Health Literacy Environment of Breast and Cervical Cancer among Black African Women Globally: A Systematic Review Protocol of Mixed Methods.
Adequate health literacy is a necessity to enable effective decision making to seek, access and utilise appropriate health care service. Evidence exists indicating a low level of general health literacy among Black African women, especially those with a refugee background. Breast and cervical are the most common cancers, with Black African women or women with African ethnicity being disproportionately overrepresented. The level of health literacy specific to breast and cervical cancer among Black African women, especially those with a refugee background, has not been reviewed systematically. The present study describes a protocol for a systematic review of the available evidence on the level of health literacy specific to breast and cervical cancer among Black African women globally. We will perform a systematic review of the available quantitative and qualitative studies. The search will include studies that describe the level of health literacy specific to breast and cervical cancer among Black African women. We will conduct a preliminary search on Google scholar to build the concepts for search terms, and a full search strategy using the identified concepts and keywords across four databases namely PubMed, SCOPUS, CINAHL and Web of Sciences. We will use Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) to schematically present the search strategy. We will use the standardized Joanna Briggs Institute quality appraisal and selection tool to recruit studies, and the data extraction tool to synthesise the information extracted from the recruited studies. We will be guided by socioecological theory and Indigenous epistemology to synthesise the non-quantifiable information thematically, and pool the quantitative information using meta-analysis, based on the availability of information.


Circular single-stranded synthetic DNA delivery vectors for microRNA.
Single-stranded (ss) circular oligodeoxynucleotides were previously found to undergo rolling circle transcription (RCT) by phage and bacterial RNA polymerases (RNAPs) into tandemly repetitive RNA multimers. Here, we redesign them to encode minimal primary miRNA mimics, with the long term aim of intracellular transcription followed by RNA processing and maturation via endogenous pathways. We describe an improved method for circularizing ss synthetic DNA for RCT by using a recently described thermostable RNA ligase, which does not require a splint oligonucleotide to juxtapose the ligating ends. In vitro transcription of four templates demonstrates that the secondary structure inherent in miRNA-encoding vectors does not impair their RCT by RNAPs previously shown to carry out RCT. A typical primary-miRNA rolling circle transcript was accurately processed by a human Drosha immunoprecipitate, indicating that if human RNAPs prove to be capable of RCT, the resulting transcripts should enter the endogenous miRNA processing pathway in human cells. Circular oligonucleotides are therefore candidate vectors for small RNA delivery in human cells, which express RNAPs related to those tested here.


Seawater Polluted with Highly Concentrated Polycyclic Aromatic Hydrocarbons Suppresses Osteoblastic Activity in the Scales of Goldfish, Carassius auratus.
We have developed an original in vitro bioassay using teleost scale, that has osteoclasts, osteoblasts, and bone matrix as each marker: alkaline phosphatase (ALP) for osteoblasts and tartrate-resistant acid phosphatase (TRAP) for osteoclasts. Using this scale in vitro bioassay, we examined the effects of seawater polluted with highly concentrated polycyclic aromatic hydrocarbons (PAHs) and nitro-polycyclic aromatic hydrocarbons (NPAHs) on osteoblastic and osteoclastic activities in the present study. Polluted seawater was collected from two sites (the Alexandria site on the Mediterranean Sea and the Suez Canal site on the Red Sea). Total levels of PAHs in the seawater from the Alexandria and Suez Canal sites were 1364.59 and 992.56 ng/l, respectively. We were able to detect NPAHs in both seawater samples. Total levels of NPAHs were detected in the seawater of the Alexandria site (12.749 ng/l) and the Suez Canal site (3.914 ng/l). Each sample of polluted seawater was added to culture medium at dilution rates of 50, 100, and 500, and incubated with the goldfish scales for 6 hrs. Thereafter, ALP and TRAP activities were measured. ALP activity was significantly suppressed by both polluted seawater samples diluted at least 500 times, but TRAP activity did not change. In addition, mRNA expressions of osteoblastic markers (ALP, osteocalcin, and the receptor activator of the NF-κB ligand) decreased significantly, as did the ALP enzyme activity. In fact, ALP activity decreased on treatment with PAHs and NPAHs. We conclude that seawater polluted with highly concentrated PAHs and NPAHs influences bone metabolism in teleosts.


Minimally invasive non-surgical management of plantar fasciitis: A systematic review.
Minimally invasive non-surgical techniques have been widely used worldwide to treat musculoskeletal injuries. Of these techniques, injectable pharmaceutical agents are the most commonly employed treatments, with corticosteroids being the most widely used drugs. The aim of this article is to review current scientific evidence as well as the effectiveness of minimally invasive non-surgical techniques, either alone or combined, for the treatment of plantar fasciitis. This systematic review was conducted from April 2016 until March 2017, in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement and was registered with PROSPERO. Randomized controlled trials (RCTs) of adult patients diagnosed with plantar fasciitis were included as well as intervention studies, with a minimal sample size of 20 subjects per study (10 per group). Assessment of study eligibility was developed by three reviewers independently in an unblinded standardized manner. The physiotherapy evidence database (PEDro) scale was used to analyse the methodological quality of studies. Twenty-nine full-text articles on minimally invasive techniques were reviewed. These articles focused on corticosteroid injections, platelet-rich plasma, Botox, dextrose injections, as well as comparative studies with dry needling vs sham needling. The treatment of plantar fasciitis has dramatically improved in the past decade with minimally invasive techniques becoming increasingly available. Research findings have shown that the long term effects of minimally invasive (non-surgical) treatments such as shock wave therapy, botulinum toxin type-A injections, platelet-rich plasma injections and intratissue percutaneous electrolysis dry needling show similar and sometimes better results when compared to only corticosteroid injections. The latter have been the mainstay of treatment for many years despite their associated side effects both locally and systemically. To date, there is no definitive treatment guideline for plantar fasciitis, however the findings of this literature review may help inform practitioners and clinicians who use invasive methods for the treatment of plantar fasciitis regarding the levels of evidence for the different treatment modalities available.


The organization of the suprachiasmatic circadian pacemaker of the rat and its regulation by neurotransmitters and modulators.
The long-term goal of our research is to understand how cells of the suprachiasmatic nucleus (SCN) are organized to form a 24-hr biological clock, and what roles specific neurotransmitters and modulators play in timekeeping and resetting processes. We have been addressing these questions by assessing the pattern of spontaneous neuronal activity, using extracellular and whole-cell patch recording techniques in long-lived SCN brain slices from rats. We have observed that a robust pacemaker persists in the ventrolateral region of microdissected SCN, and have begun to define the electrophysiological properties of neurons in this region. Furthermore, we are investigating changing sensitivities of the SCN to resetting by exogenous neurotransmitters, such as glutamate, serotonin, and neuropeptide Y, across the circadian cycle. Our findings emphasize the complexity of organization and control of mammalian circadian timing.


Leadership, followership, and evolution: some lessons from the past.
This article analyzes the topic of leadership from an evolutionary perspective and proposes three conclusions that are not part of mainstream theory. First, leading and following are strategies that evolved for solving social coordination problems in ancestral environments, including in particular the problems of group movement, intragroup peacekeeping, and intergroup competition. Second, the relationship between leaders and followers is inherently ambivalent because of the potential for exploitation of followers by leaders. Third, modern organizational structures are sometimes inconsistent with aspects of our evolved leadership psychology, which might explain the alienation and frustration of many citizens and employees. The authors draw several implications of this evolutionary analysis for leadership theory, research, and practice.


Phylogenetic networks: modeling, reconstructibility, and accuracy.
Phylogenetic networks model the evolutionary history of sets of organisms when events such as hybrid speciation and horizontal gene transfer occur. In spite of their widely acknowledged importance in evolutionary biology, phylogenetic networks have so far been studied mostly for specific data sets. We present a general definition of phylogenetic networks in terms of directed acyclic graphs (DAGs) and a set of conditions. Further, we distinguish between model networks and reconstructible ones and characterize the effect of extinction and taxon sampling on the reconstructibility of the network. Simulation studies are a standard technique for assessing the performance of phylogenetic methods. A main step in such studies entails quantifying the topological error between the model and inferred phylogenies. While many measures of tree topological accuracy have been proposed, none exist for phylogenetic networks. Previously, we proposed the first such measure, which applied only to a restricted class of networks. In this paper, we extend that measure to apply to all networks, and prove that it is a metric on the space of phylogenetic networks. Our results allow for the systematic study of existing network methods, and for the design of new accurate ones.


Investigating the transport dynamics of anthocyanins from unprocessed fruit and processed fruit juice from sour cherry (Prunus cerasus L.) across intestinal epithelial cells.
Anthocyanins can contribute to human health through preventing a variety of diseases. The uptake of these compounds from food and the parameters determining uptake efficiency within the human body are still poorly understood. Here we have employed a Caco-2 cell based system to investigate the transport of key antioxidant food components from sour cherry (Prunus cerasus L.) across the intestinal epithelial barrier. Anthocyanins and (-)-epicatechin were supplied in three contrasting matrices: fruit, processed fruit cherry juice, and polyphenolic fractions obtained by solid-phase extraction. Results show that both compound types behave differently. Fruit or juice matrices display comparable transport across the epithelial cell layer. The juice supplements sucrose and citric acid, which are regularly added to processed foods, have a positive effect on stability and transport. Polyphenolic fractions display a lower transport efficiency, relative to that of the fruit or juice, indicating the importance of food matrix components for intestinal absorption of polyphenols.


