lasso model in each group to link behavioral features with mental illness. The result is a model for each individual that incorporates information from other similar individuals to augment the limited training data available. The new group-personalized regression model showed a significant improvement over population-level models in predicting mental health severity (P<.001). Analysis of subgroups showed that different groups were characterized by different features derived from raw geolocation data. This study demonstrates the importance of handling interindividual variability when developing models of mental illness. Population-level models do not capture nuances in how different individuals respond to illness, and the group-personalized model demonstrates a potential way to overcome these limitations when estimating mental state from objective behavioral features.


Autonomic nervous function in patients with chronic renal failure at the Kenyatta National Hospital.
Autonomic nervous function was assessed in twenty two patients (16 males and 6 females) with chronic renal failure on conservative management. The presenting symptoms were postural dizziness in 10(45%), impotence in 4(18%) patients and 1 patient each with diplopia, urinary urgency and nocturnal diarrhoea. The following autonomic function tests were performed; valsalva manoeuvre, heart rate response to deep breathing, heart rate response to posture and postural change in blood pressure. Fifteen (68%) patients had abnormal autonomic function tests. Out of these patients, 14(93%) had abnormalities of the parasympathetic system and only one had abnormalities in the sympathetic system. There was a negative correlation between the creatinine levels and the following; valsalva ratio (r = -0.72 p < 0.001), heart rate response to standing (r = -0.56 p < 0.01) and heart rate response to deep breathing (r = -0.45 p < 0.05).


A critical review of environmental and public health impacts from the activities of evaporation ponds.
Evaporation ponds (EVPs) are among the most cost-effective, and simple wastewater treatment technologies used in many regions/countries with high solar radiation levels. However, its operational limitations, which include the overflow of wastewater, leakages via liners, and large surface area of the EVP that is exposed to atmosphere, creates a negative feedback to the environment. Therefore, the main aim of this review study of more than a hundred works published a little all over the continents is to provide a summary of various contaminations that are associated with EVPs activities through different environmental compartments. In addition, the impacts of EVP on fauna, human health including the current on-site sustainable mitigation strategies were also reviewed. The first conclusion from this study shows that the most commonly contaminants released into surface waters, groundwater, soil and sediments were heavy metals, pesticides, herbicides, selenium, including several major anions and cations. Non-methane hydrocarbons (NMHCs), volatile organic compounds (VOCs), and particulate matters (PMs) were the main air pollutants emitted from the surfaces of an EVP. Limited data is available about the emissions of atmospheric greenhouse gas (GHGs) especially carbon dioxide (CO2) and methane (CH4) from EVP surfaces. Migratory birds and aquatic organisms are the most vulnerable fauna as EVP wastewaters can cause obstruction of movements, affect diversity, and causes mortalities following the exposure to the toxic wastewater. The study revealed limited data about the potential health risk associated with occupational and environmental exposure to radiological hazards and contaminated drinking water from EVP activities. On-site EVP treatment strategies using bioremediation and electrochemical treatment technologies have shown to be a promising sustainable mitigation approach. Knowledge gaps in areas of GHGs monitoring/modeling, pollution exposure estimation and health risk assessments are urgently required to gain deeper understanding about the impact of EVP activities, and incorporate them into future EVP designs.


Cellular inhibitors of apoptosis are global regulators of NF-κB and MAPK activation by members of the TNF family of receptors.
Tumor necrosis factor (TNF) family members are essential for the development and proper functioning of the immune system. TNF receptor (TNFR) signaling is mediated through the assembly of protein signaling complexes that activate the nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways in a ubiquitin-dependent manner. The cellular inhibitor of apoptosis (c-IAP) proteins c-IAP1 and c-IAP2 are E3 ubiquitin ligases that are recruited to TNFR signaling complexes through their constitutive association with the adaptor protein TNFR-associated factor 2 (TRAF2). We demonstrated that c-IAP1 and c-IAP2 were required for canonical activation of NF-κB and MAPK by members of the TNFR family. c-IAPs were required for the recruitment of inhibitor of κB kinase β (IKKβ), the IKK regulatory subunit NF-κB essential modulator (NEMO), and RBCK1/Hoil1-interacting protein (HOIP) to TNFR signaling complexes and the induction of gene expression by TNF family members. In contrast, TNFRs that stimulated the noncanonical NF-κB pathway triggered translocation of c-IAPs, TRAF2, and TRAF3 from the cytosol to membrane fractions, which led to their proteasomal and lysosomal degradation. Finally, we established that signaling by B cell-activating factor receptor 3 induced the cytosolic depletion of TRAF3, which enabled noncanonical NF-κB activation. These results define c-IAP proteins as critical regulators of the activation of NF-κB and MAPK signaling pathways by members of the TNFR superfamily.


