Social capital as a resource for mental well-being in older people: a systematic review.
Social capital has previously been reviewed in relation to mental health. However, none have focused specifically on positive aspects of mental health such as mental well-being. This review aimed to explore the relationship between social capital and mental well-being in older people. Ten relevant databases were systematically searched using an extensive search strategy for studies, analyzing the link between social capital and mental well-being. Criteria for inclusion in the systematic review were: the study sample included older people (≥50 years); the study reported a mental well-being outcome; social capital was an exposure variable; and empirical research using quantitative methods and published in English, between January 1990 and September 2011. Eleven studies met the inclusion criteria. Each study was assessed against seven possible exposure measures (structural, cognitive; bonding, bridging, linking; individual, collective). The results showed that all included studies found positive associations between parts of social capital and aspects of mental well-being. Typically, the relationship between social capital and mental well-being differed within as well as between studies. Our results highlight that there is no 'gold standard' of how to measure social capital or mental well-being. Social capital is generated in the interaction between individual and collective life. A possibility for future research is therefore to follow Bronfenbrenner's classical division into macro, meso, and micro levels. We consider family and friends at the micro level to be the key factors in generating social capital and well-being in older people.


Co-transcriptional Loading of RNA Export Factors Shapes the Human Transcriptome.
During gene expression, RNA export factors are mainly known for driving nucleo-cytoplasmic transport. While early studies suggested that the exon junction complex (EJC) provides a binding platform for them, subsequent work proposed that they are only recruited by the cap binding complex to the 5' end of RNAs, as part of TREX. Using iCLIP, we show that the export receptor Nxf1 and two TREX subunits, Alyref and Chtop, are recruited to the whole mRNA co-transcriptionally via splicing but before 3' end processing. Consequently, Alyref alters splicing decisions and Chtop regulates alternative polyadenylation. Alyref is recruited to the 5' end of RNAs by CBC, and our data reveal subsequent binding to RNAs near EJCs. We demonstrate that eIF4A3 stimulates Alyref deposition not only on spliced RNAs close to EJC sites but also on single-exon transcripts. Our study reveals mechanistic insights into the co-transcriptional recruitment of mRNA export factors and how this shapes the human transcriptome.


Rapid evolution of reproductive isolation in the wild: evidence from introduced salmon.
Colonization of new environments should promote rapid speciation as a by-product of adaptation to divergent selective regimes. Although this process of ecological speciation is known to have occurred over millennia or centuries, nothing is known about how quickly reproductive isolation actually evolves when new environments are first colonized. Using DNA microsatellites, population-specific natural tags, and phenotypic variation, we tested for reproductive isolation between two adjacent salmon populations of a common ancestry that colonized divergent reproductive environments (a river and a lake beach). We found evidence for the evolution of reproductive isolation after fewer than 13 generations.


Hormonal contraceptive use and mate retention behavior in women and their male partners.
Female hormonal contraceptive use has been associated with a variety of physical and psychological side effects. Women who use hormonal contraceptives report more intense affective responses to partner infidelity and greater overall sexual jealousy than women not using hormonal contraceptives. Recently, researchers have found that using hormonal contraceptives with higher levels of synthetic estradiol, but not progestin, is associated with significantly higher levels of self-reported jealousy in women. Here, we extend these findings by examining the relationship between mate retention behavior in heterosexual women and their male partners and women's use of hormonal contraceptives. We find that women using hormonal contraceptives report more frequent use of mate retention tactics, specifically behaviors directed toward their partners (i.e., intersexual manipulations). Men partnered with women using hormonal contraceptives also report more frequent mate retention behavior, although this relationship may be confounded by relationship satisfaction. Additionally, among women using hormonal contraceptives, the dose of synthetic estradiol, but not of synthetic progesterone, positively predicts mate retention behavior frequency. These findings demonstrate how hormonal contraceptive use may influence behavior that directly affects the quality of romantic relationships as perceived by both female and male partners.


Chemotherapy drug extravasation in totally implantable venous access port systems: how effective is early surgical lavage?
Totally implantable venous access port systems (TIVAPS) are a widely used and an essential tool in the efficient delivery of chemotherapy. Chemotherapy drug extravasation (CDE) can have dire consequences and will delay treatment. The purpose of this study is to both clarify the management of CDE and show the effectiveness of early surgical lavage (ESL). Patients who had presented to the Cancer Center of Lille (France) with TIVAPS inserted between January 2004 and April 2013 and CDE had their medical records reviewed retrospectively. Thirty patients and 33 events were analyzed. Implicated agents were vesicants (51.5%), irritants (45.5%) and non-vesicants (3%). Huber needle malpositionning was involved in 27 cases. Surgery was performed in 97% of cases, 87.5% of which were for ESL with 53.1% of the latter requiring TIVAPS extraction. Six patients required a second intervention due to adverse outcomes (severe cases). Vesicants were found to be implicated in four out of six severe cases and oxaliplatin in two others. Extravasated volume was above 50 ml in 80% of cases. Only one patient required a skin graft. CDEs should be managed in specialized centers. ESL allows for limited tissue contact of the chemotherapy drug whilst using a simple, widely accessible technique. The two main factors that correlate with adverse outcome seem to be the nature of the implicated agent (vesicants) and the extravasated volume (above 50 ml) leading to worse outcomes. Oxaliplatin should be considered as a vesicant.


The Tat protein export pathway.
The Tat (twin-arginine translocation) system is a bacterial protein export pathway with the remarkable ability to transport folded proteins across the cytoplasmic membrane. Preproteins are directed to the Tat pathway by signal peptides that bear a characteristic sequence motif, which includes consecutive arginine residues. Here, we review recent progress on the characterization of the Tat system and critically discuss the structure and operation of this major new bacterial protein export pathway.


Gigaxonin glycosylation regulates intermediate filament turnover and may impact giant axonal neuropathy etiology or treatment
Gigaxonin (also known as KLHL16) is an E3 ligase adaptor protein that promotes the ubiquitination and degradation of intermediate filament (IF) proteins. Mutations in human gigaxonin cause the fatal neurodegenerative disease giant axonal neuropathy (GAN), in which IF proteins accumulate and aggregate in axons throughout the nervous system, impairing neuronal function and viability. Despite this pathophysiological significance, the upstream regulation and downstream effects of normal and aberrant gigaxonin function remain incompletely understood. Here, we report that gigaxonin is modified by <italic>O</italic>-linked β-<italic>N</italic>-acetylglucosamine (O-GlcNAc), a prevalent form of intracellular glycosylation, in a nutrient- and growth factor–dependent manner. MS analyses of human gigaxonin revealed 9 candidate sites of O-GlcNAcylation, 2 of which — serine 272 and threonine 277 — are required for its ability to mediate IF turnover in gigaxonin-deficient human cell models that we created. Taken together, the results suggest that nutrient-responsive gigaxonin O-GlcNAcylation forms a regulatory link between metabolism and IF proteostasis. Our work may have significant implications for understanding the nongenetic modifiers of GAN phenotypes and for the optimization of gene therapy for this disease.


Synergistic antileukemic activity of carnosic acid-rich rosemary extract and the 19-nor Gemini vitamin D analogue in a mouse model of systemic acute myeloid leukemia.
Differentiation therapy with the hormonal form of vitamin D, 1alpha,25-dihydroxyvitamin D(3) (1,25D(3)), is a promising approach to treatment of acute myeloid leukemia (AML); however, 1,25D(3) induces hypercalcemia at pharmacologically active doses. We investigated the in vitro and in vivoantileukemic efficacy of combined treatment with non-toxic doses of a low-calcemic 1,25D(3) analogue, 1,25-dihydroxy-21(3-hydroxy-3-methyl-butyl)-19-nor-cholecalciferol (19-nor-Gemini; Ro27-5646), and rosemary plant agents in a mouse model of AML. Proliferation and differentiation of WEHI-3B D- (WEHI) murine myelomonocytic leukemia cellsin vitro were determined by standard assays. Reactive oxygen species, glutathione and protein expression levels were measured by flow cytometry, enzymatic assay and Western blotting, respectively. Systemic AML was developed by intravenous injection of WEHI cells in syngeneic Balb/c mice. 19-nor-Gemini had a higher potency than its parent compounds, Gemini (Ro27-2310) and 1,25D(3), in the induction of differentiation (EC(50) = 0.059 +/- 0.011, 0.275 +/- 0.093 and 0.652 +/- 0.085 nM, respectively) and growth arrest (IC(50) = 0.072 +/- 0.018, 0.165 +/- 0.061 and 0.895 +/- 0.144 nM, respectively) in WEHI cells in vitro, and lower in vivo toxicity. Combined treatment of leukemia-bearing mice with 19-nor-Gemini (injected intraperitoneally) and standardized rosemary extract (mixed with food) resulted in a synergistic increase in survival (from 42.2 +/- 2.5 days in untreated mice to 66.5 +/- 4.2 days, n = 3) and normalization of white blood cell and differential counts. This was consistent with strong cooperative antiproliferative and differentiation effects of low concentrations of 19-nor-Gemini or 1,25D(3) combined with rosemary extract or its major polyphenolic component, carnosic acid, as well as with the antioxidant action of rosemary agents and vitamin D derivatives in WEHI cell cultures. Combined effectiveness of 1,25D(3) analogues and rosemary agents against mouse AML warrants further exploration of this therapeutic approach in translational models of human leukemia.