Differential regulation of monocarboxylate transporter 8 expression in thyroid cancer and hyperthyroidism.
Thyroid hormone (TH) transporters are expressed in thyrocytes and most play a role in TH release. We asked whether expression of the monocarboxylate transporter 8 (MCT8) and the L-type amino acid transporters LAT2 and LAT4 is changed with thyrocyte dedifferentiation and in hyperfunctioning thyroid tissues. Protein expression and localization of transporters was determined by immunohistochemistry in human thyroid specimen including normal thyroid tissue (NT, n = 19), follicular adenoma (FA, n = 44), follicular thyroid carcinoma (FTC, n = 45), papillary thyroid carcinoma (PTC, n = 40), anaplastic thyroid carcinoma (ATC, n = 40) and Graves' disease (GD, n = 50) by calculating the 'hybrid' (H) score. Regulation of transporter expression was investigated in the rat follicular thyroid cell line PCCL3 under basal and thyroid stimulating hormone (TSH) conditions. MCT8 and LAT4 were localized at the plasma membrane, while LAT2 transporter showed cytoplasmic localization. MCT8 expression was downregulated in benign and malignant thyroid tumours as compared to NT. In contrast, significant upregulation of MCT8, LAT2 and LAT4 was found in GD. Furthermore, a stronger expression of MCT8 was demonstrated in PCCL3 cells after TSH stimulation. Downregulation of MCT8 in thyroid cancers qualifies MCT8 as a marker of thyroid differentiation. The more variable expression of LATs in distinct thyroid malignancies may be linked with other transporter properties relevant to altered metabolism in cancer cells, i.e. amino acid transport. Consistent upregulation of MCT8 in GD is in line with increased TH release in hyperthyroidism, an assumption supported by our in vitro results showing TSH-dependent upregulation of MCT8.


Evolutionary trends of the conserved neurocranium shape in angel sharks (Squatiniformes, Elasmobranchii).
Elasmobranchii (i.e., sharks, skates, and rays) forms one of the most diverse groups of marine predators. With a fossil record extending back into the Devonian, several modifications in their body plan illustrate their body shape diversity through time. The angel sharks, whose fossil record dates back to the Late Jurassic, some 160 Ma, have a dorsoventrally flattened body, similar to skates and rays. Fossil skeletons of this group show that the overall morphology was well established earlier in its history. By examining the skull shape of well-preserved fossil material compared to extant angel sharks using geometric morphometric methods, within a phylogenetic framework, we were able to determine the conservative skull shape among angel sharks with a high degree of integration. The morphospace occupation of extant angel sharks is rather restricted, with extensive overlap. Most of the differences in skull shape are related to their geographic distribution patterns. We found higher levels of disparity in extinct forms, but lower ones in extant species. Since angel sharks display a highly specialized prey capture behaviour, we suggest that the morphological integration and biogeographic processes are the main drivers of their diversity, which might limit their capacity to display higher disparities since their origin.


A Systematic Review and Critical Appraisal of Economic Evaluations of Pharmacological Interventions for People with Bipolar Disorder.
Bipolar disorder (BD) is a chronic mood disorder that causes substantial psychological and financial burden. Various pharmacological treatments are effective in the management and prevention of acute episodes of BD. In an era of tighter healthcare budgets and a need for more efficient use of resources, several economic evaluations have evaluated the cost effectiveness of treatments for BD. The aim of this study was to systematically review and appraise published economic evaluations of pharmacological interventions for BD. A systematic search combining search terms specific to BD with a health economics search filter was conducted on six bibliographic databases (EMBASE, MEDLINE, PsycINFO, HTA, NHS EED, CENTRAL) in order to identify trial- or model-based full economic evaluations of pharmacological treatments of any phase of the disorder that were published between 1 January 1990 and 18 December 2015. Studies that met the inclusion criteria were critically appraised using the Quality of Health Economic Studies (QHES) checklist, and synthesised in a narrative way. The review included 19 economic studies, which varied with regard to the type and number of interventions assessed, the study design, the phase of treatment (acute or maintenance), the source of efficacy data and the method for evidence synthesis, the outcome measures, the time horizon and the countries/settings in which the studies were conducted. The study quality was variable but the majority of studies were of high or fair quality. Pharmacological interventions are cost effective, compared with no treatment, in the management of BD, both in the acute and maintenance phases. However, it is difficult to draw safe conclusions on the relative cost effectiveness between drugs due to differences across studies and limitations characterising many of them. Future economic evaluations need to consider the whole range of treatment options available for the management of BD and adopt appropriate methods for evidence synthesis and economic modelling, to explore more robustly the relative cost effectiveness of pharmacological interventions for people with BD.


Fibroblast growth factor receptor-1 is expressed by endothelial progenitor cells.
Recent experiments show that hematopoietic progenitor cell populations contain endothelial precursor cells. We have isolated a population of CD34(+) cells that expresses fibroblast growth factor receptor-1 (FGFR-1) and that differentiates into endothelial cells in vitro. We find that 4.5% +/- 2.1% of CD34(+) cells isolated from bone marrow, cord blood, and mobilized peripheral blood express FGFR-1 and that viable CD34(+)FGFR(+) cells are small, with little granularity, and express both primitive hematopoietic and endothelial markers on their surface. The primitive hematopoietic markers AC133, c-kit, and Thy-1 are coexpressed by 75%, 85%, and 64% of CD34(+)FGFR(+) cells, respectively. Most of the CD34(+)FGFR(+) cells also express antigens found on endothelial cells, such as CD31, vascular endothelial growth factor receptor-2, and the endothelial-specific cell surface marker, vascular endothelial cadherin (VE-cadherin), whereas 56% to 60% of the cells express Tie, Tek, and the endothelial-specific marker, P1H12. The CD34(+)FGFR(+) population is enriched in cells expressing endothelial-specific antigens compared with the CD34(+) population. Isolated CD34(+)FGFR(+) cells grow slowly in culture, are stimulated by fibroblast growth factor-2 and vascular endothelial growth factor, and give rise to cells that express von Willebrand factor and VE-cadherin and that incorporate acetylated low-density lipoprotein. These experiments show that FGFR-1 is expressed by a subpopulation of CD34(+) cells that give rise to endothelial cells in vitro, indicating that this population contains endothelial stem/progenitor cells.


Cryomicroscopy provides structural snapshots of influenza virus membrane fusion.
The lipid-enveloped influenza virus enters host cells during infection by binding cell-surface receptors and, after receptor-mediated endocytosis, fusing with the membrane of the endosome and delivering the viral genome and transcription machinery into the host cell. These events are mediated by the hemagglutinin (HA) surface glycoprotein. At the low pH of the endosome, an irreversible conformational change in the HA, including the exposure of the hydrophobic fusion peptide, activates membrane fusion. Here we used electron cryomicroscopy and cryotomography to image the fusion of influenza virus with target membranes at low pH. We visualized structural intermediates of HA and their interactions with membranes during the course of membrane fusion as well as ultrastructural changes in the virus that accompany membrane fusion. Our observations are relevant to a wide range of protein-mediated membrane-fusion processes and demonstrate how dynamic membrane events may be studied by cryomicroscopy.


Plasma asymmetric dimethylarginine and incidence of cardiovascular disease and death in the community.
Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, induces endothelial dysfunction. Although elevated ADMA has been associated with an increased risk of cardiovascular disease events and death in referral samples, the prognostic significance of ADMA in the community has not been adequately evaluated. We related plasma ADMA, l-arginine (Arg), and the ratio of Arg to ADMA to the incidence of cardiovascular disease (fatal or nonfatal myocardial infarction, coronary insufficiency, angina pectoris, stroke or transient ischemic attack, intermittent claudication, or heart failure) and death in 3320 Framingham Offspring Study participants (1769 women; mean age, 59 years). Over a follow-up period of 10.9 years, 281 individuals of 2956 free of cardiovascular disease at baseline developed incident cardiovascular disease, and 285 participants died. In multivariable models adjusting for established risk factors and other biomarkers (B-type natriuretic peptide, renin, homocysteine, urine albumin excretion, and C-reactive protein), ADMA and the ratio of Arg to ADMA were significantly associated with all-cause mortality (adjusted-hazard ratio [HR] per 1-SD increment, 1.21; 95% CI, 1.07 to 1.37; and HR per 1-SD increment, 0.80; 95% CI, 0.69 to 0.93, respectively), whereas Arg was not (HR per 1-SD increment, 0.89; 95% CI, 0.77 to 1.02). We noted effect modification by diabetes status; ADMA was associated with death in individuals without diabetes (adjusted HR per 1-SD increment, 1.30; 95% CI, 1.13 to 1.50) but not in individuals with diabetes (adjusted HR per 1-SD increment, 0.85; 95% CI, 0.62 to 1.16). ADMA, Arg, and the ratio of Arg to ADMA were not associated with cardiovascular disease incidence (P>0.10). In our large community-based sample, ADMA was significantly associated with all-cause mortality, particularly in nondiabetic individuals.