Treatment interruption in children with HIV infection.
To review studies evaluating the role of planned/structured treatment interruptions in the management of HIV-infected children. Randomized controlled treatment interruption trials in adults have reported varying results. Three trials were stopped early by their data safety and monitoring boards because of inferiority of the interruption arm, based on differences in the risk of clinical events between randomized arms. Although the risk in the treatment interruption arms relative to continuous treatment was substantial, the absolute risks of AIDS/death were low in both arms. Little research has been carried out evaluating treatment interruptions in children, even though their role may be more critical as children frequently start antiretroviral therapy at an early age with the expectation that they will need to take it for life. In addition to observational studies, two ongoing randomized paediatric trials in chronic infection are based on CD4-guided treatment interruption strategies, using higher CD4 thresholds for restart/stop of antiretroviral therapy than in adult trials. Three trials are evaluating strategies of interruption following treatment of primary infection in infancy. It is vital that this research continues as antiretroviral therapy is rolled out to increasing numbers of young children in resource-limited settings.


Unconscious activation of the prefrontal no-go network.
Cognitive control processes involving prefrontal cortex allow humans to overrule and inhibit habitual responses to optimize performance in new and challenging situations, and traditional views hold that cognitive control is tightly linked with consciousness. We used functional magnetic resonance imaging to investigate to what extent unconscious "no-go" stimuli are capable of reaching cortical areas involved in inhibitory control, particularly the inferior frontal cortex (IFC) and the pre-supplementary motor area (pre-SMA). Participants performed a go/no-go task that included conscious (weakly masked) no-go trials, unconscious (strongly masked) no-go trials, as well as go trials. Replicating typical neuroimaging findings, response inhibition on conscious no-go stimuli was associated with a (mostly right-lateralized) frontoparietal "inhibition network." Here, we demonstrate, however, that an unconscious no-go stimulus also can activate prefrontal control networks, most prominently the IFC and the pre-SMA. Moreover, if it does so, it brings about a substantial slowdown in the speed of responding, as if participants attempted to inhibit their response but just failed to withhold it completely. Interestingly, overall activation in this "unconscious inhibition network" correlated positively with the amount of slowdown triggered by unconscious no-go stimuli. In addition, neural differences between conscious and unconscious control are revealed. These results expand our understanding of the limits and depths of unconscious information processing in the human brain and demonstrate that prefrontal cognitive control functions are not exclusively influenced by conscious information.


Indigenous Wildlife Rabies in Taiwan: Ferret Badgers, a Long Term Terrestrial Reservoir.
The emerging disease of rabies was confirmed in Taiwan ferret badgers (FBs) and reported to the World Organization for Animal Health (OIE) on July 17, 2013. The spread of wildlife rabies can be related to neighborhood countries in Asia. The phylogenetic analysis was conducted by maximum likelihood (ML) methods and the Bayesian coalescent approach based on the glycoprotein (G) and nucleoprotein (N) genes. The phylogeographic and spatial temporal dynamics of viral transmission were determined by using SPREAD, QGIS. Therefore, the origin and the change with time of the viruses can be identified. Results showed the rabies virus of FB strains in Taiwan is a unique clade among other strains in Asia. According to the phylogeographic coalescent tree, three major genotypes of the FB rabies virus have circulated in three different geographical areas in Taiwan. Two genotypes have distributed into central and southern Taiwan between two ecological river barriers. The third genotype has been limited in southeastern Taiwan by the natural mountain barrier. The diversity of FB rabies viruses indicates that the biological profile of FBs could vary in different geographical areas in Taiwan. An enhanced surveillance system needs to be established near the currently identified natural barriers for early warnings of the rabies virus outbreak in Taiwan.


DGCR8 Mediates Repair of UV-Induced DNA Damage Independently of RNA Processing.
Ultraviolet (UV) radiation is a carcinogen that generates DNA lesions. Here, we demonstrate an unexpected role for DGCR8, an RNA binding protein that canonically functions with Drosha to mediate microRNA processing, in the repair of UV-induced DNA lesions. Treatment with UV induced phosphorylation on serine 153 (S153) of DGCR8 in both human and murine cells. S153 phosphorylation was critical for cellular resistance to UV, the removal of UV-induced DNA lesions, and the recovery of RNA synthesis after UV exposure but not for microRNA expression. The RNA-binding and Drosha-binding activities of DGCR8 were not critical for UV resistance. DGCR8 depletion was epistatic to defects in XPA, CSA, and CSB for UV sensitivity. DGCR8 physically interacted with CSB and RNA polymerase II. JNKs were involved in the UV-induced S153 phosphorylation. These findings suggest that UV-induced S153 phosphorylation mediates transcription-coupled nucleotide excision repair of UV-induced DNA lesions in a manner independent of microRNA processing.