The kinematics, not the orientation, of an action influences language processing.
Consistent with the embodied view of cognition, several studies have shown a link between action and the processing of action verbs. However, it is largely unknown how action properties can influence semantic activation during word processing. On the basis of the observation of point-light display (PLDs), the present study addressed this issue. Through four experiments, we assessed whether kinematics and orientation, which are two crucial characteristics of human action, can influence the link between action and language. Participants performed a semantic decision task involving action and nonaction verbs after seeing a PLD representing either a biological or a nonbiological human movement, the kinematics (Experiments 1 and 2) or orientation (Experiment 3) of which was modified. Experiment 1 showed that important modifications to the kinematics of actions have a direct influence on the link between action and language. Experiment 2 confirmed this effect and showed that the effect is somatotopic because only modifications to the relevant part of actions affected the link between action and language. In contrast, Experiment 3 showed that modifying the orientation did not disturb the influence of an action on language probably due to the use of a mental rotation strategy. Experiment 4 confirmed this view by demonstrating the use of mental rotation when participants have to recognize rotated point-light actions. These outcomes shed light on how action properties can influence action verbs processing, a crucial step to better understanding the link between action and language. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Founder mutations among the Dutch.
Many genetic disorders demonstrate mutations that can be traced to a founder, sometimes a person who can be identified. These founder mutations have generated considerable interest, because they facilitate studies of prevalence and penetrance and can be used to quantify the degree of homogeneity within a population. This paper reports on founder mutations among the Dutch and relates their occurrence to the history and demography of the Netherlands. International migration, regional and religious endogamy, and rapid population growth played key roles in shaping the Dutch population. In the first millenniums BC and AD, the Netherlands were invaded by Celts, Romans, Huns, and Germans. In more recent times, large numbers of Huguenots and Germans migrated into the Netherlands. Population growth within the Netherlands was slow until the 19th century, when a period of rapid population growth started. Today, the Dutch population numbers 16 million inhabitants. Several different classes of founder mutations have been identified among the Dutch. Some mutations occur among people who represent genetic isolates within this country. These include mutations for benign familial cholestasis, diabetes mellitus, type I, infantile neuronal ceroid lipofuscinosis, L-DOPA responsive dystonia, and triphalangeal thumb. Although not related to a specific isolate, other founder mutations were identified only within the Netherlands, including those predisposing for hereditary breast-ovarian cancer, familial hypercholesterolemia, frontotemporal dementia, hereditary paragangliomas, juvenile neuronal ceroid lipofuscinosis, malignant melanoma, protein C deficiency, and San Filippo disease. Many of these show a regional distribution, suggesting dissemination from a founder. Some mutations that occur among the Dutch are shared with other European populations and others have been transmitted by Dutch émigrés to their descendents in North America and South Africa. The occurrence of short chromosomal regions that have remained identical by descent has resulted in relatively limited genetic heterogeneity for many genetic conditions among the Dutch. These observations demonstrate the opportunity for gene discovery for other diseases and traits in the Netherlands.


Recent progress of particle migration in viscoelastic fluids.
Recently, research on particle migration in non-Newtonian viscoelastic fluids has gained considerable attention. In a viscoelastic fluid, three dimensional (3D) particle focusing can be easily realized in simple channels without the need for any external force fields or complex microchannel structures compared with that in a Newtonian fluid. Due to its promising properties for particle precise focusing and manipulation, this field has been developed rapidly, and research on the field has been shifted from fundamentals to applications. This review will elaborate the recent progress of particle migration in viscoelastic fluids, especially on the aspect of applications. The hydrodynamic forces on the micro/nano particles in viscoelastic fluids are discussed. Next, we elaborate the basic particle migration in viscoelasticity-dominant fluids and elasto-inertial fluids in straight channels. After that, a comprehensive review on the applications of viscoelasticity-induced particle migration (particle separation, cell deformability measurement and alignment, particle solution exchange, rheometry-on-a-chip and others) is presented; finally, we thrash out some perspectives on the future directions of particle migration in viscoelastic fluids.


IL22BP Mediates the Antitumor Effects of Lymphotoxin Against Colorectal Tumors in Mice and Humans.
Unregulated activity of interleukin (IL) 22 promotes intestinal tumorigenesis in mice. IL22 binds the antagonist IL22 subunit alpha 2 (IL22RA2, also called IL22BP). We studied whether alterations in IL22BP contribute to colorectal carcinogenesis in humans and mice. We obtained tumor and nontumor tissues from patients with colorectal cancer (CRC) and measured levels of cytokines by quantitative polymerase chain reaction, flow cytometry, and immunohistochemistry. We measured levels of Il22bp messenger RNA in colon tissues from wild-type, Tnf-/-, Lta-/-, and Ltb-/- mice. Mice were given azoxymethane and dextran sodium sulfate to induce colitis and associated cancer or intracecal injections of MC38 tumor cells. Some mice were given inhibitors of lymphotoxin beta receptor (LTBR). Intestine tissues were analyzed by single-cell sequencing to identify cell sources of lymphotoxin. We performed immunohistochemistry analysis of colon tissue microarrays from patients with CRC (1475 tissue cores, contained tumor and nontumor tissues) and correlated levels of IL22BP with patient survival times. Levels of IL22BP were decreased in human colorectal tumors, compared with nontumor tissues, and correlated with levels of lymphotoxin. LTBR signaling was required for expression of IL22BP in colon tissues of mice. Wild-type mice given LTBR inhibitors had an increased tumor burden in both models, but LTBR inhibitors did not increase tumor growth in Il22bp-/- mice. Lymphotoxin directly induced expression of IL22BP in cultured human monocyte-derived dendritic cells via activation of nuclear factor κB. Reduced levels of IL22BP in colorectal tumor tissues were associated with shorter survival times of patients with CRC. Lymphotoxin signaling regulates expression of IL22BP in colon; levels of IL22BP are reduced in human colorectal tumors, associated with shorter survival times. LTBR signaling regulates expression of IL22BP in colon tumors in mice and cultured human dendritic cells. Patients with colorectal tumors that express low levels of IL22BP might benefit from treatment with an IL22 antagonist.


Invasive cervical cancers in the United States, Botswana and Kenya: HPV type distribution and health policy implications.
More deaths occur in African women from invasive cervical cancer (ICC) than from any other malignancy. ICC is caused by infection with oncogenic types of human papillomavirus (HPV). Co-infection with the human immunodeficiency virus (HIV) accelerates the natural history of ICC, and may influence the HPV type distribution. Because HPV vaccines are available, this malignancy is theoretically preventable, but the vaccines are largely type-specific in protection against infection. Data on specific HPV types causing ICC in African women is limited, and many studies utilized swab samples rather than actual cancer tissue. A previous study using archived, ICC tissue from women in Botswana identified an unusual HPV type distribution. A similar study was therefore performed in a second sub-Saharan country to provide additional information on the HPV type distribution in ICC. Archived, formalin-fixed, paraffin-embedded ICCs were acquired from women in the United States, Kenya, or Botswana. DNA was extracted and HPV genotyping performed by Roche Linear Array. HIV sequences were identified in ICCs by PCR. HPV types 16 or 18 (HPV 16/18) were identified in 93.5 % of HPV-positive ICCs from the U.S., 93.8 % from Kenya, and 61.8 % from Botswana (p < 0.0001). Non-HPV 16/18 types were detected in 10.9 % of HPV-positive cancers from the U.S., 17.2 % from Kenya, and 47.8 % from Botswana (p < 0.0001). HIV was detected in 2.2, 31.5, and 32.4 % from ICCs from the U.S., Kenya, or Botswana, respectively (p = 0.0002). The distribution of HPV types was not significantly different between HIVinfected or HIV-uninfected women. The percentages of ICCs theoretically covered by the bivalent/quadrivalent HPV vaccines were 93.5, 93.9, and 61.8 % from the U.S., Kenya and Botswana, respectively, and increased to 100, 98, and 77.8 % for the nanovalent vaccine. HPV 16/18 caused most ICCs from the U.S. and western Kenya. Fewer ICCs contained HPV 16/18 in Botswana. HIV co-infection did not influence the HPV type distribution in ICCs from African women from the two countries. Available HPV vaccines should provide protection against most ICCs in the U.S. and Kenya. The recently developed nanovalent vaccine may be more suitable for countries where non-HPV 16/18 types are frequently detected in ICC.


Associations between age and the course of major depressive disorder: a 2-year longitudinal cohort study.
Although there is some evidence that older people might have a poorer course of major depressive disorder (MDD) than younger or middle-aged people, and that age-related course differences might affect the optimisation of MDD treatment, large-scale studies with a broad age range, including consistent course assessments, are needed to properly address this issue. Therefore, we aimed to longitudinally examine whether older age was associated with a poorer naturalistic course trajectory of MDD than that of younger ages and to establish which prognostic-clinical, social, and health-factors could explain this potentially poorer course. For this longitudinal cohort study, we used baseline and 2-year follow-up data from the Netherlands Study of Depression and Anxiety (NESDA) and the Netherlands Study of Depression in Older Persons (NESDO) cohorts. People aged between 18 and 88 years, with an MDD diagnosis at baseline, and a valid clinical assessment at 2-year follow-up were included. The primary outcome was the 2-year course of MDD, which was assessed by use of four indicators: having a depression diagnosis (MDD or dysthymia) after 2 years, having a chronic symptom course (depressive symptoms present during 80% or more of the 2-year follow-up period), time to remission, and depression severity change. We used multivariate analyses to examine associations between continuous age and these MDD course indicators. We also examined whether prognostic clinical (eg, comorbid anxiety), social (loneliness and social support), and health (body-mass index, pain, and chronic diseases) factors contributed to the differences in the course of MDD between age groups. Between 2004-2012, baseline and 2-year follow-up data were obtained for 1042 participants from the NESDA and NESDO cohorts, of whom 690 (66%) were women. Older age was significantly associated with a worse 2-year MDD course for all four indicators (MDD diagnosis: odds ratio [OR] 1·08, 95% CI 1·00-1·17; chronic symptom course: OR 1·24, 1·13-1·35; time to remission: hazard ratio [HR] 0·91, 0·87-0·96; and depression severity change: regression coefficient 1·06, p<0·0001; all per 10-year increase). The course of MDD worsened linearly with age, and people aged 70 years or older had the worst outcomes compared with those of the reference group of people aged 18-29 years (MDD diagnosis: OR 2·02, 95% CI 1·18-3·45; chronic symptom course: OR 3·19, 1·74-5·84; time to remission: HR 0·60, 0·44-0·83; and depression severity change: -12·64 [SD 10·85] in those aged 18-29 years and -5·57 [11·14] in those aged 70 years or older). These results were slightly reduced, but remained mostly significant when adjusting for prognostic clinical, social, and health factors. Older age was found to be a consistent and important risk factor for a poorer MDD course, which could not be explained by a range of well established risk factors. Further investigation of potential underlying mechanisms-including the effect of cognitive impairment, for example-is needed to prevent the negative consequences of a long-term MDD burden in older people. Netherlands Organisation for Health Research and Development, Fonds NutsOhra, Stichting tot Steun VCVGZ, NARSAD The Brain and Behaviour Research Fund, and European Union's 7th Framework Programme.