An optical-fiber-scale electro-optic probe for minimally invasive high-frequency field sensing.
A sub-millimeter-dimension electro-optic probe that provides enhanced scanning accessibility with significantly less intrusiveness than metal-based or even other dielectric probes during electromagnetic characterization of microwave devices is presented. The quantitative and qualitative relative invasiveness of the probe on the operation of an example antenna device-under-test is explored with respect to previously demonstrated fiber and wafer electro-optic sensors. We also demonstrate that the miniaturized probe, with a diameter of 125 microm, can be used to reconstruct the three orthogonal vector components of near-electric fields without the need for different probe crystals or multiple calibration procedures. Finally, the advantages of the reduced size and invasiveness of the new micro-scale probe are demonstrated through the enhanced resolution of detailed images extracted from planar antennas, as well as the capability of reaching into circuit locations heretofore inaccessible.


Spatial patterns of gluten protein and polymer distribution in wheat grain.
The starchy endosperm is the major storage tissue in the mature wheat grain and exhibits quantitative and qualitative gradients in composition, with the outermost cell layers being rich in protein, mainly gliadins, and the inner cells being low in protein but enriched in high-molecular-weight (HMW) subunits of glutenin. We have used sequential pearling to produce flour fractions enriched in particular cell layers to determine the protein gradients in four different cultivars grown at two nitrogen levels. The results show that the steepness of the protein gradient is determined by both genetic and nutritional factors, with three high-protein breadmaking cultivars being more responsive to the N treatment than a low-protein cultivar suitable for livestock feed. Nitrogen also affected the relative abundances of the three main classes of wheat prolamins: the sulfur-poor ω-gliadins showed the greatest response to nitrogen and increased evenly across the grain; the HMW subunits also increased in response to nitrogen but proportionally more in the outer layers of the starchy endosperm than near the core, while the sulfur-rich prolamins showed the opposite trend.


A generic cell surface ligand system for studying cell-cell recognition.
Dose-response experiments are a mainstay of receptor biology studies and can reveal valuable insights into receptor function. Such studies of receptors that bind cell surface ligands are currently limited by the difficulty in manipulating the surface density of ligands at a cell-cell interface. Here, we describe a generic cell surface ligand system that allows precise manipulation of cell surface ligand densities over several orders of magnitude. These densities are robustly quantifiable, a major advance over previous studies. We validate the system for a range of immunoreceptors, including the T-cell receptor (TCR), and show that this generic ligand stimulates via the TCR at a similar surface density as its native ligand. We also extend our work to the activation of chimeric antigen receptors. This novel system allows the effect of varying the surface density, valency, dimensions, and affinity of the ligand to be investigated. It can be readily broadened to other receptor-cell surface ligand interactions and will facilitate investigation into the activation of, and signal integration between, cell surface receptors.


Interactions between Activation and Repolarization Restitution Properties in the Intact Human Heart: In-Vivo Whole-Heart Data and Mathematical Description.
The restitution of the action potential duration (APDR) and conduction velocity (CVR) are mechanisms whereby cardiac excitation and repolarization adapt to changes in heart rate. They modulate the vulnerability to dangerous arrhythmia, but the mechanistic link between restitution and arrhythmogenesis remains only partially understood. This paper provides an experimental and theoretical study of repolarization and excitation restitution properties and their interactions in the intact human epicardium. The interdependence between excitation and repolarization dynamic is studied in 8 patients (14 restitution protocols, 1722 restitution curves) undergoing global epicardial mapping with multi-electrode socks before open heart surgery. A mathematical description of the contribution of both repolarization and conduction dynamics to the steepness of the APDR slope is proposed. This study demonstrates that the APDR slope is a function of both activation and repolarization dynamics. At short cycle length, conduction delay significantly increases the APDR slope by interacting with the diastolic interval. As predicted by the proposed mathematical formulation, the APDR slope was more sensitive to activation time prolongation than to the simultaneous shortening of repolarization time. A steep APDR slope was frequently identified, with 61% of all cardiac sites exhibiting an APDR slope > 1, suggesting that a slope > 1 may not necessarily promote electrical instability in the human epicardium. APDR slope did not change for different activation or repolarization times, and it was not a function of local baseline APD. However, it was affected by the spatial organization of electrical excitation, suggesting that in tissue APDR is not a unique function of local electrophysiological properties. Spatial heterogeneity in both activation and repolarization restitution contributed to the increase in the modulated dispersion of repolarization, which for short cycle length was as high as 250 ms. Heterogeneity in conduction velocity restitution can translate into both activation and repolarization dispersion and increase cardiac instability. The proposed mathematical formulation shows an excellent agreement with the experimental data (correlation coefficient r = 0.94) and provides a useful tool for the understanding of the complex interactions between activation and repolarization restitution properties as well as between their measurements.


Ischemia, Immunosuppression and Infection--Tackling the Predicaments of Post-Stroke Complications.
The incidence of stroke has risen over the past decade and will continue to be one of the leading causes of death and disability worldwide. While a large portion of immediate death following stroke is due to cerebral infarction and neurological complications, the most common medical complication in stroke patients is infection. In fact, infections, such as pneumonia and urinary tract infections, greatly worsen the clinical outcome of stroke patients. Recent evidence suggests that the disrupted interplay between the central nervous system and immune system contributes to the development of infection after stroke. The suppression of systemic immunity by the nervous system is thought to protect the brain from further inflammatory insult, yet this comes at the cost of increased susceptibility to infection after stroke. To improve patient outcome, there have been attempts to lessen the stroke-associated bacterial burden through the prophylactic use of broad-spectrum antibiotics. However, preventative antibiotic treatments have been unsuccessful, and therefore have been discouraged. Additionally, with the ever-rising obstacle of antibiotic-resistance, future therapeutic options to reverse immune impairment after stroke by augmentation of host immunity may be a viable alternative option. However, cautionary steps are required to ensure that collateral ischemic damage caused by cerebral inflammation remains minimal.


Splicing, cis genetic variation and disease.
Splicing is a post-transcriptional modification of RNA during which introns are removed and exons are joined. Most of the mammalian genes undergo constitutive and alternative splicing events. In addition to the strong signals of the splice sites, splicing is influenced at a distance by a range of trans factors that interact with cis regulatory elements and influence the spliceosome. The intention of the present mini-review is to give some insights into the complexity of this interaction and to introduce the consequences of some kinds of detrimental genetic variation on alternative splicing and disease.


Novel insights into seed fatty acid synthesis and modification pathways from genetic diversity and quantitative trait Loci analysis of the Brassica C genome.
Natural genetic variation in fatty acid synthesis and modification pathways determine the composition of vegetable oils, which are major components of human diet and renewable products. Based on known pathways we combined diversity and genetic analysis of metabolites to infer the existence of enzymes encoded by distinct loci, and associated these with specific elongation steps or subpathways. A total of 107 lines representing different Brassica genepools revealed considerable variation for 18 seed fatty acid products. The effect of genetic variation within a single biochemical step on subsequent products was demonstrated using a correlation matrix of scatterplots, and by calculating relative step yields. Surprisingly, diploid Brassica oleracea segregating populations had a similar range of variation for individual fatty acids as across the whole genepool. This allowed identification of 22 quantitative trait loci (QTL) associated with activity in the plastid, early stages of synthesis, desaturation, and elongases. Four QTL were assigned to early stages of synthesis, seven to subpathway specific or general elongase activity, one to ketoacyl acyl-carrier protein synthetase, and two each to fatty acid desaturase and either desaturase or fatty acyl-carrier protein thioesterase. An additional 10 QTL had distinct effects but were not assigned specific functions. Where contrasting behavior in more than one subpathway was detected, we inferred QTL specificity for particular combinations of substrate and product. The assignment of enzyme function to QTL was consistent with the known position of some Brassicaeae candidate genes and collinear regions of the Arabidopsis (Arabidopsis thaliana) genome.


Trade-offs between Error Exponents and Excess-Rate Exponents of Typical Slepian-Wolf Codes.
Typical random codes (TRCs) in a communication scenario of source coding with side information in the decoder is the main subject of this work. We study the semi-deterministic code ensemble, which is a certain variant of the ordinary random binning code ensemble. In this code ensemble, the relatively small type classes of the source are deterministically partitioned into the available bins in a one-to-one manner. As a consequence, the error probability decreases dramatically. The random binning error exponent and the error exponent of the TRCs are derived and proved to be equal to one another in a few important special cases. We show that the performance under optimal decoding can be attained also by certain universal decoders, e.g., the stochastic likelihood decoder with an empirical entropy metric. Moreover, we discuss the trade-offs between the error exponent and the excess-rate exponent for the typical random semi-deterministic code and characterize its optimal rate function. We show that for any pair of correlated information sources, both error and excess-rate probabilities exponential vanish when the blocklength tends to infinity.


Identifying typologies of diurnal patterns in desk-based workers' sedentary time.
The purpose of this study was to identify typologies of diurnal sedentary behavior patterns and sociodemographic characteristics of desk-based workers. The sedentary time of 229 desk-based workers was measured using accelerometer devices. The within individual diurnal variations in sedentary time was calculated for both workdays and non-workdays. Diurnal variations in sedentary time during each time period (morning, afternoon, and evening) was calculated as the percentage of sedentary time during each time period divided by the percentage of the total sedentary time. A hierarchical cluster analysis (Ward's method) was used to identify the optimal number of clusters. To refine the initial clusters, a non-hierarchical cluster analysis (k-means method) was performed. Four clusters were identified: stable sedentary cluster (46.7%), off-morning break cluster (26.6%), off-afternoon break cluster (8.3%), and evening sedentary cluster (18.3%). The stable sedentary cluster had the lowest variations in sedentary time throughout the day and the highest amount of total sedentary time. Participants in the off-morning and off-afternoon break clusters had nearly the same sedentary patterns but took short-term breaks during non-workday mornings or afternoons. The evening sedentary cluster had a completely different pattern, with a longer sedentary time during the evening both on workdays and non-workdays. Sociodemographic attributes such as sex, household income, educational attainment, employment status, sleep duration, and residential area, differed significantly between groups. Initiatives to address desk-based workers' sedentary behavior need to focus not only on the workplace but also on the appropriate timing for reducing excessive sedentary time in non-work contexts depending on the characteristics and diurnal patterns of target subgroups.