Effects of a Mindfulness-Based Intervention on Distress, Weight Gain, and Glucose Control for Pregnant Low-Income Women: A Quasi-Experimental Trial Using the ORBIT Model.
Stress can lead to excessive weight gain. Mindfulness-based stress reduction that incorporates mindful eating shows promise for reducing stress, overeating, and improving glucose control. No interventions have tested mindfulness training with a focus on healthy eating and weight gain during pregnancy, a period of common excessive weight gain. Here, we test the effectiveness of such an intervention, the Mindful Moms Training (MMT), on perceived stress, eating behaviors, and gestational weight gain in a high-risk sample of low income women with overweight/obesity. We conducted a quasi-experimental study assigning 115 pregnant women to MMT for 8 weeks and comparing them to 105 sociodemographically and weight equivalent pregnant women receiving treatment as usual. Our main outcomes included weight gain (primary outcome), perceived stress, and depression. Women in MMT showed significant reductions in perceived stress (β = - 0.16) and depressive symptoms (β = - 0.21) compared to the treatment as usual (TAU) control group. Consistent with national norms, the majority of women (68%) gained excessive weight according to Institute of Medicine weight-gain categories, regardless of group. Slightly more women in the MMT group gained below the recommendation. Among secondary outcomes, women in MMT reported increased physical activity (β = 0.26) and had lower glucose post-oral glucose tolerance test (β = - 0.23), being 66% less likely to have impaired glucose tolerance, compared to the TAU group. A short-term intervention led to significant improvements in stress, and showed promise for preventing glucose intolerance. However, the majority of women gained excessive weight. A longer more intensive intervention may be needed for this high-risk population. Clinical Trials.gov #NCT01307683.


Fibrinogen in relation to personal history of prevalent hypertension, diabetes, stroke, intermittent claudication, coronary heart disease, and family history: the Scottish Heart Health Study.
To determine the relations of plasma fibrinogen to family history of premature heart disease, personal history of hypertension, diabetes, stroke, coronary heart disease, and to presence of intermittent claudication. Random population survey across 22 local government districts in Scotland. 10,359 men and women aged 40 to 59 years. Plasma fibrinogen was measured in 8824. Plasma fibrinogen concentration. Persons with a family history of heart disease or a personal history of high blood pressure, diabetes, stroke, or presence of intermittent claudication all had higher plasma fibrinogen concentrations than those without. When compared with participants without cardiovascular or related disease (men: 2.27 (SE = 0.01) g/l, n = 3367; women 2.34 (0.01) g/l, n = 3096), predefined cases of either myocardial infarction (men: 2.51 (0.02) g/l, n = 248; women: 2.63 (0.04) g/l, n = 72) or angina (men: 2.45 (0.02) g/l, n = 394; women: 2.50 (0.02) g/l, n = 398) had significantly higher plasma fibrinogen concentrations (p < 0.001). After adjustment for 10 other coronary risk factors, there was a noticeable linear trend in the odds ratios for myocardial infarction across all quartiles (quarters) of plasma fibrinogen concentrations in both sexes. Similarly, the risk of angina increased linearly with increasing fibrinogen concentrations, although the test for a linear trend was NS among women. This large population study confirms that plasma fibrinogen is not only a risk factor for coronary heart disease and stroke, but it is also raised with family history of premature heart disease and with personal history of hypertension, diabetes, and presence of intermittent claudication.


Subtle differences in virus composition affect disinfection kinetics and mechanisms.
Viral disinfection kinetics have been studied in depth, but the molecular-level inactivation mechanisms are not understood. Consequently, it is difficult to predict the disinfection behavior of nonculturable viruses, even when related, culturable viruses are available. The objective of this work was to determine how small differences in the composition of the viral genome and proteins impact disinfection. To this end, we investigated the inactivation of three related bacteriophages (MS2, fr, and GA) by UV254, singlet oxygen ((1)O2), free chlorine (FC), and chlorine dioxide (ClO2). Genome damage was quantified by PCR, and protein damage was assessed by quantitative matrix-assisted laser desorption ionization (MALDI) mass spectrometry. ClO2 caused great variability in the inactivation kinetics between viruses and was the only treatment that did not induce genome damage. The inactivation kinetics were similar for all viruses when treated with disinfectants possessing a genome-damaging component (FC, (1)O2, and UV254). On the protein level, UV254 subtly damaged MS2 and fr capsid proteins, whereas GA's capsid remained intact. (1)O2 oxidized a methionine residue in MS2 but did not affect the other two viruses. In contrast, FC and ClO2 rapidly degraded the capsid proteins of all three viruses. Protein composition alone could not explain the observed degradation trends; instead, molecular dynamics simulations indicated that degradation is dictated by the solvent-accessible surface area of individual amino acids. Finally, despite the similarities of the three viruses investigated, their mode of inactivation by a single disinfectant varied. This explains why closely related viruses can exhibit drastically different inactivation kinetics.