Cross-conjugation and quantum interference: a general correlation?
We discuss the relationship between the π-conjugation pattern, molecular length, and charge transport properties of molecular wires, both from an experimental and a theoretical viewpoint. Specifically, we focus on the role of quantum interference in the conductance properties of cross-conjugated molecules. For this, we compare experiments on two series of dithiolated wires. The first set we synthesized consists of three dithiolated oligo(phenylene ethynylene) (OPE) benchmark compounds with increasing length. The second series synthesized comprises three molecules with different π-conjugation patterns, but identical lengths, i.e. an anthracene (linear conjugation), an anthraquinone (cross-conjugation), and a dihydroanthracene (broken conjugation) derivative. To benchmark reliable trends, conductance experiments on these series have been performed by various techniques. Here, we compare data obtained by conductive-probe atomic force microscopy (CP-AFM) for self-assembled monolayers (SAMs) with single-molecule break junction and multi-molecule EGaIn data from other groups. For the benchmark OPE-series, we consistently find an exponential decay of the conductance with molecular length characterized by β = 0.37 ± 0.03 Å(-1) (CP-AFM). Remarkably, for the second series, we do not only find that the linearly conjugated anthracene-containing wire is the most conductive, but also that the cross-conjugated anthraquinone-containing wire is less conductive than the broken-conjugated derivative. We attribute the low conductance values for the cross-conjugated species to quantum interference effects. Moreover, by theoretical modeling, we show that destructive quantum interference is a robust feature for cross-conjugated structures and that the energy at which complete destructive interference occurs can be tuned by the choice of side group. The latter provides an outlook for future devices in this fascinating field connecting chemistry and physics.


Variants in ST8SIA1 do not play a major role in susceptibility to multiple sclerosis in Canadian families.
Multiple sclerosis (MS) is a complex trait with a significant genetic component. Recent work has implicated the ST8SIA1 gene, encoding a ganglioside synthase, in susceptibility to the disease, perhaps with a parent-of-origin effect. In this investigation of 1318 MS patients from 756 Canadian families, we analysed the transmission of the four single nucleotide polymorphisms in ST8SIA previously shown to be associated with MS. No significant association was found in the entire sample or when stratifying by transmitting parent, indicating that this gene plays little or no role in susceptibility to MS in the Canadian population.


Dynamic chemotactic response of fibroblasts to local stimulation using EGF-immobilized microbeads.
Directional cellular migrations as a chemotactic response to spatially inhomogeneous growth factor stimulation play an important role in establishing physiological mechanisms and pathological events in cells. We developed epidermal growth factor (EGF)-immobilized microbeads by photoreaction and evaluated its local stimulatory effects on the dynamic chemotactic motility of fibroblasts. The local stimulation resulted in global activation of ERK 1/2 and directionality of cellular migration. The cellular migration by stimulation using 3-μm diameter EGF-immobilized microbeads persisted for a longer time, were involved a wider field and their number were further increased with stimulation. This effective technique allows cellular migration and biochemical analyses that will help elucidate the mechanisms involved in signal transduction by spatially inhomogeneous stimulation of the growth factor.


A quantitative comparison of mechanoelectrical transduction in vestibular and auditory hair cells of neonatal mice.
Vestibular hair cells (VHCs) and cochlear outer hair cells (OHCs) of neonatal mice were stimulated by a fluid jet directed at their stereociliary bundles. Relations between the force exerted by the jet, bundle displacement, and the resulting transducer current were studied. The mean maximum transducer conductance in VHCs (2.6 nS) was about half that of the OHCs (5.5 nS), with the largest recorded values being 4.1 nS and 9.2 nS, respectively. In some OHCs activity of a single, 112 pS transducer channel was observed, allowing an estimate of the maximum number of channels: up to 36 in VHCs and 82 in OHCs, corresponding to about one transducer channel per tip link. The VHC bundles required about 330 nm of tip displacement to activate 90% of the maximum transducer conductance, compared to 150 nm for the OHC bundles. This corresponded to 2 deg of rotation about their pivots for both, due to the greater length of the VHC bundles. The VHC bundles' translational stiffness was one-seventh of that of the OHCs. Conversion to rotational stiffness almost abolished this difference. Rotation of the hair bundle rather than translation determines the gating of the transducer channels, independent of bundle height or origin of the cells.


Molecular Behavior of HMGB1 in the Cochlea Following Noise Exposure and in vitro.
Noise-induced hearing loss (NIHL) is characterized by cellular damage to the inner ear, which is exacerbated by inflammation. High-mobility group box 1 (HMGB1), a representative damage-associated molecular pattern (DAMP), acts as a mediator of inflammation or an intercellular messenger according to its cellular localization. Blocking or regulating HMGB1 offers an attractive approach in ameliorating NIHL. However, the precise therapeutic intervention must be based on a deeper understanding of its dynamic molecular distribution and function in cochlear pathogenesis after acoustic trauma. Here, we have presented the spatiotemporal dynamics of the expression of HMGB1, exhibiting distribution variability in specific cochlear regions and cells following noise exposure. After gene manipulation, we further investigated the characteristics of cellular HMGB1 in HEI-OC1 cells. The higher cell viability observed in the HMGB1 knocked-down group after stimulation with H2O2 indicated the possible negative effect of HMGB1 on cellular lifespan. In conclusion, this study demonstrated that HMGB1 is involved in NIHL pathogenesis and its molecular biology has essential and subtle influences, preserving a translational potential for pharmacological intervention.


The ANISEED database: digital representation, formalization, and elucidation of a chordate developmental program.
Developmental biology aims to understand how the dynamics of embryonic shapes and organ functions are encoded in linear DNA molecules. Thanks to recent progress in genomics and imaging technologies, systemic approaches are now used in parallel with small-scale studies to establish links between genomic information and phenotypes, often described at the subcellular level. Current model organism databases, however, do not integrate heterogeneous data sets at different scales into a global view of the developmental program. Here, we present a novel, generic digital system, NISEED, and its implementation, ANISEED, to ascidians, which are invertebrate chordates suitable for developmental systems biology approaches. ANISEED hosts an unprecedented combination of anatomical and molecular data on ascidian development. This includes the first detailed anatomical ontologies for these embryos, and quantitative geometrical descriptions of developing cells obtained from reconstructed three-dimensional (3D) embryos up to the gastrula stages. Fully annotated gene model sets are linked to 30,000 high-resolution spatial gene expression patterns in wild-type and experimentally manipulated conditions and to 528 experimentally validated cis-regulatory regions imported from specialized databases or extracted from 160 literature articles. This highly structured data set can be explored via a Developmental Browser, a Genome Browser, and a 3D Virtual Embryo module. We show how integration of heterogeneous data in ANISEED can provide a system-level understanding of the developmental program through the automatic inference of gene regulatory interactions, the identification of inducing signals, and the discovery and explanation of novel asymmetric divisions.


Altered levels of hsromega lncRNAs further enhance Ras signaling during ectopically activated Ras induced R7 differentiation in Drosophila.
We exploited the high Ras activity induced differentiation of supernumerary R7 cells in Drosophila eyes to examine if hsrω lncRNAs influence active Ras signaling. Surprisingly, either down- or up-regulation of hsrω lncRNAs in sev-GAL4>RasV12 expressing eye discs resulted in complete pupal lethality and substantially greater increase in R7 photoreceptor number at the expense of cone cells. Enhanced nuclear p-MAPK and presence of sev-GAL4 driven RasV12 bound RafRBDFLAG in cells not expressing the sev-GAL4 driver indicated non-cell autonomous spread of Ras signaling when hsrω levels were co-altered. RNA-sequencing revealed that down-and up-regulation of hsrω transcripts in sev-GAL4>RasV12 expressing eye discs elevated transcripts of positive or negative modulators, respectively, of Ras signaling so that either condition enhances it. Altered hsrω transcript levels in sev-GAL4>RasV12 expressing discs also affected sn/sno/sca RNAs and some other RNA processing transcript levels. Post-transcriptional changes due to the disrupted intra-cellular dynamicity of omega speckle associated hnRNPs and other RNA-binding proteins that follow down- or up-regulation of hsrω lncRNAs appear to be responsible for the further elevated Ras signaling. Cell autonomous and non-autonomous enhancement of Ras signaling by lncRNAs like hsrω has implications for cell signaling during high Ras activity commonly associated with some cancers.


Arterial Stiffness is an Independent Risk Factor for Anemia After Percutaneous Native Kidney Biopsy.
Bleeding is the most common complication after renal biopsy. Although numerous predictors of bleeding have been reported, it remains unclear whether arterial stiffness affects bleeding complications. We performed an observational study of the renal biopsies performed in our division over an approximately 6-year period (May 2010 to May 2016). The clinical and laboratory factors were analyzed to reveal the risk factors associated with bleeding, with a focus on anemia (defined as a ≥10% decrease in hemoglobin [Hb] after biopsy). The brachial-ankle pulse wave velocity (baPWV) was measured to evaluate arterial stiffness. This study included 462 patients (male, n=244; female, n=218). Anemia (defined above) was observed in 54 patients (11.7%). The risk of anemia was higher in women, older patients, and patients with lower serum albumin, lower eGFR and lower diastolic blood pressure after biopsy. We then performed a further analysis of 187 patients whose baPWV data were available. Multivariate analysis revealed that a higher baPWV was an independent risk factor for anemia. ROC analysis for predicting anemia found that a baPWV value of 1839 cm/s had the best performance (AUC 0.689). An increased baPWV may be a more valuable predictor of bleeding than any of the other reported risk factors.