Animal welfare and the harp seal hunt in Atlantic Canada.
Much attention has been given over the years to animal welfare issues surrounding the seal hunt in Atlantic Canada. However, very little information is available on this subject in the scientific literature. This article reports the results of observations made by representatives of the Canadian Veterinary Medical Association at the hunt in recent years and compares them with observations made by members of the International Fund for Animal Welfare. The conclusion is that the large majority of seals taken during this hunt (at best, 98% in work reported here) are killed in an acceptably humane manner. However, the small proportion of animals that are not killed effectively justifies continued attention to this hunt on the part of the veterinary profession.


Fate of tetanus toxin bound to the surface of primary neurons in culture: evidence for rapid internalization.
We examined the nature of the tetanus toxin receptor in primary cultures of mouse spinal cord by ligand blotting techniques. Membrane components were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred to nitrocellulose sheets, which were overlaid with 125I-labeled tetanus toxin. The toxin bound only to material at or near the dye front, which was lost when the cells were delipidated before electrophoresis. Gangliosides purified from the lipid extract were separated by thin-layer chromatography and the chromatogram was overlaid with 125I-toxin. The toxin bound to gangliosides corresponding to GD1b and GT1b. Similar results were obtained with brain membranes; thus, gangliosides rather than glycoproteins appear to be the toxin receptors both in vivo and in neuronal cell cultures. To follow the fate of tetanus toxin bound to cultured neurons, we developed an assay to measure cell-surface and internalized toxin. Cells were incubated with tetanus toxin at 0 degree C, washed, and sequentially exposed to antitoxin and 125I-labeled protein A. Using this assay, we found that much of the toxin initially bound to cell surface disappeared rapidly when the temperature was raised to 37 degrees C but not when the cells were kept at 0 degree C. Some of the toxin was internalized and could only be detected by our treating the cells with Triton X-100 before adding anti-toxin. Experiments with 125I-tetanus toxin showed that a substantial amount of the toxin bound at 0 degree C dissociated into the medium upon warming of the cells. Using immunofluorescence, we confirmed that some of the bound toxin was internalized within 15 min and accumulated in discrete structures. These structures did not appear to be lysosomes, as the cell-associated toxin had a long half-life and 90% of the radioactivity released into the medium was precipitated by trichloroacetic acid. The rapid internalization of tetanus toxin into a subcellular compartment where it escapes degradation may be important for its mechanism of action.


Encephalitis due to Mycobacterium tuberculosis in France.
Two hundred and fifty-three patients were included in a study on the etiology of encephalitis, carried out in France in 2007. Tuberculosis was the second most frequently identified cause, after HSV and with the same number of cases as VZV. The authors report the specific features of patients presenting with tuberculosis encephalitis (TE). TE patients were defined as patients presenting with encephalitis, with positive culture or PCR for Mycobacterium tuberculosis, or the association of clinical, biological, imaging, and epidemiological evidence (possible cases). Clinical, microbiological, and brain imaging data was analyzed and compared to that of other included patients. Twenty cases of TE were identified. The M/F sex-ratio was 1.5, the mean age 53 years. Four (20%) patients had a history of tuberculosis before the encephalitis. The median delay between the onset of general and neurological symptoms was significantly longer for tuberculosis cases than for others (10 days vs. 2; P<10(-10)). The median CSF protein level was significantly higher for tuberculosis cases (2.1 g/L vs. 0.8 g/L, P=0.002). CT scan and MRI were normal on admission for eight patients out of 17. Fourteen isolated strains of M. tuberculosis were susceptible to first-line anti-tuberculosis drugs and one was rifampicin-resistant. Six (33%) patients died during hospitalization and two were lost to follow-up. Ten out of 12 (78.6%) had persisting neurological symptoms on discharge. Despite non-multiresistant MT strains, the case fatality rate among TE patients was high in our series. Early brain imaging is poor contributive for the diagnosis of TE.


In vivo delivery of silica nanorattle encapsulated docetaxel for liver cancer therapy with low toxicity and high efficacy.
Mesoporous silica nanomaterial is one of the most promising candidates as drug carrier for cancer therapy. Herein, in vitro and in vivo study of silica nanorattle (SN) with mesoporous and rattle-type structure as a drug delivery system was first reported. Hydrophobic antitumor drug docetaxel (Dtxl) was loaded into the PEGylated silica nanorattle (SN-PEG) with a diameter of 125 nm via electrostatic absorption. In human liver cancer cell Hep-G2, the half-maximum inhibiting concentration (IC(50)) of silica nanorattle encapsulated docetaxel (SN-PEG-Dtxl) was only 7% of that of free Dtxl at 72 h. In vivo toxicity assessment showed that both nanocarrier of silica nanorattle (40 mg/kg, single dose) and SN-PEG-Dtxl (20 mg/kg of Dtxl, three doses) had low systematic toxicity in healthy ICR mice. The SN-PEG-Dtxl (20 mg/kg, intravenously) showed greater antitumor activity with about 15% enhanced tumor inhibition rate compared with Taxotere on the marine hepatocarcinoma 22 subcutaneous model. The results prove that the SN-PEG-Dtxl has low toxicity and high therapy efficacy, which provides convincing evidence for the silica nanorattle as a promising candidate for a drug delivery system.


Enhanced charge transport and photovoltaic performance of PBDTTT-C-T/PC70BM solar cells via UV-ozone treatment.
In this work, the electron transport layer of PBDTTT-C-T/PC70BM polymer solar cells were subjected to UV-ozone treatment, leading to improved cell performances from 6.46% to 8.34%. The solar cell efficiency reached a maximum of 8.34% after an optimal 5 minute UV-ozone treatment, and then decreased if treated for a longer time. To the best of our knowledge, the mechanism behind the effects of UV-ozone treatment on the improvement of charge transport and cell performance is not fully understood. We have developed a fundamental understanding of the UV-ozone treatment mechanism, which explains both the enhancements in charge transport and photovoltaic performance at an optimal treatment time, and also the phenomenon whereby further treatment time leads to a drop in cell efficiency. Transient photocurrent measurements indicated that the cell charge transport times were 1370 ns, 770 ns, 832 ns, 867 ns, and 1150 ns for the 0 min, 5 min, 10 min, 15 min, and 20 min UV-ozone treatment times, respectively. Therefore the 5 min UV-ozone treatment time led to the shortest transport time and the most efficient charge transport in the cells. The 5 min UV-ozone treated sample exhibited the highest peak intensity (E2) in the Raman spectra of the treated films, at about 437 cm(-1), indicating that it possessed the best wurtzite phase crystallinity of the ZnO films. Further increasing the UV-ozone treatment time from 5 to 20 min induced the formation of p-type defects (e.g. interstitial oxygen atoms), pushing the ZnO Fermi-level further away from the vacuum level, and decreasing the wurtzite crystallinity.


Violence and women's mental health: the impact of physical, sexual, and psychological aggression.
The reach of violence against women (VAW) has been profoundly felt by women across the United States and around the globe. VAW has been documented for decades as a legal and social justice problem, but as illuminated in this review, it is also a substantial mental health concern. A full understanding of the phenomenon must include discussion of how often it occurs, in what forms, and to whom. This review defines violence against women in its variant forms and examines the literature on the mental health effects associated with these abuse experiences. The effectiveness of the mental health system's response to the complex needs of women suffering battering, rape, stalking, and psychological aggression is also examined. The future of research and the important role of the discipline of psychology in the future of this field of study are discussed.


Interleukin-26 Production in Human Primary Bronchial Epithelial Cells in Response to Viral Stimulation: Modulation by Th17 cytokines.
Interleukin (IL)-26 is abundant in human airways and this cytokine is involved in the local immune response to a bacterial stimulus in vivo. Specifically, local exposure to the toll-like receptor (TLR) 4 agonist endotoxin does increase IL-26 in human airways and this cytokine potentiates chemotactic responses in human neutrophils. In addition to T-helper (Th) 17 cells, alveolar macrophages can produce IL-26, but it remains unknown whether this cytokine can also be produced in the airway mucosa per se in response to a viral stimulus. Here, we evaluated whether this is the case using primary bronchial epithelial cells from the airway epithelium in vitro, and exploring the signaling mechanisms involved, including the modulatory effects of additional Th17 cytokines. Finally, we assessed IL-26 and its archetype signaling responses in healthy human airways in vivo. We found increased transcription and release of IL-26 protein after stimulation with the viral-related double stranded (ds) RNA polyinosinic-polycytidylic acid (poly-IC) and showed that this IL-26 release involved mitogen-activated protein (MAP) kinases and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). The release of IL-26 in response to a viral stimulus was modulated by additional Th17 cytokines. Moreover, there was transcription of IL26 mRNA and expression of the protein in epithelial cells of bronchial brush and tissue biopsies respectively after harvest in vivo. In addition, the extracellular IL-26 protein concentrations in bronchoalveolar lavage (BAL) samples did correlate with increased epithelial cell transcription of an archetype intracellular signaling molecule downstream of the IL-26-receptor complex, STAT1, in the bronchial brush biopsies. Thus, our study suggests that viral stimulation causes the production of IL-26 in lining epithelial cells of human airway structural cells that constitute a critical immune barrier and that this production is modulated by Th17 cytokines.