Long-term outcomes of pancreas after kidney transplantation in small centers: is it justified?
Currently, the long-term advantages of having a pancreas transplantation (PT) are debated, particularly in patients receiving pancreas after kidney (PAK) allografts. The United Network for Organ Sharing (UNOS) requires that a transplant center perform a minimum number of PT per year to remain an active PT center. The long-term outcomes and challenges of PAK in small pancreas transplant centers are not well studied. In this retrospective analysis, we report short- and long-term outcomes in a small center performing 2-9 PT annually. Forty-eight PT (25 simultaneous pancreas and kidney transplantation [SPK], 23 PAK) were performed in our center. Donor and recipient demographics were similar in both groups. All suitable local donors were used for SPK. All organs for PAK transplantation were imported from other UNOS regions. Mean follow-up was 61 ± 46 and 74 ± 46 months for SPK and PAK, respectively. Patient and graft survival rates were similar in SPK and PAK groups and better than the reported national average. Four patients (11%) died (1 due to trauma, 1 brain lymphoma, 1 ruptured aneurysm; and 1 unknown cause). Two patients (4%; 1 SPK, 1 PAK) lost their grafts because of thrombosis on postoperative days 3 and 5 in 2002. No graft thrombosis occurred since 2002. Seven patients (15%) required reoperation (4 for bleeding, 2 anastomotic leaks, 1 small bowel perforation). Two patients (4%) developed post-transplantation lymphoproliferative disease. Five patients (11%) experienced cytomegalovirus antigenemia which responded well to antiviral therapy. Compared with outcomes for diabetic patients on dialysis, current SPK and PAK short- and long-term results are favorable even in a small PT center. Therefore, unless there is a contraindication, PT should be offered to all type 1 diabetic patients with end-stage renal disease at the time of kidney transplantation or afterward.


SIG1273: a new cosmetic functional ingredient to reduce blemishes and Propionibacterium acnes in acne prone skin.
Propionibacterium acnes is a major contributing factor to the inflammatory component of acne. The interaction of P. acnes with keratinocytes leads to an innate immune response via activation of toll-like receptors (TLR2, TLR4) resulting in the production and secretion of pro-inflammatory mediators. SIG1273, an isoprenylcysteine small molecule modulates inflammatory signaling pathways and kills P. acnes. SIG1273 represents a novel cosmetic functional ingredient that provides relief from blemishes in acne prone skin. To assess the keratinocyte response and microbial growth of SIG1273 in vitro and evaluate the tolerability of SIG1273 gel applied topically in acne prone subjects. For in vitro studies, human keratinocytes were exposed in culture to live P. acnes and peptidoglycan (PGN) to induce IL-8 production. P. acnes were cultured to determine minimal inhibitory concentration and minimal bactericidal concentration values. A total of 30 subjects were randomized in a double-blind controlled trial receiving 3% SIG1273 gel or vehicle for 6 weeks. Evaluation included inflammatory lesions, noninflammatory lesions, microcomedones, Sebutape scores, and P. acnes counts. In vitro studies demonstrate SIG1273 inhibits P. acnes-induced IL-8 production and inhibits P. acnes growth. SIG1273 gel was well tolerated with no signs of stinging, redness, or itching. Furthermore, improvement in some aspects of acne was observed in subjects applying SIG1273 gel, including inflammatory lesions, microcomedone counts and Sebutape scores. Facial scrubs taken to measure P. acnes colony-forming units showed those applying SIG1273 gel had ~1.0 Log 10 colony reduction over the length of the study, a statistically significantly improvement when compared with vehicle. No significant effects above vehicle were observed for noninflammatory lesions. SIG1273 represents a novel cosmetic functional ingredient that provides a safe dual modulating benefit to individuals with acne prone skin by reducing P. acnes counts and reducing inflammation.


The underreporting of self-reported symptoms following sports-related concussion.
This cohort study was conducted to examine patterns of symptom reporting in concussed athletes in two different testing environments. A prospective cohort study was conducted with repeated measures. Self-reported symptoms collected by team athletic trainers using the ImPACT Post-Concussion Scale (PCS) were compared to symptoms collected in a confidential setting using structured interviews for depression and anxiety. Ratings were scaled to match scoring of the PCS and categorized into symptom-domains. Scores collected 2 days post-concussion were compared across different rating scales. Confidential self-report scores approximately 9 days post-concussion in cleared athletes were compared to PCS scores collected during return-to-play decisions. Finally, confidential self-report scores collected 9 days post-concussion were compared between cleared and not cleared athletes. Athletes self-reported significantly fewer symptoms to team athletic trainers using the ImPACT test compared to self-reported symptoms collected in a confidential setting during the acute phase of concussion using standard psychiatric interviews. Athletes cleared to play continued to underreport symptoms 9 days post-concussion, particularly psychiatric symptoms. Finally, cleared athletes self-reported similar magnitude of symptoms than non-cleared athletes 9 days post-concussion in confidential research setting. The systematic underreporting of post-concussion symptoms may represent motivated behavior or differences in self-reporting data acquisition. By underreporting symptoms, many cleared athletes are still symptomatic over 1-week post-concussion. This study highlights the need for objective measures for somatic and psychiatric symptoms.