Induction of complete and molecular remissions in acute myeloid leukemia by Wilms' tumor 1 antigen-targeted dendritic cell vaccination.
Active immunization using tumor antigen-loaded dendritic cells holds promise for the adjuvant treatment of cancer to eradicate or control residual disease, but so far, most dendritic cell trials have been performed in end-stage cancer patients with high tumor loads. Here, in a phase I/II trial, we investigated the effect of autologous dendritic cell vaccination in 10 patients with acute myeloid leukemia (AML). The Wilms' tumor 1 protein (WT1), a nearly universal tumor antigen, was chosen as an immunotherapeutic target because of its established role in leukemogenesis and superior immunogenic characteristics. Two patients in partial remission after chemotherapy were brought into complete remission after intradermal administration of full-length WT1 mRNA-electroporated dendritic cells. In these two patients and three other patients who were in complete remission, the AML-associated tumor marker returned to normal after dendritic cell vaccination, compatible with the induction of molecular remission. Clinical responses were correlated with vaccine-associated increases in WT1-specific CD8+ T cell frequencies, as detected by peptide/HLA-A*0201 tetramer staining, and elevated levels of activated natural killer cells postvaccination. Furthermore, vaccinated patients showed increased levels of WT1-specific IFN-gamma-producing CD8+ T cells and features of general immune activation. These data support the further development of vaccination with WT1 mRNA-loaded dendritic cells as a postremission treatment to prevent full relapse in AML patients.


The human PAF complex coordinates transcription with events downstream of RNA synthesis.
The yeast PAF (yPAF) complex interacts with RNA polymerase II and coordinates the setting of histone marks associated with active transcription. We report the isolation and functional characterization of the human PAF (hPAF) complex. hPAF shares four subunits with yPAF (hCtr9, hPaf1, hLeo1, and hCdc73), but contains a novel higher eukaryotic-specific subunit, hSki8. RNAi against hSki8 or hCtr9 reduces the cellular levels of other hPAF subunits and of mono- and trimethylated H3-Lys 4 and dimethylated H3-Lys 79. The hSki8 subunit is also a component of the human SKI (hSKI) complex. Yeast SKI complex is cytoplasmic and together with Exosome mediates 3'-5' mRNA degradation. However, hSKI complex localizes to both nucleus and cytoplasm. Immunoprecipitation experiments revealed that hPAF and hSKI complexes interact, and ChIP experiments demonstrated that hSKI associates with transcriptionally active genes dependent on the presence of hPAF. Thus, in addition to coordinating events during transcription (initiation, promoter clearance, and elongation), hPAF also coordinates events in RNA quality control.


Arousal-induced modulation of memory storage processes in humans.
We recently demonstrated in human subjects that muscle-tension-induced arousal can enhance later retention performance and that this effect is attenuated by beta-adrenergic receptor antagonists. In that study, each subject established a baseline for muscle tension by squeezing a hand dynamometer for 30 s with maximum force. This may have served to "prime" subsequent arousal produced by muscle tension. Two experiments were performed to address this issue. At the beginning of each experiment, young adult subjects were asked to squeeze the hand dynamometer at maximum effort either for 30 s (Prime) or for only 1 s (No prime). Then, during the task, arousal was induced by having each subject exert a moderate amount of tension (25 to 50% of baseline maximum). In the first experiment, subjects were shown four consecutive lists of 20 highly imageable nouns, given immediate recall tests of each, and then given a comprehensive recall and recognition test at the conclusion of the experiment. Moderate arousal was induced once for each list (at encoding, consolidation, or retrieval) or not at all for one list. The sequence of arousal induction was counterbalanced. Significant enhancement of delayed recall was seen in the 30-s group for those lists in which arousal was induced during the consolidation or retrieval period with no significant effects in the 1-s group. These results demonstrate that arousal can modulate memory consolidation when induced shortly after learning and that an initial priming event may affect the response to subsequent similar arousing events. In the second experiment, subjects read paragraphs, some of which contained highlighted words (working memory task); half of the subjects were given the 30-s procedure and half the 1-s procedure. Only those subjects in the 30-s group showed significant arousal-induced enhancement of delayed recognition of the highlighted words. Again, no significant effect on retention performance was seen in the group that squeezed the hand dynamometer for only 1 s during the priming period. Pulse data suggested that there may be somewhat greater heart-rate reactivity in the 30-s group. These findings suggest that memory modulation by arousal may be primed, or enhanced, by a relevant preliminary arousal event.


Lattice simulation method to model diffusion and NMR spectra in porous materials.
A coarse-grained simulation method to predict nuclear magnetic resonance (NMR) spectra of ions diffusing in porous carbons is proposed. The coarse-grained model uses input from molecular dynamics simulations such as the free-energy profile for ionic adsorption, and density-functional theory calculations are used to predict the NMR chemical shift of the diffusing ions. The approach is used to compute NMR spectra of ions in slit pores with pore widths ranging from 2 to 10 nm. As diffusion inside pores is fast, the NMR spectrum of an ion trapped in a single mesopore will be a sharp peak with a pore size dependent chemical shift. To account for the experimentally observed NMR line shapes, our simulations must model the relatively slow exchange between different pores. We show that the computed NMR line shapes depend on both the pore size distribution and the spatial arrangement of the pores. The technique presented in this work provides a tool to extract information about the spatial distribution of pore sizes from NMR spectra. Such information is difficult to obtain from other characterisation techniques.


Genome-wide analysis of the oxyntic proliferative isthmus zone reveals ASPM as a possible gastric stem/progenitor cell marker over-expressed in cancer.
The oxyntic proliferative isthmus zone contains the main stem/progenitor cells that provide for physiological renewal of the distinct mature cell lineages in the oxyntic epithelium of the stomach. These cells are also proposed to be the potential cells-of-origin of gastric cancer, although little is known about their molecular characteristics and specific biological markers are lacking. In this study, we developed a method for serial section-navigated laser microdissection to isolate cells from the proliferative isthmus zone of rat gastric oxyntic mucosa for genome-wide microarray gene expression analysis. Enrichment analysis showed a distinct gene expression profile for the isthmus zone, with genes regulating intracellular processes such as the cell cycle and ribosomal activity. The profile was also related to stem cell transcriptional networks and stomach neoplasia. Genes expressed uniquely in the isthmus zone were associated with E2F transcription factor 1 (E2F1), which participates in the self-renewal of stem cells and in gastric carcinogenesis. One of the unique genes was Aspm [Asp (abnormal spindle) homologue, microcephaly-associated (Drosophila)]. Here we show ASPM in single scattered epithelial cells located in the proliferative isthmus zone of rat, mouse and human oxyntic mucosa, which do not seem to be actively dividing. The ASPM-expressing cells are mainly mature cell marker-deficient, except for a limited overlap with cells with neuroendocrine and tuft cell features. Further, both ASPM and E2F1 were expressed in human gastric cancer cell lines and increased and correlated in human gastric adenocarcinomas compared to non-tumour mucosa, as shown by expression profile analyses and immunohistochemistry. The association between ASPM and the transcription factor E2F1 in gastric tissue is relevant, due to their common involvement in crucial cell fate-regulatory mechanisms. Our results thus introduce ASPM as a novel possible oxyntic stem/progenitor cell marker that may be involved in both normal gastric physiology and gastric carcinogenesis.


Thrombin modulates phosphoinositide metabolism, cytosolic calcium, and impulse initiation in the heart.
Thrombin stimulates phosphoinositide hydrolysis and increases cytosolic calcium in several types of cells. To determine whether thrombin exerts similar stimulatory actions in the heart and whether this mechanism is linked to changes in cardiac electrical activity, the effects of thrombin on several biochemical and electrophysiological parameters were examined. In neonatal rat ventricular myocyte cultures freed of fibroblast contamination by irradiation, thrombin rapidly induced the breakdown of phosphoinositides. Formation of inositol trisphosphate was detectable within 5 seconds and was followed by the sequential accumulation of inositol bisphosphate and inositol monophosphate. The effect of thrombin to stimulate phosphoinositide hydrolysis was inhibited by hirudin, but not by propranolol, prazosin, or pretreatment with pertussis toxin. The inositol phospholipid response was unassociated with changes in intracellular cAMP levels. To determine the electrophysiological effects of thrombin, we used microelectrode techniques to study canine Purkinje fibers. Thrombin increased the beating rate of fibers depolarized using barium, but not those at normal maximal diastolic potential. In addition, thrombin prolonged the action potential duration in fibers driven at a constant cycle length. This response was inhibited by hirudin and nisoldipine, but not by propranolol, prazosin, or pretreatment with pertussis toxin. Thrombin also augmented cesium-induced early afterdepolarizations. Using the fluorescent calcium indicator fura-2, we demonstrated that thrombin increased the beating rate, diastolic calcium, and peak systolic calcium of spontaneously contracting cultured ventricular myocytes. Cytosolic calcium also increased in both rat ventricular myocytes and canine Purkinje myocytes that were electrically driven at a constant basic cycle length, indicating that thrombin modulates cellular calcium metabolism independent of its actions to enhance automaticity. Taken together, these findings demonstrate several novel biological actions of thrombin in the mammalian heart that may be functionally related. The actions of thrombin to enhance automaticity and prolong repolarization may contribute to the electrical abnormalities observed in the setting of myocardial ischemia and infarction.


Recommendations for intraoperative mesh brachytherapy: Report of AAPM Task Group No. 222.
Mesh brachytherapy is a special type of a permanent brachytherapy implant: it uses low-energy radioactive seeds in an absorbable mesh that is sutured onto the tumor bed immediately after a surgical resection. This treatment offers low additional risk to the patient as the implant procedure is carried out as part of the tumor resection surgery. Mesh brachytherapy utilizes identification of the tumor bed through direct visual evaluation during surgery or medical imaging following surgery through radiographic imaging of radio-opaque markers within the sources located on the tumor bed. Thus, mesh brachytherapy is customizable for individual patients. Mesh brachytherapy is an intraoperative procedure involving mesh implantation and potentially real-time treatment planning while the patient is under general anesthesia. The procedure is multidisciplinary and requires the complex coordination of multiple medical specialties. The preimplant dosimetry calculation can be performed days beforehand or expediently in the operating room with the use of lookup tables. In this report, the guidelines of American Association of Physicists in Medicine (AAPM) are presented on the physics aspects of mesh brachytherapy. It describes the selection of radioactive sources, design and preparation of the mesh, preimplant treatment planning using a Task Group (TG) 43-based lookup table, and postimplant dosimetric evaluation using the TG-43 formalism or advanced algorithms. It introduces quality metrics for the mesh implant and presents an example of a risk analysis based on the AAPM TG-100 report. Recommendations include that the preimplant treatment plan be based upon the TG-43 dose calculation formalism with the point source approximation, and the postimplant dosimetric evaluation be performed by using either the TG-43 approach, or preferably the newer model-based algorithms (viz., TG-186 report) if available to account for effects of material heterogeneities. To comply with the written directive and regulations governing the medical use of radionuclides, this report recommends that the prescription and written directive be based upon the implanted source strength, not target-volume dose coverage. The dose delivered by mesh implants can vary and depends upon multiple factors, such as postsurgery recovery and distortions in the implant shape over time. For the sake of consistency necessary for outcome analysis, prescriptions based on the lookup table (with selection of the intended dose, depth, and treatment area) are recommended, but the use of more advanced techniques that can account for real situations, such as material heterogeneities, implant geometric perturbations, and changes in source orientations, is encouraged in the dosimetric evaluation. The clinical workflow, logistics, and precautions are also presented.