Comparison of dot chromosome sequences from D. melanogaster and D. virilis reveals an enrichment of DNA transposon sequences in heterochromatic domains.
Chromosome four of Drosophila melanogaster, known as the dot chromosome, is largely heterochromatic, as shown by immunofluorescent staining with antibodies to heterochromatin protein 1 (HP1) and histone H3K9me. In contrast, the absence of HP1 and H3K9me from the dot chromosome in D. virilis suggests that this region is euchromatic. D. virilis diverged from D. melanogaster 40 to 60 million years ago. Here we describe finished sequencing and analysis of 11 fosmids hybridizing to the dot chromosome of D. virilis (372,650 base-pairs) and seven fosmids from major euchromatic chromosome arms (273,110 base-pairs). Most genes from the dot chromosome of D. melanogaster remain on the dot chromosome in D. virilis, but many inversions have occurred. The dot chromosomes of both species are similar to the major chromosome arms in gene density and coding density, but the dot chromosome genes of both species have larger introns. The D. virilis dot chromosome fosmids have a high repeat density (22.8%), similar to homologous regions of D. melanogaster (26.5%). There are, however, major differences in the representation of repetitive elements. Remnants of DNA transposons make up only 6.3% of the D. virilis dot chromosome fosmids, but 18.4% of the homologous regions from D. melanogaster; DINE-1 and 1360 elements are particularly enriched in D. melanogaster. Euchromatic domains on the major chromosomes in both species have very few DNA transposons (less than 0.4 %). Combining these results with recent findings about RNAi, we suggest that specific repetitive elements, as well as density, play a role in determining higher-order chromatin packaging.


Implementation of a Cross-Layer Sensing Medium-Access Control Scheme.
In this paper, compressed sensing (CS) theory is utilized in a medium-access control (MAC) scheme for wireless sensor networks (WSNs). We propose a new, cross-layer compressed sensing medium-access control (CL CS-MAC) scheme, combining the physical layer and data link layer, where the wireless transmission in physical layer is considered as a compress process of requested packets in a data link layer according to compressed sensing (CS) theory. We first introduced using compressive complex requests to identify the exact active sensor nodes, which makes the scheme more efficient. Moreover, because the reconstruction process is executed in a complex field of a physical layer, where no bit and frame synchronizations are needed, the asynchronous and random requests scheme can be implemented without synchronization payload. We set up a testbed based on software-defined radio (SDR) to implement the proposed CL CS-MAC scheme practically and to demonstrate the validation. For large-scale WSNs, the simulation results show that the proposed CL CS-MAC scheme provides higher throughput and robustness than the carrier sense multiple access (CSMA) and compressed sensing medium-access control (CS-MAC) schemes.


A solid-state colorimetric fluorescence Pb2+-sensing scheme: mechanically-driven CsPbBr3 nanocrystallization in glass.
Highly toxic Pb2+ poses a great threat to the health of human beings and ecosystems, urgently calling for an efficient Pb2+ detection method. Herein, we demonstrated a brand-new solid-state fluorescence Pb2+-sensing scheme based on a type of Pb2+-responsive borate glass powder that is able to precipitate CsPbBr3 nanocrystals on the glass surface upon grinding with Pb2+ sources, following a mechanically driven glass crystallization mechanism. Pb2+ sensing is achieved via the Pb2+ concentration-dependent green emission of CsPbBr3 as an indicator signal and independent red emission of Eu3+ as a reference signal. Under UV light irradiation, the obvious emissive color variation from red to green as Pb2+ concentration varies enables the intuitive Pb2+-sensing by naked eyes. With the aid of a spectrometer and smartphone, Pb2+ concentration can be quantitatively determined with the detection limit as low as ∼70 ppm and ∼400 ppm, respectively. The semi-quantitative Pb2+ detection is also possible by comparing the emissive color with the calibrated color card. Hopefully, the proposed solid-state fluorescence Pb2+-sensing strategy with high selectivity can be used for portable and quick Pb2+ analysis in daily life.


Probing the Rhipicephalusbursa Sialomes in Potential Anti-Tick Vaccine Candidates: A Reverse Vaccinology Approach.
In the wake of the 'omics' explosion of data, reverse vaccinology approaches are being applied more readily as an alternative for the discovery of candidates for next generation diagnostics and vaccines. Promising protective antigens for the control of ticks and tick-borne diseases can be discovered by mining available omics data for immunogenic epitopes. The present study aims to explore the previously obtained Rhipicephalus bursa sialotranscriptome during both feeding and Babesia infection, to select antigenic targets that are either membrane-associated or a secreted protein, as well as unique to the ectoparasite and not present in the mammalian host. Further, they should be capable of stimulating T and B cells for a potential robust immune response, and be non-allergenic or toxic to the host. From the R. bursa transcriptome, 5706 and 3025 proteins were identified as belonging to the surfaceome and secretome, respectively. Following a reverse genetics immunoinformatics pipeline, nine preferred candidates, consisting of one transmembrane-related and eight secreted proteins, were identified. These candidates showed a higher predicted antigenicity than the Bm86 antigen, with no homology to mammalian hosts and exposed regions. Only four were functionally annotated and selected for further in silico analysis, which examined their protein structure, surface accessibility, flexibility, hydrophobicity, and putative linear B and T-cell epitopes. Regions with overlapping coincident epitopes groups (CEGs) were evaluated to select peptides that were further analyzed for their physicochemical characteristics, potential allergenicity, toxicity, solubility, and potential propensity for crystallization. Following these procedures, a set of three peptides from the three R. bursa proteins were selected. In silico results indicate that the designed epitopes could stimulate a protective and long-lasting immune response against those tick proteins, reflecting its potential as anti-tick vaccines. The immunogenicity of these peptides was evaluated in a pilot immunization study followed by tick feeding to evaluate its impact on tick behavior and pathogen transmission. Combining in silico methods with in vivo immunogenicity evaluation enabled the screening of vaccine candidates prior to expensive infestation studies on the definitive ovine host animals.


Improved production of cytotoxic thailanstatins A and D through metabolic engineering of Burkholderia thailandensis MSMB43 and pilot scale fermentation.
Thailanstatin A (TST-A) is a potent antiproliferative natural product discovered by our group from Burkholderia thailandensis MSMB43 through a genome-guided approach. The limited supply of TST-A, due to its low titer in bacterial fermentation, modest stability and very low recovery rate during purification, has hindered the investigations of TST-A as an anticancer drug candidate. Here we report the significant yield improvement of TST-A and its direct precursor, thailanstatin D (TST-D), through metabolic engineering of the thailanstatin biosynthetic pathway in MSMB43. Deletion of tstP, which encodes a dioxygenase involved in converting TST-A to downstream products including FR901464 (FR), resulted in 58% increase of the TST-A titer to 144.7 ± 2.3 mg/L and 132% increase of the TST-D titer to 14.6 ± 0.5 mg/L in the fermentation broth, respectively. Deletion of tstR, which encodes a cytochrome P450 involved in converting TST-D to TST-A, resulted in more than 7-fold increase of the TST-D titer to 53.2 ± 12.1 mg/L in the fermentation broth. An execution of 90 L pilot-scale fed-batch fermentation of the tstP deletion mutant in a 120-L fermentor led to the preparation of 714 mg of TST-A with greater than 98.5% purity. The half-life of TST-D in a phosphate buffer was found to be at least 202 h, significantly longer than that of TST-A or FR, suggesting superior stability. However, the IC50 values of TST-D against representative human cancer cell lines were determined to be greater than those of TST-A, indicating weaker antiproliferative activity. This work enabled us to prepare sufficient quantities of TST-A and TST-D for our ongoing translational research.


Diruthenium(ii,iii) metallodrugs of ibuprofen and naproxen encapsulated in intravenously injectable polymer-lipid nanoparticles exhibit enhanced activity against breast and prostate cancer cells.
A unique class of diruthenium(ii,iii) metallodrugs containing non-steroidal anti-inflammatory drug (NSAID), Ru2(NSAID), have been reported to show anticancer activity in glioma models in vitro and in vivo. This work reports the encapsulation of the lead metallodrug of ibuprofen (HIbp), [Ru2(Ibp)4Cl] or RuIbp, and also of the new analogue of naproxen (HNpx), [Ru2(Npx)4Cl] or RuNpx, in novel intravenously (i.v.) injectable solid polymer-lipid nanoparticles (SPLNs). A rationally selected composition of lipids/polymers rendered nearly spherical Ru2(NSAID)-SPLNs with a mean size of 120 nm and zeta potential of about -20 mV. The Ru2(NSAID)-SPLNs are characterized by spectroscopic techniques and the composition in terms of ruthenium-drug species is analyzed by mass spectrometry. The metallodrug-loaded nanoparticles showed high drug loading (17-18%) with ∼100% drug loading efficiency, and good colloidal stability in serum at body temperature. Fluorescence-labeled SPLNs were taken up by the cancer cells in a time- and energy-dependent manner as analyzed by confocal microscopy and fluorescence spectrometry. The Ru2(NSAID)-SPLNs showed enhanced cytotoxicity (IC50 at 60-100 μmol L-1 ) in relation to the corresponding Ru2(NSAID) metallodrugs in breast (EMT6 and MDA-MB-231) and prostate (DU145) cancer cells in vitro. The cell viability of both metallodrug nanoformulations is also compared with those of the parent NSAIDs, HIbp and HNpx, and their corresponding NSAID-SPLNs. In vivo and ex vivo fluorescence imaging revealed good biodistribution and high tumor accumulation of fluorescence-labeled SPLNs following i.v. injection in an orthotopic breast tumor model. The enhanced anticancer activity of the metallodrug-loaded SPLNs in these cell lines can be associated with the advantages of the nanoformulations, assigned mainly to the stability of the colloidal nanoparticles suitable for i.v. injection and enhanced cellular uptake. The findings of this work encourage future in vivo efficacy studies to further exploit the potential of the novel Ru2(NSAID)-SPLN nanoformulations for clinical application.