Identification of an extracellular plasmin binding protein from nephritogenic streptococci.
Examination of the extracellular products of nephritis(+) and nephritis(-) group A streptococci revealed the presence of a 46-kD protein secreted by nephritogenic strains that binds to human plasmin. Immunological data revealed that this protein, called nephritis plasmin binding protein (NPBP), is not related to group A streptokinase nor to a recently described streptococcal dehydrogenase protein. The binding of human plasmin to this protein can be blocked by epsilon-amino caproic acid, indicating the importance of lysine groups in the binding process. Mutanolysin extracts of cell walls from these nephritogenic strains probed with anti-NPBP antibody were negative for cell wall-bound NPBP. Serological data with acute poststreptococcal glomerulonephritis (APSGN) and acute rheumatic fever sera indicated that the protein reacts preferentially with APSGN sera. Amino acid sequence analysis and immunological reactivity suggest NPBP is the streptococcal pyrogenic exotoxin B precursor, also previously described as zymogen (streptococcal proteinase precursor). The secretion of both group A streptokinase and a secreted plasmin binding protein in the same nephritogenic strain raises an intriguing hypothesis of the mechanisms of action of this protein in APSGN.


Change in Angina Symptom Status After Acute Myocardial Infarction and Its Association With Readmission Risk: An Analysis of the Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status (TRIUMPH) Registry.
Angina is common both before and after myocardial infarction (MI). Whether the change in angina status within the first 30 days after MI is associated with subsequent readmission and angina persistence is unknown. We studied 2915 MI patients enrolled at 24 hospitals in the Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status (TRIUMPH) registry. Angina before and 30 days after MI was assessed with the Seattle Angina Questionnaire. Patients were divided into angina-free pre- and post-MI (-/-), resolved angina (+/-), new angina (-/+), and persistent angina (+/+) groups. Multivariable proportional hazards and hierarchical modified Poisson models were performed to assess the association of each group with all-cause readmission, readmission for MI or unplanned revascularization, and angina persistence at 1 year. Overall, 1293 patients (44%) had angina before their MI and 849 (29%) reported angina within 30 days of discharge. Patients with post-MI angina were more likely to be younger, nonwhite, and uninsured. Compared with patients who were angina-free pre- and post-MI, 1-year all-cause readmission risks were significantly higher for patients with persistent angina (hazard ratio [HR], 1.35; 95% CI 1.06-1.71) or new angina (HR, 1.40; 95% CI, 1.08-1.82). At 1 year, angina was present in 22% of patients and was more likely if angina was persistent (HR, 3.55; 95% CI, 3.05-4.13) or new (HR, 3.38; 95% CI, 2.59-4.42) at 30 days compared with patients who were angina-free pre- and post-MI. Post-MI angina, whether new or persistent, is associated with higher likelihood of readmission. Prioritizing post-MI angina management is a potential means of improving 1-year outcomes.


Horizontal acquisition of Symbiodiniaceae in the Anemonia viridis (Cnidaria, Anthozoa) species complex.
All metazoans are in fact holobionts, resulting from the association of several organisms, and organismal adaptation is then due to the composite response of this association to the environment. Deciphering the mechanisms of symbiont acquisition in a holobiont is therefore essential to understanding the extent of its adaptive capacities. In cnidarians, some species acquire their photosynthetic symbionts directly from their parents (vertical transmission) but may also acquire symbionts from the environment (horizontal acquisition) at the adult stage. The Mediterranean snakelocks sea anemone, Anemonia viridis (Forskål, 1775), passes down symbionts from one generation to the next by vertical transmission, but the capacity for such horizontal acquisition is still unexplored. To unravel the flexibility of the association between the different host lineages identified in A. viridis and its Symbiodiniaceae, we genotyped both the animal hosts and their symbiont communities in members of host clones in five different locations in the North Western Mediterranean Sea. The composition of within-host-symbiont populations was more dependent on the geographical origin of the hosts than their membership to a given lineage or even to a given clone. Additionally, similarities in host-symbiont communities were greater among genets (i.e. among different clones) than among ramets (i.e. among members of the same given clonal genotype). Taken together, our results demonstrate that A. viridis may form associations with a range of symbiotic dinoflagellates and suggest a capacity for horizontal acquisition. A mixed-mode transmission strategy in A. viridis, as we posit here, may help explain the large phenotypic plasticity that characterizes this anemone.


Periodic dielectric waveguide beam splitter based on co-directional coupling.
A compact beam splitter consisting of three branches of periodic dielectric waveguides (PDW) is designed and analyzed theoretically. Both the symmetrical and asymmetrical configurations of the beam splitter are studied. The band structure for the guided modes is calculated by using finite-difference time-domain (FDTD) method with Bloch-type boundary conditions applying in an appropriate supercell. The field patterns for the whole structure and the transmissions for the output ports are calculated using the multiple scattering method. By utilizing the co-directional coupling mechanism, the light injected into the input branch can be efficiently transferred into the two output branches if the phase matching conditions are satisfied. The coupling length is short and the broad-band requirement can be achieved. Bending loss is small and high transmission (above 95%) can be preserved for arbitrarily bent PDW if the bend radius of each bend exceeds five wavelengths. This feature indicates that the periodic dielectric waveguide beam splitter (PDWBS) is a high efficiency device for power redistribution while avoiding the lattice orientation restriction of the photonic crystal waveguides (PCW).