Induced pluripotent stem cell lines derived from human somatic cells.
Somatic cell nuclear transfer allows trans-acting factors present in the mammalian oocyte to reprogram somatic cell nuclei to an undifferentiated state. We show that four factors (OCT4, SOX2, NANOG, and LIN28) are sufficient to reprogram human somatic cells to pluripotent stem cells that exhibit the essential characteristics of embryonic stem (ES) cells. These induced pluripotent human stem cells have normal karyotypes, express telomerase activity, express cell surface markers and genes that characterize human ES cells, and maintain the developmental potential to differentiate into advanced derivatives of all three primary germ layers. Such induced pluripotent human cell lines should be useful in the production of new disease models and in drug development, as well as for applications in transplantation medicine, once technical limitations (for example, mutation through viral integration) are eliminated.


Differences in young driver crash involvement in states with varying licensure practices.
Teenage driver licensing practices and the crashes of teenagers were compared in several states with differing laws and policies regarding licensure. High school seniors in Delaware, a state with laws that allow early driving and licensure, reported that they first drove on a public road, obtained a learner's permit and obtained a driver's license at younger ages than high school seniors in other northeastern states (Connecticut, New Jersey and upstate New York). State crash data indicated that Delaware and Connecticut, which allow unrestricted licensing at age 16, showed the highest rates of 16-year-old driver involvements in nonfatal and fatal injury crashes. Pennsylvania and upstate New York, which have night driving curfews for 16 year-olds, showed lower crash rates overall and much lower crash rates during their respective curfew hours. New Jersey and Nassau and Suffolk counties, where unsupervised driving by 16 year-olds is generally not allowed, showed the lowest crash rates for 16 year-olds. Graduated licensing programs that include delayed full-privilege licensure, night driving curfews, and extended periods of supervised practice driving are a possible countermeasure for the high motor vehicle crash rates of young drivers.


Molecular Subgrouping of Medulloblastoma: Impact Upon Research and Clinical Practice.
Medulloblastoma, the most common primary pediatric malignant brain tumor is a molecularly heterogeneous disease with different developmental origins, distinct phenotypes, diverse biological behaviour, and contrasting clinical outcomes. The current clinico-radiological risk-classification fails to take account of this heterogeneity and existent prognostic variability. It is widely accepted that dysregulation of normal developmental processes constitute a key mechanism of tumorigenesis in at least a subset of medulloblastomas. Several attempts at biological classification have successfully identified distinct subgroups with subgroup-specific gene signatures, demographics, histologic subtypes, and rates of metastases. Several research groups have classified medulloblastoma into molecular subgroups using a variety of different genomic approaches and platforms such as gene expression profiling, microRNA profiling and methylation arrays. Recently, a consensus has emerged that classifies medulloblastoma into four distinct molecular subgroups named as wingless (WNT), sonic hedgehog (SHH), Group 3 and Group 4 respectively. However, such integrative approaches have limited applicability in the clinic due to the need of fresh-frozen tissues and elaborate molecular biology tools. In parallel, some groups have proposed and validated traditional antibody-based approaches using immunohistochemistry on archival specimen for rapid and reliable molecular subgrouping to be applied in any basic neuropathology laboratory. Heterogeneity within each of these four consensus subgroups has also been demonstrated that needs to be considered in the design of future clinical trials. There is a compelling need to integrate molecular biomarkers with clinico-pathologic outcome indicators to refine risk-stratification as well as develop novel molecularly targeted agents for optimizing therapeutic index and personalizing therapy.


Making care decisions in home-based dementia care: why context matters.
The hours of unpaid elder care by family members are projected to triple by 2038. Because living with dementia can inhibit decision-making abilities, family members are often besought to assist in this process. In this ethnographic study, relationships within home-based dementia care were critically examined through face-to-face interviews and participant observations with clients, family caregivers, and home care providers (n = 51). The findings revealed how the formalized home care system contextually imposes decisions, and revealed three themes: (1) accommodating clinically defined competence/incompetence, (2) making untimely decisions, and (3) reinforcing exclusion in decision making. These themes shed light on how cultural values (competency), beliefs (immutability of the system), and practices (timing of decisions) of the home care system are ultimately deterministic in decision making for persons with dementia and caregivers. Additional attention to the collaborative and inclusive practices of all family members in dementia home care is imperative in order to optimize health.


Comparative landscape genetic analyses show a Belgian motorway to be a gene flow barrier for red deer (Cervus elaphus), but not wild boars (Sus scrofa).
While motorways are often assumed to influence the movement behaviour of large mammals, there are surprisingly few studies that show an influence of these linear structures on the genetic make-up of wild ungulate populations. Here, we analyse the spatial genetic structure of red deer (Cervus elaphus) and wild boars (Sus scrofa) along a stretch of motorway in the Walloon part of Belgium. Altogether, 876 red deer were genotyped at 13 microsatellite loci, and 325 wild boars at 14 loci. In the case of the red deer, different genetic clustering tools identified two genetic subpopulations whose borders matched the motorway well. Conversely, no genetic structure was identified in the case of the wild boar. Analysis of isolation-by-distance patterns of pairs of individuals on the same side and on different sides of the motorway also suggested that the road was a barrier to red deer, but not to wild boar movement. While telemetry studies seem to confirm that red deer are more affected by motorways than wild boar, the red deer sample size was also much larger than that of the wild boars. We therefore repeated the analysis of genetic structure in the red deer with randomly sub-sampled data sets of decreasing size. The power to detect the genetic structure using clustering methods decreased with decreasing sample size.


Metabarcoding Reveals Temporal Patterns of Community Composition and Realized Thermal Niches of Thalassiosira Spp. (Bacillariophyceae) from the Narragansett Bay Long-Term Plankton Time Series.
Diatoms generate nearly half of marine primary production and are comprised of a diverse array of species that are often morphologically cryptic or difficult to identify using light microscopy. Here, species composition and realized thermal niches of species in the diatom genus Thalassiosira were examined at the site of the Narragansett Bay (NBay) Long-Term Plankton Time Series using a combination of light microscopy (LM), high-throughput sequencing (HTS) of the 18S rDNA V4 region and historical records. Thalassiosira species were identified over 6 years using a combination of LM and DNA sequences. Sixteen Thalassiosira taxa were identified using HTS: nine were newly identified in NBay. Several newly identified species have small cell diameters and are difficult to identify using LM. However, they appeared frequently and thus may play a significant ecological role in NBay, particularly since their realized niches suggest they are eurythermal and able to tolerate the >25 °C temperature range of NBay. Four distinct species assemblages that grouped by season were best explained by surface water temperature. When compared to historical records, we found that the cold-water species Thalassiosira nordenskioeldii has decreased in persistence over time, suggesting that increasing surface water temperature has influenced the ecology of phytoplankton in NBay.


The role of oxidative stress and endothelial injury in diabetic neuropathy and neuropathic pain.
The roles of endothelin-1 (ET-1) and oxidative stress causing vascular injury in the pathogenesis of diabetic neuropathy are debatable. The present study was undertaken to clarify the possible effects of oxidative stress and ET-1 in diabetic patients with and without peripheric neuropathy. We studied plasma ET-1, nitric oxide (NO), catalase, glutathione (GSH) levels of fifty (22 females, 28 males) patients with Type 2 diabetes in order to evaluate endothelial dysfunction and oxidative stress. The neuropathy types (motor, sensorial and sensorimotor), comorbid diseases, antidiabetic treatments, smoking, diabetes duration were also considered. Short McGill Pain Questionnaire (SF-MPQ) was also performed for patients with neuropathy. There were no significant differences between patients with (n=23) and without (n=27) neuropathy with regards to demographic features except diabetic disease duration. The statistical analysis was done considering this difference. Although NO and ET-1 levels were higher, and catalase and GSH levels were decreased in neuropathic patients, no statistical significancy was found. We also couldn't find any correlations between the parameters and SF-MPQ scores. Although there were no relationships between neuropathy and the studied parameters, we found lower levels of catalase and GSH as intracelluler antioxidants and higher NO and ET-1 as markers of endothelial injury in patients with neuropathy. Our data suggest that there is a need of further studies with larger study groups in order to clear out the role of endothelial injury and oxidative status in the pathogenesis of diabetic neuropathy.


To be or not to be in sexual desire: the androgen dilemma.
The androgen milieu and sexual desire in women seem to be tightly linked because they both decline with age. However, we are still missing a cut-off plasma level for androgens (total testosterone, free testosterone) or androgen precursors (androstenedione, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS)) to diagnose androgen deficiency in clinical practice. Apart from the complex multidimensional nature of sexual desire across the reproductive lifespan, the correlation between measurements of testosterone and specific signs and symptoms has been difficult because, according to guidelines, most available assays are unreliable at baseline and under hormonal treatments. Recent data obtained with accurate methods based on mass spectrometry to measure total testosterone levels found a significant positive association with sexual desire, arousal and masturbation in midlife US women across the menopausal transition. Even in a European cohort of healthy women aged 19-65 years, sexual desire, measured with a validated questionnaire, correlated overall with free testosterone and androstenedione measured with mass spectrometry. Collectively, these data support the therapeutic use of testosterone for low desire and sexual dysfunction in those clinical conditions in which androgen deficiency may be accurately diagnosed.