Nanoantenna coupled UV subwavelength photodetectors based on GaN.
The integration of nano structures with opto-electronic devices has many potential applications. It allows the coupling of more light into or out of the device while decreasing the size of the device itself. Such devices are reported in the VIS and NIR regions. However, making plasmonic structures for the UV region is still a challenge. Here, we report on a UV nano-antenna integrated metal semiconductor metal (MSM) photodetector based on GaN. We designed and fabricated Al grating structures. Well defined plasmonic resonances were measured in the reflectance spectra. Optimized grating structure integrated photodetectors exhibited more than sevenfold photocurrent enhancement. Finite difference time domain simulations revealed that both geometrical and plasmonic effects played role in photocurrent enhancement.


Diagnosis and treatment of urolithiasis in client-owned chelonians: 40 cases (1987-2012).
To calculate the prevalence of urolithiasis in client-owned chelonians examined at a veterinary teaching hospital and to describe the clinical signs, diagnosis, and treatment of urolithiasis in chelonians. Retrospective case series. 40 client-owned turtles and tortoises with urolithiasis. The medical record database of a veterinary teaching hospital was searched from 1987 through 2012 for records of client-owned chelonians with urolithiasis. The prevalence of urolithiasis was calculated for client-owned chelonians examined at the hospital. Signalment and physical examination, hematologic, biochemical, urinalysis, diagnostic imaging, treatment, and necropsy results were described. The mean prevalence of urolithiasis in client-owned chelonians for the study period was 5.1 cases/100 client-owned chelonians examined. Thirty-one of the 40 chelonians were desert tortoises. Only 5 of 40 chelonians had physical examination abnormalities associated with the urogenital tract. Surgery was performed on 17 chelonians; 5 developed postoperative complications, and 4 of those died. Necropsy was performed on 18 chelonians, and urolithiasis contributed to the decision to euthanize or was the cause of death for 9. Uroliths from 13 chelonians were analyzed, and all were composed of 100% urate. Results indicated chelonians with urolithiasis have various clinical signs and physical examination findings that may or may not be associated with the urinary tract. Hematologic, biochemical, and urinalysis findings were nonspecific for diagnosis of urolithiasis. Many chelonians died or were euthanized as a consequence of urolithiasis, which suggested the disease should be identified early and appropriately treated.


A mortality study of foundry workers.
The mortality of foundry workers was studied from a sample of all those men employed in 20 representative iron, steel, and nonferrous foundries for any period of time during 1950 through 1972. A statistical sample of 3,876 men from all those 15,401 workers with at least 3 months' exposure formed the cohort under study. The actual number of person-years of follow-up became 47,160. Total and cause-specific mortality was studied in the entire cohort and in different categories based on exposure time and occupation. The foundry workers' experience was compared to that expected on the basis of the general male population's death rates in Finland, and different categories of the cohort were compared to each other through direct standardization. During the period from 1950 through 1973, there had occurred 224 deaths. The mortality approached the expected value computed from the age-adjusted general male population, the standardized mortality ratio (SMR) being 90 for all foundry workers and 95 for workers in "typical" foundry occupations. The corresponding standard mortality ratios based on the estimated total number of person-years, after the application of corrections for sampling fractions, were 86 and 95, respectively. There was a slight shift of the age of death towards younger age groups among the casters, fettlers, and furnace tenders. Mortality from coronary heart disease showed a standardized mortality ratio of 80 for the whole cohort; no significant differences were found for any occupational category. Lung cancer mortality was higher than expected (SMR 150) in the entire cohort; closer analysis revealed that the excess was confined to iron foundries, and especially to molders with more than 5 years of exposure. There were no more violent deaths than expected, not even from work accidents. Because most occupational cohorts have standardized mortality ratios that are well below 90, the present results were interpreted as probably indicating slightly elevated mortality. The most important finding was the concentration of lung cancer among molders in iron foundries.


Global trends in emerging infectious diseases.
Emerging infectious diseases (EIDs) are a significant burden on global economies and public health. Their emergence is thought to be driven largely by socio-economic, environmental and ecological factors, but no comparative study has explicitly analysed these linkages to understand global temporal and spatial patterns of EIDs. Here we analyse a database of 335 EID 'events' (origins of EIDs) between 1940 and 2004, and demonstrate non-random global patterns. EID events have risen significantly over time after controlling for reporting bias, with their peak incidence (in the 1980s) concomitant with the HIV pandemic. EID events are dominated by zoonoses (60.3% of EIDs): the majority of these (71.8%) originate in wildlife (for example, severe acute respiratory virus, Ebola virus), and are increasing significantly over time. We find that 54.3% of EID events are caused by bacteria or rickettsia, reflecting a large number of drug-resistant microbes in our database. Our results confirm that EID origins are significantly correlated with socio-economic, environmental and ecological factors, and provide a basis for identifying regions where new EIDs are most likely to originate (emerging disease 'hotspots'). They also reveal a substantial risk of wildlife zoonotic and vector-borne EIDs originating at lower latitudes where reporting effort is low. We conclude that global resources to counter disease emergence are poorly allocated, with the majority of the scientific and surveillance effort focused on countries from where the next important EID is least likely to originate.


Epidemiology, biology and therapy of Merkel cell carcinoma: conclusions from the EU project IMMOMEC.
Merkel cell carcinoma (MCC) is a highly aggressive, often lethal neuroendocrine cancer. Its carcinogenesis may be either caused by the clonal integration of the Merkel cell polyomavirus into the host genome or by UV-induced mutations. Notably, virally-encoded oncoproteins and UV-induced mutations affect comparable signaling pathways such as RB restriction of cell cycle progression or p53 inactivation. Despite its low incidence, MCC recently received much attention based on its exquisite immunogenicity and the resulting major success of immune modulating therapies. Here, we summarize current knowledge on epidemiology, biology and therapy of MCC as conclusion of the project 'Immune Modulating strategies for treatment of Merkel Cell Carcinoma', which was funded over a 5-year period by the European Commission to investigate innovative immunotherapies for MCC.


Resistance exercise increases postprandial muscle protein synthesis in humans.
We examined the impact of an acute bout of resistance-type exercise on mixed muscle protein synthesis in the fed state. After a standardized breakfast, 10 untrained males completed a single, unilateral lower-limb resistance-type exercise session. A primed, continuous infusion of l-[ring-C6]phenylalanine was combined with muscle biopsy collection from both the exercised (Ex) and the nonexercised (NEx) leg to assess the impact of local muscle contractions on muscle protein synthesis rates after food intake. Western blotting with phosphospecific and pan antibodies was used to determine the phosphorylation status of AMP-activated kinase (AMPK), 4E-binding protein (4E-BP1), mammalian target of rapamycin (mTOR), and p70 ribosomal protein S6 kinase (S6K1). Muscle protein synthesis rates were approximately 20% higher in Ex compared with NEx (0.098% +/- 0.005% vs 0.083% +/- 0.002%.h, respectively, P < 0.01). In the fed state, resistance-type exercise did not elevate AMPK phosphorylation. However, the phosphorylation status of 4E-BP1 was approximately 20% lower after cessation of exercise in Ex compared with NEx (P < 0.05). Conversely, 4E-BP1 phosphorylation was significantly higher in Ex compared with NEx after 6 h of recovery (P < 0.05) with no changes in mTOR phosphorylation. S6 phosphorylation was greater in Ex versus NEx after cessation of exercise (P < 0.05), although S6K1 phosphorylation at T was not up-regulated (P > 0.05). We conclude that resistance-type exercise performed in a fed state further elevates postprandial muscle protein synthesis rates, which is accompanied by an increase in S6 and 4E-BP1 phosphorylation state.


Ejection fraction response to exercise in patients with chest pain, coronary artery disease and normal resting ventricular function.
We studied the ejection fraction (EF) response to upright exercise using first-pass radionuclide angiography (RNA) in 281 patients with chest pain, significant coronary artery disease and normal resting ventricular function. A wide range of resting function (heart rate and EF) and exercise function (heart rate, EF and peak work load) was measured in this population. The EF response to exercise (delta EF) varied widely, ranging from a decrease of 36% to an increase of 26%. Twenty-eight clinical, catheterization and RNA variables were examined to determine their relationship to delta EF. Considered individually, the variables showing the strongest relationship were resting pulse pressure, positive exercise ECG changes and adequate exercise. Multivariable analysis identified resting pulse pressure, adequate exercise, resting EF, the change in end-diastolic volume index with exercise, positive exercise ECG changes and, to a lesser degree, the number of diseased vessels as variables that were significant independent predictors of delta EF. These observations indicate that delta EF is a complex response that is influenced by many pathophysiologic variables in the presence of coronary artery disease. Several of these variables are not related to the extent of coronary artery disease.