Fish oil improves gene targets of Down syndrome in C57BL and BALB/c mice.
We have considered a novel gene targeting approach for treating pathologies and conditions whose genetic bases are defined using diet and nutrition. One such condition is Down syndrome, which is linked to overexpression of RCAN1 on human chromosome 21 for some phenotypes. We hypothesize that a decrease in RCAN1 expression with dietary supplements in individuals with Down syndrome represents a potential treatment. Toward this, we used in vivo studies and bioinformatic analysis to identify potential healthy dietary RCAN1 expression modulators. We observed Rcan1 isoform 1 (Rcan1-1) protein reduction in mice pup hippocampus after a 4-week curcumin and fish oil supplementation, with only fish oil reduction being statistically significant. Focusing on fish oil, we observed a 17% Rcan1-1 messenger RNA (mRNA) and 19% Rcan1-1 protein reduction in BALB/c mice after 5 weeks of fish oil supplementation. Fish oil supplementation starting at conception and in a different mouse strain (C57BL) led to a 27% reduction in hippocampal Rcan1-1 mRNA and a 34% reduction in spleen Rcan1-1 mRNA at 6 weeks of age. Hippocampal protein results revealed a modest 11% reduction in RCAN1-1, suggesting translational compensation. Bioinformatic mining of human fish oil studies also revealed reduced RCAN1 mRNA expression, consistent with the above studies. These results suggest the potential use of fish oil in treating Down syndrome and support our strategy of using select healthy dietary agents to treat genetically defined pathologies, an approach that we believe is simple, healthy, and cost-effective.


Molecules to Ecosystems: Actinomycete Natural Products In situ.
Actinomycetes, filamentous actinobacteria found in numerous ecosystems around the globe, produce a wide range of clinically useful natural products (NP). In natural environments, actinomycetes live in dynamic communities where environmental cues and ecological interactions likely influence NP biosynthesis. Our current understating of these cues, and the ecological roles of NP, is in its infancy. We postulate that understanding the ecological context in which actinomycete metabolites are made is fundamental to advancing the discovery of novel NP. In this review we explore the ecological relevance of actinomycetes and their secondary metabolites from varying ecosystems, and suggest that investigating the ecology of actinomycete interactions warrants particular attention with respect to metabolite discovery. Furthermore, we focus on the chemical ecology and in situ analysis of actinomycete NP and consider the implications for NP biosynthesis at ecosystem scales.


The transcriptional corepressor MTGR1 regulates intestinal secretory lineage allocation.
Notch signaling largely determines intestinal epithelial cell fate. High Notch activity drives progenitors toward absorptive enterocytes by repressing secretory differentiation programs, whereas low Notch permits secretory cell assignment. Myeloid translocation gene-related 1 (MTGR1) is a transcriptional corepressor in the myeloid translocation gene/Eight-Twenty-One family. Given that Mtgr1(-/-) mice have a dramatic reduction of intestinal epithelial secretory cells, we hypothesized that MTGR1 is a key repressor of Notch signaling. In support of this, transcriptome analysis of laser capture microdissected Mtgr1(-/-) intestinal crypts revealed Notch activation, and secretory markers Mucin2, Chromogranin A, and Growth factor-independent 1 (Gfi1) were down-regulated in Mtgr1(-/-) whole intestines and Mtgr1(-/-) enteroids. We demonstrate that MTGR1 is in a complex with Suppressor of Hairless Homolog, a key Notch effector, and represses Notch-induced Hairy/Enhancer of Split 1 activity. Moreover, pharmacologic Notch inhibition using a γ-secretase inhibitor (GSI) rescued the hyperproliferative baseline phenotype in the Mtgr1(-/-) intestine and increased production of goblet and enteroendocrine lineages in Mtgr1(-/-) mice. GSI increased Paneth cell production in wild-type mice but failed to do so in Mtgr1(-/-) mice. We determined that MTGR1 can interact with GFI1, a transcriptional corepressor required for Paneth cell differentiation, and repress GFI1 targets. Overall, the data suggest that MTGR1, a transcriptional corepressor well characterized in hematopoiesis, plays a critical role in intestinal lineage allocation.