Reconstruction of Orbital Floor With Auricular Concha.
Orbital floor fractures of varying sizes commonly occur after orbital injuries and remain a serious challenge. Serious complications of such fractures include enopthalmos, restriction of extraocular movement, and diplopia. There is a dearth of literature that can be applied widely, easily, and successfully in all such situations, and therefore there is no consensus on the treatment protocol of this pathology yet. Autogenous grafts and alloplastic and allogenic materials with a wide variety of advantages and disadvantages have been discussed. The value of preoperative and postoperative ophthalmological examination should be standard of care in all orbital fracture patients. An ideal reconstructed orbital floor fracture should accelerate the restoration of orbital function with acceptable cosmetic results. Management parameters of orbital fractures such as timing of surgery, incision type, and implant materials, though widely discussed, remain controversial. In this study, 55 patients with orbital floor fractures surgically reconstructed with conchal cartilage grafts between 2008 and 2014 were retrospectively evaluated. Complications and long-time follow-up visit results have been reported with clinical and radiographic findings. The aim of this study was to present the authors' clinical experiences of reconstruction of blow-out fractures with auricular conchal graft and to evaluate the other materials available for use.


The development of arithmetical abilities.
Arithmetical skills are essential to the effective exercise of citizenship in a numerate society. How these skills are acquired, or fail to be acquired, is of great importance not only to individual children but to the organisation of formal education and its role in society. The evidence on the normal and abnormal developmental progression of arithmetical abilities is reviewed; in particular, evidence for arithmetical ability arising from innate specific cognitive skills (innate numerosity) vs. general cognitive abilities (the Piagetian view) is compared. These include evidence from infancy research, neuropsychological studies of developmental dyscalculia, neuroimaging and genetics. The development of arithmetical abilities can be described in terms of the idea of numerosity -- the number of objects in a set. Early arithmetic is usually thought of as the effects on numerosity of operations on sets such as set union. The child's concept of numerosity appears to be innate, as infants, even in the first week of life, seem to discriminate visual arrays on the basis of numerosity. Development can be seen in terms of an increasingly sophisticated understanding of numerosity and its implications, and in increasing skill in manipulating numerosities. The impairment in the capacity to learn arithmetic -- dyscalculia -- can be interpreted in many cases as a deficit in the concept in the child's concept of numerosity. The neuroanatomical bases of arithmetical development and other outstanding issues are discussed. The evidence broadly supports the idea of an innate specific capacity for acquiring arithmetical skills, but the effects of the content of learning, and the timing of learning in the course of development, requires further investigation.


The efficacy-effectiveness distinction in trials of alcohol brief intervention.
Three recent sets of null findings from trials of alcohol brief intervention (BI) have been disappointing to those who wish to see a reduction in alcohol-related harm through the widespread dissemination of BI. Saitz (7) has suggested that these null findings result from a failure to translate the effects of BI seen in efficacy trials, which are thought to contribute mainly to the beneficial effects of BI shown in meta-analyses, to effectiveness trials conducted in real-world clinical practice. The present article aims to: (i) clarify the meaning of the terms "efficacy" and "effectiveness" and other related concepts; (ii) review the method and findings on efficacy-effectiveness measurement in the 2007 Cochrane Review by Kaner and colleagues; and (iii) make suggestions for further research in this area. Conclusions are: 1) to avoid further confusion, terms such as "efficacy trial", "effectiveness trial", "clinical representativeness", etc. should be clearly defined and carefully used; 2) applications of BI to novel settings should begin with foundational research and developmental studies, followed by efficacy trials, and political pressures for quick results from premature effectiveness trials should be resisted; 3) clear criteria are available in the literature to guide progress from efficacy research, through effectiveness research, to dissemination in practice; 4) to properly interpret null findings from effectiveness studies, it is necessary to ensure that interventions are delivered as intended; 5) in future meta-analyses of alcohol BI trials, more attention should be paid to the development and application of a psychometrically robust scale to measure efficacy-effectiveness or clinical representativeness; 6) the null findings under consideration cannot be firmly attributed to a failure to translate effects from efficacy trials to real-world practice, because it is possible that the majority of trials included in meta-analyses on which the evidence for the beneficial effects of alcohol BI was based tended to be effectiveness rather than efficacy trials; and 7) a hypothesis to explain the null findings in question is that they are due to lack of fidelity in the implementation of BI in large, organizationally complex, cluster randomized trials.


Estimating the value of medical treatments to patients using probabilistic multi criteria decision analysis.
Estimating the value of medical treatments to patients is an essential part of healthcare decision making, but is mostly done implicitly and without consulting patients. Multi criteria decision analysis (MCDA) has been proposed for the valuation task, while stated preference studies are increasingly used to measure patient preferences. In this study we propose a methodology for using stated preferences to weigh clinical evidence in an MCDA model that includes uncertainty in both patient preferences and clinical evidence explicitly. A probabilistic MCDA model with an additive value function was developed and illustrated using a case on hypothetical treatments for depression. The patient-weighted values were approximated with Monte Carlo simulations and compared to expert-weighted results. Decision uncertainty was calculated as the probability of rank reversal for the first rank. Furthermore, scenario analyses were done to assess the relative impact of uncertainty in preferences and clinical evidence, and of assuming uniform preference distributions. The patient-weighted values for drug A, drug B, drug C, and placebo were 0.51 (95% CI: 0.48 to 0.54), 0.51 (95% CI: 0.48 to 0.54), 0.54 (0.49 to 0.58), and 0.15 (95% CI: 0.13 to 0.17), respectively. Drug C was the most preferred treatment and the rank reversal probability for first rank was 27%. This probability decreased to 18% when uncertainty in performances was not included and increased to 41% when uncertainty in criterion weights was not included. With uniform preference distributions, the first rank reversal probability increased to 61%. The expert-weighted values for drug A, drug B, drug C, and placebo were 0.67 (95% CI: 0.65 to 0.68), 0.57 (95% CI: 0.56 to 0.59), 0.67 (95% CI: 0.61 to 0.71), and 0.19 (95% CI: 0.17 to 0.21). The rank reversal probability for the first rank according to experts was 49%. Preferences elicited from patients can be used to weigh clinical evidence in a probabilistic MCDA model. The resulting treatment values can be contrasted to results from experts, and the impact of uncertainty can be quantified using rank probabilities. Future research should focus on integrating the model with regulatory decision frameworks and on including other types of uncertainty.


CoCoScore: context-aware co-occurrence scoring for text mining applications using distant supervision.
Information extraction by mining the scientific literature is key to uncovering relations between biomedical entities. Most existing approaches based on natural language processing extract relations from single sentence-level co-mentions, ignoring co-occurrence statistics over the whole corpus. Existing approaches counting entity co-occurrences ignore the textual context of each co-occurrence. We propose a novel corpus-wide co-occurrence scoring approach to relation extraction that takes the textual context of each co-mention into account. Our method, called CoCoScore, scores the certainty of stating an association for each sentence that co-mentions two entities. CoCoScore is trained using distant supervision based on a gold-standard set of associations between entities of interest. Instead of requiring a manually annotated training corpus, co-mentions are labeled as positives/negatives according to their presence/absence in the gold standard. We show that CoCoScore outperforms previous approaches in identifying human disease-gene and tissue-gene associations as well as in identifying physical and functional protein-protein associations in different species. CoCoScore is a versatile text mining tool to uncover pairwise associations via co-occurrence mining, within and beyond biomedical applications. CoCoScore is available at: https://github.com/JungeAlexander/cocoscore. Supplementary data are available at Bioinformatics online.


Global pattern of experienced and anticipated discrimination against people with schizophrenia: a cross-sectional survey.
Many people with schizophrenia experience stigma caused by other people's knowledge, attitudes, and behaviour; this can lead to impoverishment, social marginalisation, and low quality of life. We aimed to describe the nature, direction, and severity of anticipated and experienced discrimination reported by people with schizophrenia. We did a cross-sectional survey in 27 countries, in centres affiliated to the INDIGO Research Network, by use of face-to-face interviews with 732 participants with schizophrenia. Discrimination was measured with the newly validated discrimination and stigma scale (DISC), which produces three subscores: positive experienced discrimination; negative experienced discrimination; and anticipated discrimination. Negative discrimination was experienced by 344 (47%) of 729 participants in making or keeping friends, by 315 (43%) of 728 from family members, by 209 (29%) of 724 in finding a job, 215 (29%) of 730 in keeping a job, and by 196 (27%) of 724 in intimate or sexual relationships. Positive experienced discrimination was rare. Anticipated discrimination affected 469 (64%) in applying for work, training, or education and 402 (55%) looking for a close relationship; 526 (72%) felt the need to conceal their diagnosis. Over a third of participants anticipated discrimination for job seeking and close personal relationships when no discrimination was experienced. Rates of both anticipated and experienced discrimination are consistently high across countries among people with mental illness. Measures such as disability discrimination laws might, therefore, not be effective without interventions to improve self-esteem of people with mental illness.


Rational design of fiber-optic probes for visible and pulsed-ultraviolet resonance Raman spectroscopy.
We investigated the performance of fiber-optic resonance Raman probes with a series of experiments to determine the working curves of such probes using model analytes and to investigate the effects of absorbing media. A computer model designed to simulate these experiments is presented, and numerical results are found to be in agreement with the experimental data. Design considerations resulting from these studies are discussed, and novel designs for overcoming problems of coupling efficiency, damage threshold, and sensitivity in absorbing samples are presented. These findings are applied to the design of fiber-optic probes for ultraviolet resonance Raman spectroscopy involving nanosecond pulsed-ultraviolet excitation (225 and 266 nm). These probes have been used to collect what is, to our knowledge, the first reported fiber-optic-linked ultraviolet resonance Raman spectra of tryptophan and DNA.