The effects of alloying with Cu and Mn and thermal treatments on the mechanical instability of Zn-0.05Mg alloy.
The detrimental effect of natural aging on mechanical properties of zinc alloys restricts their application as bioresorbable medical implants. In this study, aging of Zn-0.05Mg alloy and the effect of 0.5 Cu and 0.1 Mn (in weight percent) addition on the microstructure and tensile properties were studied. The alloys were cold rolled, aged and annealed; aiming to investigate the effects of precipitates and grain size on the mechanical properties and their stability. TEM analysis revealed that in ultrafine-grained binary Zn-0.05Mg alloy, the natural aging occurred due to the formation of nano-sized Mg2Zn11 precipitates. After 90 days of natural aging, the yield strength and ultimate tensile strength of Zn-0.05Mg alloy increased from 197±4 MPa and 227±5 MPa to 233±8 MPa and 305±7 MPa, respectively, while the elongation was drastically reduced from 34±3% to 3±1%. This natural aging was retarded by adding the third element at either 0.1Mn or 0.5Cu quantities, which interacted with Mg in Zn solid solution and impeded the formation of Mg2Zn11 precipitates. The addition of Cu and Mn elements increased alloy's strength, ductility, and its mechanical stability at a room temperature. The measured tensile strength and elongation were 274±5 MPa and 41±1% for Zn-0.1Mn-0.05Mg and 312±2 MPa and 44±2% for Zn-0.5Cu-0.05Mg, respectively. Annealing the alloys at elevated temperatures caused increase in both grain size and dissolution of secondary phases, and both affected alloy deformation mechanisms.


Performance of fused silica as a filter in a wide field-of-view earth radiation budget radiometer.
An analysis of the thermal response of a fused silica hemispherical dome filter in a wide field-of-view (WFOV) shortwave radiometer for obtaining earth radiation budget measurements is presented. The impact of the filter thermal response on the dc detector (a thermopile) and on the resulting measurement uncertainty is evaluated. It is shown that the hemispherical filter material maintains neither a uniform nor constant temperature distribution as it responds to changes in the radiation emitted from earth. Accurate determination of terrestrial shortwave irradiance requires knowledge of the dome filter thermal response because the thermopile responds to changes in the dome temperature as well as the shortwave scene. Data are presented that show that variations in the dome temperature distribution from calibration conditions can result in a measurement uncertainty of several W/m(2) if not properly accounted for in the interpretation f the measurement. Design approaches, ground calibration, and data reduction techniques that can reduce this measurement uncertainty by an order of magnitude are presented.


The carbohydrate-binding module family 20--diversity, structure, and function.
Starch-active enzymes often possess starch-binding domains (SBDs) mediating attachment to starch granules and other high molecular weight substrates. SBDs are divided into nine carbohydrate-binding module (CBM) families, and CBM20 is the earliest-assigned and best characterized family. High diversity characterizes CBM20s, which occur in starch-active glycoside hydrolase families 13, 14, 15, and 77, and enzymes involved in starch or glycogen metabolism, exemplified by the starch-phosphorylating enzyme glucan, water dikinase 3 from Arabidopsis thaliana and the mammalian glycogen phosphatases, laforins. The clear evolutionary relatedness of CBM20s to CBM21s, CBM48s and CBM53s suggests a common clan hosting most of the known SBDs. This review surveys the diversity within the CBM20 family, and makes an evolutionary comparison with CBM21s, CBM48s and CBM53s, discussing intrafamily and interfamily relationships. Data on binding to and enzymatic activity towards soluble ligands and starch granules are summarized for wild-type, mutant and chimeric fusion proteins involving CBM20s. Noticeably, whereas CBM20s in amylolytic enzymes confer moderate binding affinities, with dissociation constants in the low micromolar range for the starch mimic beta-cyclodextrin, recent findings indicate that CBM20s in regulatory enzymes have weaker, low millimolar affinities, presumably facilitating dynamic regulation. Structures of CBM20s, including the first example of a full-length glucoamylase featuring both the catalytic domain and the SBD, are summarized, and distinct architectural and functional features of the two SBDs and roles of pivotal amino acids in binding are described. Finally, some applications of SBDs as affinity or immobilization tags and, recently, in biofuel and in planta bioengineering are presented.


Characterization of a chemical affinity probe targeting Akt kinases.
Protein kinases are key regulators of cellular processes, and aberrant function is often associated with human disease. Consequently, kinases represent an important class of therapeutic targets and about 20 kinase inhibitors (KIs) are in clinical use today. Detailed knowledge about the selectivity of KIs is important for the correct interpretation of their pharmacological and systems biological effects. Chemical proteomic approaches for systematic kinase inhibitor selectivity profiling have emerged as important molecular tools in this regard, but the coverage of the human kinome is still incomplete. Here, we describe a new affinity probe targeting Akt and many other members of the AGC kinase family that considerably extends the scope of KI profiling by chemical proteomics. In combination with the previously published kinobeads, the synthesized probe was applied to selectivity profiling of the Akt inhibitors GSK690693 and GSK2141795 in human cancer cells. The results confirmed the inhibition of all Akt isoforms and of a number of known as well as CDC42BPB as a novel putative target for GSK690693. This work also established, for the first time, the kinase selectivity profile of the clinical phase I drug GSK2141795 and identified PRKG1 as a low nanomolar kinase target as well as the ATP-dependent 5'-3' DNA helicase ERCC2 as a potential new non-kinase off-target.


Targeting fatty acid synthase-driven lipid rafts: a novel strategy to overcome trastuzumab resistance in breast cancer cells.
Trastuzumab (Herceptin) is a humanized antibody directed against the extracellular domain of the tyrosine kinase orphan receptor Her-2/neu (erbB-2) that has shown therapeutic efficacy against Her-2/neu-overexpressing breast tumors. However, less than 35% of patients with Her-2/neu-overexpressing metastatic breast cancer respond to trastuzumab as a single agent, whereas the remaining cases do not demonstrate tumor regression. Furthermore, the majority of patients who achieve an initial response generally acquire resistance within one year. Therefore, the identification of the potential mechanisms of resistance to trastuzumab can be very helpful for the development of new compounds, which might overcome that resistance and/or have additive/synergistic antitumor effect when given in association with trastuzumab. Recent studies in breast cancer cells have revealed a bi-directional connection between Her-2/neu and fatty acid synthase (FAS), a major lipogenic enzyme catalyzing the synthesis of long-chain saturated fatty acids from the 2-carbon donors malonyl-CoA and acetyl-CoA. Her-2/neu overexpression stimulates the FAS promoter and ultimately mediates increased endogenous fatty synthesis, and this Her-2/neu-mediated induction of breast cancer-associated FAS is inhibitable by trastuzumab. On the other hand, chemical FAS inhibitors as well as RNA interference-mediated silencing of FAS gene repress Her-2/neu gene expression at the transcriptional level. Moreover, specific FAS blockade synergistically sensitizes breast cancer cells carrying Her-2/neu-oncogene amplification and/or overexpression to trastuzumab-induced cell growth inhibition and apoptotic cell death. Strikingly, FAS inhibition synergistically interacts with trastuzumab in Her-2/neu-negative breast cancer cells engineered to overexpress Her-2/neu, thus suggesting that the molecular linkage between FAS activity and functioning of Her-2/neu cannot be explained only on the basis of a transcriptional repression of Her-2/neu gene promoter. Interestingly, while in liver and adipose tissue FAS produces fat from excess carbon consumed as carbohydrates, which is ultimately stored as triglycerides, in epithelial cancer cells, FAS activity is mainly involved in the production of phospholipids partitioning into detergent-resistant membrane microdomains (lipid raft-aggregates), which point to an active role of FAS in the deregulation of membrane functioning in tumor cells. Importantly, clusters of Her-2/neu and EGFR (erbB-1) co-localize with lipid rafts and the lipid environment in the cell membrane of breast cancer cells profoundly influences their association properties and biological functions. We hypothesize that pharmacological or small interference RNA-induced inhibition of breast cancer-associated FAS will result in major changes in the synthesis of phospholipids which, in turn, should impair a correct cellular localization of Her-2/neu at the cellular membrane of breast cancer cells. In this working model, FAS inhibition could induce a shift in the equilibrium between transport of Her-2/neu to and from the membrane favoring an increased Her-2/neu internalization followed by intracellular degradation, thus enhancing the mechanism of action of the anti-Her-2/neu antibody trastuzumab. Moreover, the inhibition of FAS-driven lipid rafts will also negatively affect EGFR-Her-2/neu cross-talk, an important mechanism of trastuzumab resistance. In summary, the specific blockade of a novel molecular linkage between FAS-regulated membrane composition and functioning of transmembrane growth factor receptors EGFR and Her-2/neu may represent a previously unrecognized therapeutic approach circumventing trastuzumab resistance in breast carcinomas.