A longitudinal study of changes in asylum seekers ability regarding activities of daily living during their stay in the asylum center.
The aim was to assess change in activities of daily living (ADL) ability amongst asylum seekers and if there were any difference between tortured and non-torture following a 10 months post-arrival period, and if self-reported health and exposure to torture were factors related to change in ADL-ability. The study was a combined baseline, follow-up correlational study amongst individuals from Afghanistan, Iran and Syria, living in Danish asylum centers. Forty-three persons aged 20-50, were invited and participated in the baseline study. Twenty-two were still in asylum center at the follow-up and 17 of them participated. ADL-ability was measured using Assessment of Motor and Process Skills and questionnaires about exposure to torture, self-reported mental health and pain. ADL motor and process measures, well-being and self-rated health declined from baseline to follow-up. Measures of pain and depression increased. Exposure to physical torture and change in ADL motor (r = 0.525) measures were associated, as well as change in current pain and change in ADL process (r = 0.525) measures. Due to preponderance of torture survivors analysis of group difference was not applicable. Health care workers should be aware of ADL concerns and exposure to torture in this population to best address their needs within rehabilitation settings.


The Health Sciences and Technology Academy (HSTA): Providing 26 Years of Academic and Social Support to Appalachian Youth in West Virginia.
The Health Sciences and Technology Academy's, (HSTA) goals are to increase college attendance of African American, financially disadvantaged, first generation college and rural Appalachian youth and increase health-care providers and STEM professionals in underserved communities. Students enter in the 9th grade and remain in HSTA four years. They engage in a rigorous academic program within the nurturing environment of small after-school clubs punctuated by yearly summer camps on multiple college campuses. A distinctive piece of HSTA is its students' development of research projects under the mentorship of teachers and researchers that examine and address health issues faced by their communities. The projects help HSTA students to understand the health dynamics in their local community, transforming them into community advocates who address health and social issues at home as they prepare to move on to college and beyond. Substantial in-state tuition waivers inspire 99% of the 3,021 HSTA graduates to attend college versus 56% of WV high school graduates. Approximately 85% of matriculating HSTA students graduate with a four-year degree or higher versus less than 50% of all college entrants. To date, 57% of HSTA students go into health and other STEM majors, much higher than the state and national figures.


Hyperapobetalipoproteinemia. Plasma lipoprotein responses to oral fat load.
To better define lipid transport in patients with hyperapobetalipoproteinemia (HyperapoB), the response to an oral fat load was studied in six normotriglyceridemic patients with the disorder. Plasma triglycerides; Sf greater than 400, and Sf 20 to 400 triglycerides; Sf greater than 20 B100; total HDL and HDL subfractions (HDL2 and HDL3) were measured serially for a 7-hour period after an oral fat load and changes in these parameters were compared to those observed in six normolipidemic controls. In addition, plasma triglyceride levels and HDL2 and HDL3 cholesterol were also determined in seven patients with Type IV hyperlipoproteinemia: three with normal LDL apo B levels and four with HyperapoB. When the two normotriglyceridemic groups were compared, the patients with HyperapoB had significantly higher fasting levels of SF greater than 400 lipoproteins and higher fasting VLDL and LDL levels than the normal patients. After the fat load, Sf 20 to 400 triglycerides and Sf greater than 20 B100 levels increased in both groups. Plasma triglycerides rose to a higher level in the HyperapoB patients than in the normal group, but more strikingly, remained elevated in the HyperapoB patients, an elevation due principally to a persistant increase in Sf greater than 400 triglycerides. On the other hand, HDL2 cholesterol dropped substantially in the HyperapoB patients but not in the normal patients. Finally, in the hypertriglyceridemic group, after the fat load, HDL2 cholesterol levels did not change in the patients with normal LDL apo B levels but did decrease in those with elevated plasma LDL apo B.


Glycogen synthase kinase-3 beta inhibitors protectagainst the acute lung injuries resulting from acute necrotizing pancreatitis.
The research is intended for clarification of the efficacy as well as the underlying mechanism of GSK-3β inhibitors on the advancement of acute lung injuries in acute necrotizing pancreatitis (ANP) in rats. Seventy-two rats were randomly divided into 6 groups: (1)ANP-vehicle; (2)ANP-TDZD-8;(3)ANP-SB216763;(4)Sham-vehicle;(5)Sham-TDZD-8;(6)Sham-SB216763; Blood biochemical test, histopathological examination and immunohistochemical analysis of rats pancreas and lung tissues were performed. The protein expression of GSK-3β, phospho-GSK-3β (Ser9), iNOS, ICAM-1, TNF-α, and IL-10 were detected in lung tissues by Western-blot. The outcomes revealed that the intervention of GSK-3β inhibitors alleviated the pathological damage of pancreas and lung (P<0.01), reduced serum amylase, lipase, hydrothorax and lung Wet-to-Dry Ratio, attenuated serum concentrations of IL-1β and IL-6 (P<0.01), inhibited the activation of NF-κB, and abated expression of iNOS, ICAM-1 and TNF-α protein, but up-regulated IL-10 expression in lung of ANP rats (P<0.01). The inflammatory response and various indicators in ANP-TDZD-8 groups were lower than those in ANP-SB216763 groups. Inhibition of GSK-3β weakens acute lung injury related to ANP via the inhibitory function of NF-κB signaling pathway. Different kinds of GSK-3β inhibitors have different effects to ANP acute lung injury.