Heart rate variability in the individual fetus.
The change in fetal heart rate and its variability (HRV) during the course of gestation has been documented by numerous studies. The overall drop in heart rate and increase in fetal HRV is associated with fetal growth in general and with the increase in neural integration in particular. The increased complexity of the demands on the cardiovascular system leads to more variation in the temporal course of the heart rate. Most studies that document and interpret these changes are based on data acquired in groups of fetuses. The aim of this work was to investigate HRV within single fetuses. We acquired 213 5min fetal magnetocardiograms in 11 fetuses during the second and third trimesters (at least 10 data sets per fetus, median 17). From the magnetocardiograms we determined the fetal RR interval time series and calculated the standard deviation (SDNN), root mean square of successive differences (RMSSD), approximate entropy (ApEn) and temporal asymmetry (Irrev). For each subject and HRV measure, we performed regression analysis with respect to gestational age, alone and in combination with RR interval. The coefficient of determination R(2) was used to estimate goodness-of-fit. The coefficient of quartile dispersion (CQD) was used to compare the regression parameters for each HRV measure. Overall, the HRV measures increased with age and RR interval. The consistency of the HRV measures within the individual fetuses was greater than in the data pooled over all fetuses. The individual R(2) for the model including age and RR interval was best for ApEn (.79, .59-.94; median, 90% CI), followed by RMSSD (.71, .25-.88), SDNN (.55, .18-.90) and Irrev (.16, .01-.39). These values, except for Irrev, were higher than those calculated over all 213 data sets (R(2)=.65, .63, .35, .28, respectively). The slopes of the regressions of each individual's data were most consistent over all subjects for ApEn, followed by RMSSD and SDNN and Irrev. Interindividually, the time domain measures showed discrepancies and the within-fetus courses were more consistent than the course over all fetuses. On the other hand, the course of ApEn during gestation was not only very consistent within each fetus but also very similar between most of subjects. Complexity measures such as ApEn may thus more consistently reflect prenatal developmental factors influencing cardiovascular regulation.


The acute and chronic toxic effects of vitamin A.
The acute and chronic effects of vitamin A toxicity are well documented in the literature. Emerging evidence suggests that subtoxicity without clinical signs of toxicity may be a growing concern, because intake from preformed sources of vitamin A often exceeds the recommended dietary allowances (RDA) for adults, especially in developed countries. Osteoporosis and hip fracture are associated with preformed vitamin A intakes that are only twice the current RDA. Assessing vitamin A status in persons with subtoxicity or toxicity is complicated because serum retinol concentrations are nonsensitive indicators in this range of liver vitamin A reserves. The metabolism in well-nourished persons of preformed vitamin A, provided by either liver or supplements, has been studied by several research groups. To control vitamin A deficiency, large therapeutic doses are administered in developing countries to women and children, who often are undernourished. Nevertheless, little attention has been given to the short-term kinetics (ie, after absorption but before storage) of a large dose of vitamin A or to the short- and long-term effects of such a dose given to lactating women on serum and breast-milk concentrations of retinol and its metabolites. Moreover, appropriate dosing regimens have not been systematically evaluated to ascertain the quantitative improvement in vitamin A status of the women and children who receive these supplements. The known acute and chronic effects of vitamin A toxicity have been reported previously. However, further research is needed to ascertain the areas of the world in which subclinical toxicity exists and to evaluate its effects on overall health and well-being.


Enhancing Therapeutic Efficacy of Oncolytic Herpes Simplex Virus-1 with Integrin β1 Blocking Antibody OS2966.
Integrin β1 receptor, expressed on the surface of tumor cells and macrophages in the tumor microenvironment (TME), has been implicated in both tumor progression and resistance to multiple modalities of therapy. OS2966 is the first clinical-ready humanized monoclonal antibody to block integrin β1 and was recently orphan designated by the FDA Office of Orphan Products Development. Here, we tested therapeutic potential of OS2966-mediated integrin β1 blockade to enhance the efficacy of oncolytic herpes simplex virus-1 (oHSV) through evaluation of virus replication, tumor cell killing efficiency, effect on the antiviral signaling pathway, co-culture assays of oHSV-infected cells with macrophages, and in vivo bioluminescence imaging on mammary fat pad triple-negative breast cancer xenograft and subcutaneous and intracranial glioma xenografts. OS2966 treatment decreased interferon signaling and proinflammatory cytokine induction in oHSV-treated tumor cells and inhibited migration of macrophages, resulting in enhanced oHSV replication and cytotoxicity. OS2966 treatment also significantly enhanced oHSV replication and oHSV-mediated antitumor efficacy in orthotopic xenograft models, including triple-negative breast cancer and glioblastoma. The results demonstrated the synergistic potential of the combinatory treatment approach with OS2966 to improve antitumor efficacy of conventional oHSV therapy.


Nature of macrophage-T cell interaction in secondary helper cell generation in vitro. Genetic restriction of macrophage-T cell interaction, which determines T-B genetic restriction.
To investigate the histocompatibility requirements for the macrophage-T cell interaction in the secondary antibody response, splenic T cells from antigen (carrier)-primed F1 hybrid mice were restimulated in vitro with carrier-pulsed F1, parental or allogeneic macrophages. Surviving T cell were cocultured with hapten-primed F1 or parental "B cells" and restimulated with the appropriate hapten-carrier conjugate. The IgG antibody-forming cell response was then measured using a plaque assay. Mapping of the genetic restriction was performed by use of different strain combinations. T helper cells could be restimulated in the presence of macrophages only provided they shared the I-A subregion of the major histocompatibility complex with the F1 T cells frm F1 hybrids restimulated with parental or I-A-identical macrophages were shown to only cooperate with parental B cells of the same I-A haplotype as the macrophages used for restimulation. The defect was at the level of the macrophage, as addition of macrophages of the I-A haplotype used for the restimulation culture reconstituted ability of F1 helper cells to cooperate with the I-A-nonidentical B cells.


Accumulation of high-value bioproducts in planta can improve the economics of advanced biofuels.
Coproduction of high-value bioproducts at biorefineries is a key factor in making biofuels more cost-competitive. One strategy for generating coproducts is to directly engineer bioenergy crops to accumulate bioproducts in planta that can be fractionated and recovered at biorefineries. Here, we develop quantitative insights into the relationship between bioproduct market value and target accumulation rates by investigating a set of industrially relevant compounds already extracted from plant sources with a wide range of market prices and applications, including <$10/kg (limonene, latex, and polyhydroxybutyrate [PHB]), $10 to $100/kg (cannabidiol), and >$100/kg (artemisinin). These compounds are used to identify a range of mass fraction thresholds required to achieve net economic benefits for biorefineries and the additional amounts needed to reach a target $2.50/gal biofuel selling price, using cellulosic ethanol production as a test case. Bioproduct market prices and recovery costs determine the accumulation threshold; we find that moderate- to high-value compounds (i.e., cannabidiol and artemisinin) offer net economic benefits at accumulation rates of just 0.01% dry weight (dwt) to 0.02 dwt%. Lower-value compounds, including limonene, latex, and PHB, require at least an order-of-magnitude greater accumulation to overcome additional extraction and recovery costs (0.3 to 1.2 dwt%). We also find that a diversified approach is critical. For example, global artemisinin demand could be met with fewer than 10 biorefineries, while global demand for latex is equivalent to nearly 180 facilities. Our results provide a roadmap for future plant metabolic engineering efforts aimed at increasing the value derived from bioenergy crops.


Carbon storage in old-growth forests of the Mid-Atlantic: toward better understanding the eastern forest carbon sink.
Few old-growth stands remain in the matrix of secondary forests that dominates the eastern North American landscape. These remnant stands offer insight on the potential carbon (C) storage capacity of now-recovering secondary forests. We surveyed the remaining old-growth forests on sites characteristic of the general Mid-Atlantic United States and estimated the size of multiple components of forest C storage. Within and between old-growth stands, variability in C density is high and related to overstory tree species composition. The sites contain 219 ± 46 Mg C/ha (mean ± SD), including live and dead aboveground biomass, leaf litter, and the soil O horizon, with over 20% stored in downed wood and snags. Stands dominated by tulip poplar (Liriodendron tulipifera) store the most live biomass, while the mixed oak (Quercus spp.) stands overall store more dead wood. Total C density is 30% higher (154 Mg C/ha), and dead wood C density is 1800% higher (46 Mg C/ha) in the old-growth forests than in the surrounding younger forests (120 and 5 Mg C/ha, respectively). The high density of dead wood in old growth relative to secondary forests reflects a stark difference in historical land use and, possibly, the legacy of the local disturbance (e.g., disease) history. Our results demonstrate the potential for dead wood to maintain the sink capacity of secondary forests for many decades to come.


virilizer regulates Sex-lethal in the germline of Drosophila melanogaster.
In Drosophila, the gene Sex-lethal (Sxl) is required for female development. It controls sexual differentiation in the soma, dosage compensation and oogenesis. The continuous production of SXL proteins in XX animals is maintained by autoregulation and depends on virilizer (vir). This gene is required in somatic cells for the female-specific splicing of Sxl primary transcripts and for an unknown vital process in both sexes. In the soma, clones of XX cells lacking Sxl or vir are sexually transformed and form male structures; in the germline, XX cells mutant for Sxl extensively proliferate, but are unable to differentiate. We now studied the role of vir in the germline by generating germline chimeras. We found that XX germ cells mutant for vir, in contrast to cells mutant for Sxl, perform oogenesis. We show that the early production of SXL in undifferentiated germ cells is independent of vir while, later in oogenesis, expression of Sxl becomes dependent on vir. We conclude that the early SXL proteins are sufficient for the production of eggs whereas the later SXL proteins are dispensable for this process. However, vir must be active in the female germline to allow normal embryonic development because maternal products of vir are required for the early post-transcriptional regulation of Sxl in XX embryos and for a vital process in embryos of both sexes.


Multilayer and Surface Immobilization of EDOT-Decorated Nanocapsules.
To assess the feasibility of utilizing reagent-loaded, porous polymeric nanocapsules (NCs) for chemical and biochemical sensor design, the surfaces of the NCs were decorated with 3,4-ethylenedioxythiophene (EDOT) moieties. The pores in the capsule wall allow unhindered bidirectional diffusion of molecules smaller than the programmed pore sizes, while larger molecules are either entrapped inside or blocked from entering the interior of the nanocapsules. Here, we investigate two electrochemical deposition methods to covalently attach acrylate-based porous nanocapsules with 3,4-ethylenedioxythiophene moieties on the nanocapsule surface, i.e., EDOT-decorated NCs to the surface of an existing PEDOT film: (1) galvanostatic or bilayer deposition with supporting EDOT in the deposition solution and (2) potentiostatic deposition without supporting EDOT in the deposition solution. The distribution of the covalently attached NCs in the PEDOT films was studied by variable angle FTIR-ATR and XPS depth profiling. The galvanostatic deposition of EDOT-decorated NCs over an existing PEDOT (tetrakis(pentafluorophenyl)borate) [PEDOT(TPFPhB)] film resulted in a bilayer structure, with an interface between the NC-free and NC-loaded layers, that could be traced with variable angle FTIR-ATR measurements. In contrast, the FTIR-ATR and XPS analyses of the films deposited potentiostatically from a solution without EDOT and containing only the EDOT-decorated NCs showed small amounts of NCs in the entire cross section of the films.


Dual use of tobacco among Bangladeshi men.
Dual use of tobacco (using smoking and smokeless forms) in Bangladesh is uncommon in women but common in men. Dual users are at additional risk of cancers and heart diseases compared with a single form of tobacco use. Knowledge about their socioeconomic background is necessary for planning appropriate interventions. We report here socioeconomic background of the dual users of tobacco from a nationally representative survey. The study adopted a probability proportionate to size sampling technic of divisional population stratified into urban and rural areas to recruit men aged 25 years or older from their households. A total of 4312 men were recruited. Variables included questions on 20 household assets, tobacco use and other behavioral risk factors, and measurement of body weight and height. The average age of dual users was 46.7 years old compared to 43.4 and 52.3 years for smokers and smokeless tobacco users. Prevalence of "smoking only," "smokeless only" and "dual use" of tobacco was 40.6%, 15.2%, and 14.2%, respectively. Among all tobacco users, dual users constituted 20%. These dual users had lower educational achievement, rural residence, lower intake of fruit, and higher intake of alcohol. They were more undernourished as indicated by a thin body mass index compared to nonusers and smokers. Dual users were of socioeconomically deprived as measured by wealth quartiles constructed out of household assets. Dual use of tobacco is common in Bangladesh, and it is intimately linked with socioeconomic deprivation. Poverty reduction strategy and campaigns should address tobacco control not only tobacco in general, but its dual use in particular.


Prevention of type II collagen-induced arthritis by in vivo treatment with anti-L3T4.
The effect of in vivo administration of monoclonal anti-L3T4 antibody on the development of murine collagen-induced arthritis (CIA) was assessed. Treatment with anti-L3T4 resulted in a greater than 90% depletion of L3T4+ T cells in lymph nodes and spleen, an effect that appears entirely reversed 30 d after treatment. Administration of anti-L3T4 before immunization with type II collagen resulted in a significant decrease in arthritis incidence and delayed onset of the disease while treatment begun after a strong anticollagen IgG humoral response was underway was not effective in altering disease expression. These results suggest a prominent role for L3T4+ T cells in the pathogenesis of CIA.


The NLM value set authority center.
The Value Set Authority Center (VSAC) at the National Library of Medicine (NLM) provides downloadable access to all official versions of vocabulary value sets contained in the Clinical Quality Measures (CQMs) used in the certification criteria for electronic health record systems ("Meaningful Use" incentive program). Each value set consists of the numerical values (codes) and human-readable names (descriptions), drawn from standard vocabularies such as LOINC, RxNorm and SNOMED CT®, that are used to define clinical data elements used in clinical quality measures (e.g., patients with diabetes, tricyclic antidepressants). The content of the VSAC will gradually expand to incorporate value sets for other use cases, as well as for new measures and updates to existing measures.


Structure of the DMPC lipid bilayer ripple phase.
High resolution structure is presented for the ripple (Pβ') phase of the phospholipid dimyristoylphosphatidylcholine. Low angle X-ray scattering from oriented samples yielded 57 orders, more than twice as many as recorded previously. The determined electron density map has a sawtooth profile similar to the result from lower resolution data, but the features are sharper allowing better estimates for the modulated bilayer profile and the distribution of headgroups along the aqueous interface. Analysis of high resolution wide angle X-ray data shows that the hydrocarbon chains in the longer, major side of the asymmetric sawtooth are packed similarly to the LβF gel phase, with chains in both monolayers coupled and tilted by 18° in the same direction. The absence of Bragg rods that could be associated with the minor side is consistent with disordered chains, as often suggested in the literature. However, the new high resolution bilayer profile strongly suggests that the chains in the two monolayers in the minor side and the curved region are not in registry. This staggered monolayer modulated melting suggests a direction for improving theories of the ripple phase.


The global north: HIV epidemiology in high-income countries.
The epidemiology of HIV epidemics provides the roadmap for prioritization of programmes and serves over time to evaluate broadly the successes and challenges in prevention. The purpose of this review was to summarize recent information about the epidemiology of HIV in high-income countries with concentrated HIV epidemics. Data from 26 countries were organized and analysed, and a systematic review of published literature relating to epidemiology in these countries was conducted. Our major findings illustrated strong patterns in epidemiology by mode of HIV acquisition: in most high-income countries, new HIV diagnoses attributable to male-female sex have been stable or decreasing, whereas new HIV diagnoses attributable to male-male sex have been stable or increasing. Late diagnoses of HIV infection are common. Prevalence of HIV in high-income countries has risen over the past 5 years as death rates have been stable or decreasing. Reports of the epidemiology of HIV among sex workers and transgendered persons are rare. The epidemiology of HIV in high-income countries in 2013 depicts both the successes and challenges of HIV prevention. The stable to decreasing death rates and stable or declining trends in heterosexual populations are likely attributable, at least in part, to the broader availability of effective treatments for HIV and relatively broad availability of antiretroviral treatment in these countries. However, late diagnoses undermine the individual and public health value of antiretroviral treatment, and epidemics of HIV among MSM remain largely uncontrolled despite broad availability and coverage of treatment.


Examining racial and ethnic disparities and predictors of medication use among California's African-American, Latino, and White children with asthma.
The purpose of this study was to determine the factors that are associated with the use of prescription medication to control asthma in California's African-American, Latino, and White children from 1 to 11 years of age. This was a secondary analysis of parental reports of the use of prescription medication by children with current asthma symptoms (defined as MD diagnosis of asthma). These children were identified from a cross-sectional survey called the California Health Interview Survey (CHIS), 2001. An overall sample of 1,313 children with current asthma was used in the study. It was found that African-American children were 1.85 times (95% CI: 1.82, 1.88) more likely than White children were and 1.87 times (95% CI: 1.86, 1.90) more likely than Latino children to use prescription medication to control their asthma. Multivariate analysis showed an association with severity (mild, moderate, and severe symptoms), two childhood disability factors, and medication use. Asthma severity and disability (defined as affects to social role function) predicts the use of medications for African-American, Latino, and White children with asthma in California.


Consensus and variant cAMP-regulated enhancers have distinct CREB-binding properties.
Recent determination of the cAMP response element-binding protein (CREB) basic leucine zipper (bZIP) consensus CRE crystal structure revealed key dimerization and DNA binding features that are conserved among members of the CREB/CREM/ATF-1 family of transcription factors. Dimerization appeared to be mediated by a Tyr(307)-Glu(312) interhelical hydrogen bond and a Glu(319)-Arg(314) electrostatic interaction. An unexpected hexahydrated Mg(2+) ion was centered above the CRE in the dimer cavity. In the present study, we related these features to CREB dimerization and DNA binding. A Y307F substitution reduced dimer stability and DNA binding affinity, whereas a Y307R mutation produced a stabilizing effect. Mutation of Glu(319) to Ala or Lys attenuated dimerization and DNA binding. Mg(2+) ions enhanced the binding affinity of wild-type CREB to the palindromic CRE by approximately 20-fold but did not do so for divergent CREs. Similarly, mutation of Lys(304), which mediates the CREB interaction with the hydrated Mg(2+), blocked CREB binding to the palindromic but not the variant CRE sequences. The distinct binding characteristics of the K304A mutants to the consensus and variant CRE sequences indicate that CREB binding to these elements is differentially regulated by Mg(2+) ions. We suggest that CREB binds the consensus and variant CRE sequences through fundamentally distinct mechanisms.


Molecular mechanisms of vascular renin-angiotensin system in myointimal hyperplasia.
Angiotensin II has been shown by many investigators to be a potent growth factor for vascular smooth cells in culture as well as in vivo. Depending on the conditions, the response of these cells is either hypertrophy or hyperplasia. These observations have important clinical implications, because it has been shown that angiotensin II participates in the hypertrophic response of the vessel wall during hypertension and the hyperplastic response after balloon angioplasty. Thus, an understanding of the molecular mechanism of these responses is important in the development of potential treatment strategies. This review examines the evidence for the growth-promoting properties of angiotensin II, concentrating on these molecular mechanisms. Hypotheses are presented that may explain the bifunctional effects (hypertrophy versus hyperplasia) of angiotensin II. These hypotheses revolve around the interaction of angiotensin with endothelium- and smooth muscle cell-derived products. These autocrine and paracrine interactions play important roles in the modulation of vascular structure.


A resolution adaptive deep hierarchical (RADHicaL) learning scheme applied to nuclear segmentation of digital pathology images.
Deep learning (DL) has recently been successfully applied to a number of image analysis problems. However, DL approaches tend to be inefficient for segmentation on large image data, such as high-resolution digital pathology slide images. For example, typical breast biopsy images scanned at 40× magnification contain billions of pixels, of which usually only a small percentage belong to the class of interest. For a typical naïve deep learning scheme, parsing through and interrogating all the image pixels would represent hundreds if not thousands of hours of compute time using high performance computing environments. In this paper, we present a resolution adaptive deep hierarchical (RADHicaL) learning scheme wherein DL networks at lower resolutions are leveraged to determine if higher levels of magnification, and thus computation, are necessary to provide precise results. We evaluate our approach on a nuclear segmentation task with a cohort of 141 ER+ breast cancer images and show we can reduce computation time on average by about 85%. Expert annotations of 12,000 nuclei across these 141 images were employed for quantitative evaluation of RADHicaL. A head-to-head comparison with a naïve DL approach, operating solely at the highest magnification, yielded the following performance metrics: .9407 vs .9854 Detection Rate, .8218 vs .8489 F-score, .8061 vs .8364 true positive rate and .8822 vs 0.8932 positive predictive value. Our performance indices compare favourably with state of the art nuclear segmentation approaches for digital pathology images.