The effect of hydroxychloride trace minerals on the growth performance and carcass quality of grower/finisher pigs: a meta-analysis.
The current study compared the effect of hydroxychloride trace minerals (HTM) with the effect of inorganic trace minerals (ITM) on growth performance and carcass quality in grower-finisher pigs. The results of 6 studies conducted throughout Europe were combined into one meta-analysis. All included studies were performed using pigs from about 19 kg of body weight until slaughter. In all studies, 2 different mineral sources were compared, HTM and sulfates as ITM. Zn from either HTM or ITM was added at a level of 80 ppm to the diet, and Cu was added at a level of 15 ppm from the same source as Zn. In most studies, an additional treatment was included in which 20 ppm Zn was used from either source in combination with 15 ppm Cu from the same source. Diets were fed in 3 phases according to local commercial standards. The body weight, average daily gain, average daily feed intake, and gain:feed ratio were measured at the end of each phase. At the end of each study, the carcass yield, back fat thickness, and lean meat percentage were measured at commercial slaughterhouses. The meta-analysis was conducted using a MIXED model in SAS taking into account the within-study and between-study variation. The comparison was done only between HTM and ITM added at the same Zn level. No statistical differences were observed for growth performance or carcass characteristics between the mineral sources in pigs fed 20 ppm Zn. When 80 ppm Zn was used, a significant improvement in lean meat percentage was observed in pigs fed HTM compared with pigs fed ITM. In the overall study period, there was a tendency towards an increased gain:feed ratio in pigs fed 80 ppm Zn from HTM. In the last feeding phase, before slaughter gain:feed ratio and average daily gain were both significantly improved by 3.9%. In conclusion, HTM addition improved growth performance and lean meat percentage in grower-finisher pigs.


Rapidly degraded terpolymers of dl-lactide, glycolide, and epsilon-caprolactone with increased hydrophilicity by copolymerization with polyethers.
A series of 66 terpolymers of dl-lactide, glycolide, and epsilon-caprolactone was synthesized for the purpose of identifying those materials which exhibited rapid degradation in vitro. Polymers having half-lives from a few weeks to several months were identified. The morphology of each material was characterized by differential scanning calorimetry. A terpolymeric composition of 60% glycolide, 30% dl-lactide, and 10% epsilon-caprolactone, which exhibited a half-life of 17 days, was selected for further investigation. The hydrophilicity of this material was increased by performing the polymerization in the presence of a polyether prepolymer, Pluronic F-68, with the motivation of concomitantly reducing cell and tissue adhesion. An increase in the hydrophilicity of the material was apparent from contact angle measurements. Copolymerization with the prepolymer also resulted in a stronger and partly crystalline material which was mechanically stable at physiological temperature in water. A slight increase was observed in the half-life of the polymer relative to the base polymer due to the presence of the prepolymer.


Altered white matter microstructural organization in posttraumatic stress disorder across 3047 adults: results from the PGC-ENIGMA PTSD consortium.
A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3047 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1426 individuals with PTSD and 1621 controls (2174 males/873 females) between ages 18-83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohen's d = -0.11, p = 0.0055). The tapetum connects the left and right hippocampus, for which structure and function have been consistently implicated in PTSD. Results were consistent even after accounting for the effects of multiple potentially confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications. Our results show that PTSD may be associated with alterations in the broader hippocampal network.


Interindividual Variations in Foveal Anatomy and Artifacts Seen on Inner Retinal Probability Maps from Spectral Domain OCT Scans of the Macula.
We tested the hypothesis that variations in foveal morphology can account for artifacts seen on optical coherence tomography (OCT) retinal ganglion cell (RGC) layer probability maps. A total of 126 healthy subjects were tested with spectral domain (sd) OCT. Thickness and probability maps of the macular RGC plus inner plexiform layer (RGC+) were obtained with customized software. Macular b-scans were analyzed to derive three foveal anatomic parameters: width, depth, and slope. The distribution of these parameters was compared between eyes with and without circumfoveal artifacts seen in the central 4° of macular RGC+ probability maps. Of 126 healthy subjects, 12 (9.5%) had an abnormal circumfoveal region (artifact) on RGC+ probability maps. Based upon the normal distribution of the three anatomic parameters, only three of the 12 eyes (25%) fell outside the 95% confidence interval of one or more of the three foveal morphologic parameters. Multivariable logistic regression revealed that the parameter slope was significantly associated with the presence of these artifacts (odds ratio = 0.26; P = 0.019). However, the combination of these parameters and age explained only 11% of the total variance of these artifacts. Fovea morphology, as measured based upon width, depth, and slope, has a minor role in explaining artifacts seen on macular scans. Variations in the distribution of RGC+ thickness that are not reflected in our measures warrant further investigation as potential sources of artifacts. A small proportion of circumfoveal artifacts seen on RGC+ probability maps can be explained by variations in foveal anatomy.