Catching Up or Missing Out? Human Papillomavirus Vaccine Acceptability Among 18- to 26-Year-old Men Who Have Sex With Men in a US National Sample.
Men who have sex with men (MSM) are disproportionately affected by human papillomavirus (HPV)-related outcomes and would benefit from HPV vaccination in adolescence. We assessed HPV vaccine attitudes, uptake, and barriers in this high-risk young MSM (YMSM) population. An online US sample of 1457 YMSM aged 18 to 26 years were recruited in December 2011 to examine HPV vaccine acceptability and uptake. The online survey included sociodemographics, HPV vaccine attitudes, acceptability, HPV vaccination status, health care use, and HPV knowledge. Despite high use of health care in the past year (86%) and high acceptability (87.8/100) for free HPV vaccine, only 6.8% had received one or more vaccine doses. In addition, only 4% of unvaccinated men had been offered the vaccine by their health care provider (HCP). In a multivariate regression of unvaccinated men, increased vaccine acceptability was associated with an HCP recommendation, worry about getting infected with HPV, and being tested for a sexually transmitted disease in the past year, whereas safety concerns, lower perceived risk of infection, and shame associated with HPV infection/disease were associated with decreased vaccine acceptability. Through logistic regression, vaccine uptake was associated with being tested for a sexually transmitted disease in the past year, disclosure of being gay or bisexual to a doctor, and greater HPV knowledge. Health care providers need to use routine points of contact with YMSM patients to vaccinate against HPV. These data indicated missed opportunities to vaccinate YMSM who are open to HPV vaccination. In the future, HCPs of YMSM should be careful to avoid missed opportunities to vaccinate.


Applying a gender lens to understand pathways through care for acutely ill young children in Kenyan urban informal settlements.
In many African settings, gender strongly influences household treatment-seeking and decision-making for childhood illnesses. While mothers are often the primary engagers with health facilities, their independence in illness-related decisions is shaped by various factors. Drawing on a gender lens, we explored treatment-seeking pathways pre- and post-hospital admission for acutely ill young children living in low income settlements in Nairobi, Kenya; and the gendered impact of child illness both at the household and health system level. Household members of 22 children admitted to a public hospital were interviewed in their homes several times post hospital discharge. In-depth interviews covered the child's household situation, health and illness; and the family's treatment-seeking choices and experiences. Children were selected from an observational cohort established by the Childhood Acute Illness and Nutrition (CHAIN) Network. Treatment-seeking pathways were often long and complex, with mothers playing the key role in caring for their children and in treatment decision-making. Facing many anxieties and dilemmas, mothers often consulted with significant influencers - primarily women - particularly where illnesses were prolonged or complex. In contrast to observations in rural African contexts, fathers were less prominent as influencers than (often female) neighbours, grandparents and other relatives. Mothers were sometimes blamed for their child's condition at home and at health facilities. Children's illness episode and associated treatment-seeking had significant gendered socio-economic consequences for households, including through mothers having to take substantial time off work, reduce their working hours and income, or even losing their jobs. Women in urban low-income settings are disproportionately impacted by acute child illness and the related treatment-seeking and recovery process. The range of interventions needed to support mothers as they navigate their way through children's illnesses and recovery include: deliberate engagement of men in child health to counteract the dominant perception of child health and care as a 'female-domain'; targeted economic strategies such as cash transfers to safeguard the most vulnerable women and households, combined with more robust labour policies to protect affected women; as well as implementing strategies at the health system level to improve interactions between health workers and community members.


Plasmodium falciparum parasite prevalence in East Africa: a review.
Empirical data on malaria endemicity are rarely available for public domain use to guide effective malaria control. This paper describes the work carried in East Africa since 1997 as part of a pan-African collaboration to map the risk of malaria, Mapping Malaria Risk in Africa (MARA) aimed at redressing deficiency. Studies of cross-sectional community estimates of Plasmodium falciparum prevalence among children aged 0-15 years were identified from a variety of sources including electronic searches of published material, manual review of pre-electronic peer reviewed journals and searches of libraries and archives in Kenya, Tanzania and Uganda. Each survey source, infection prevalence, date, longitude and latitude and survey characteristics were recorded. All data were subjected to a number of selection criteria including minimum sample sizes, samples randomly selected, community-based surveys, age ranges of sampled communities within 0-15 years, and surveys that were spatially unique. Of the 2,003 survey data points identified since 1907 in East Africa, only 503 were eligible for inclusion in the analysis dating from 1927 to 2003. The spatial plots of the data demonstrate the paucity of information on malaria prevalence from a number of densely populated areas and highlight the concentration of empirical data in concert with research centres in the sub-region. Models are required to define malaria risk in areas of East Africa where no empirical data are available so that limited resources can be better targeted to those in greatest need.


A systematic review of published evidence on intervention impact on condom use in sub-Saharan Africa and Asia.
There has been much debate about the value of condoms in HIV/STI programming. This should be informed by evidence about intervention impact on condom use, but there is limited compiled literature. This review aims to quantify intervention impact on condom use in sub-Saharan Africa and Asia, in different types of partnership. A systematic review was conducted of papers published between 1998 and 2006 presenting evaluations of interventions involving condom promotion in sub-Saharan Africa and Asia. Data on reported postintervention levels of condom use, and various measures of changes in condom use, by partnership type, were compiled. A total of 1374 abstracts were identified. Sixty-two met the inclusion criteria (42 reporting significant increases in condom use): 44 from sub-Saharan Africa and 18 from Asia. Many (19) reported on condom use in commercial sex (15 significant), six on use with casual partners (three significant), 11 on use in marital/steady partnerships (nine significant), 14 on use by youths (eight significant) and 20 combined partnership types (11 significant). There is substantial evidence of interventions targeted at sex workers and clients achieving large increases in condom use. Far less evidence exists of intervention impact on condom use in casual relationships. In primary partnerships, postintervention condom use was low unless one partner was knowingly HIV-infected or at high-risk, or avoiding pregnancy. Evaluations of interventions targeting youths recorded limited increases in condom use. The findings illustrate the range of evidence about postintervention condom use in different partnerships, and how patterns of use are influenced by partnership type and perceptions of risk. Where possible, intervention studies should also assess biological endpoints, since prevention of infection is the measure of most interest in the evaluation of condom promotion interventions.


TcI Isolates of Trypanosoma cruzi Exploit the Antioxidant Network for Enhanced Intracellular Survival in Macrophages and Virulence in Mice.
Trypanosoma cruzi species is categorized into six discrete typing units (TcI to TcVI) of which TcI is most abundantly noted in the sylvatic transmission cycle and considered the major cause of human disease. In our study, the TcI strains Colombiana (COL), SylvioX10/4 (SYL), and a cultured clone (TCC) exhibited different biological behavior in a murine model, ranging from high parasitemia and symptomatic cardiomyopathy (SYL), mild parasitemia and high tissue tropism (COL), to no pathogenicity (TCC). Proteomic profiling of the insect (epimastigote) and infective (trypomastigote) forms by two-dimensional gel electrophoresis/matrix-assisted laser desorption ionization-time of flight mass spectrometry, followed by functional annotation of the differential proteome data sets (≥2-fold change, P < 0.05), showed that several proteins involved in (i) cytoskeletal assembly and remodeling, essential for flagellar wave frequency and amplitude and forward motility of the parasite, and (ii) the parasite-specific antioxidant network were enhanced in COL and SYL (versus TCC) trypomastigotes. Western blotting confirmed the enhanced protein levels of cytosolic and mitochondrial tryparedoxin peroxidases and their substrate (tryparedoxin) and iron superoxide dismutase in COL and SYL (versus TCC) trypomastigotes. Further, COL and SYL (but not TCC) were resistant to exogenous treatment with stable oxidants (H2O2 and peroxynitrite [ONOO(-)]) and dampened the intracellular superoxide and nitric oxide response in macrophages, and thus these isolates escaped from macrophages. Our findings suggest that protein expression conducive to increase in motility and control of macrophage-derived free radicals provides survival and persistence benefits to TcI isolates of T. cruzi.


Activation of postsynaptic metabotropic glutamate receptors by trans-ACPD hyperpolarizes neurons of the basolateral amygdala.
Glutamate has traditionally been regarded as an excitatory neurotransmitter. Synaptic activation of ionotropic glutamate receptors mediates fast EPSPs in the CNS. Moreover, activation of metabotropic glutamate receptors (mGluRs), which are coupled to second messenger effector systems via GTP-binding proteins (G-proteins), results in the expression of slow EPSPs. We have now examined the response of basolateral amygdala (BLA) neurons to activation of postsynaptic mGluRs. In approximately 78% of BLA neurons examined, activation of postsynaptic mGluRs results in membrane hyperpolarization and an associated decrease in membrane input resistance or a hyperpolarization followed by a depolarization associated with an increase in input resistance. The purpose of this study was to address the mechanisms underlying the membrane hyperpolarization. Here, we report that the ACPD-induced hyperpolarization is insensitive to TTX, is dependent on extracellular K+ concentrations, and has a reversal potential (-84 mV) close to that estimated from the Nernst equation for an increase in a K+ conductance. In addition, the ACPD response is resistant to (1) intracellular chloride loading, (2) the GABAB receptor antagonist CGP55845A, (3) the ACh receptor antagonist atropine, and (4) the ionotropic glutamate receptor antagonists CNQX and APV. These data suggest that the hyperpolarization results from a direct activation of postsynaptic mGluRs on neurons of the BLA. Furthermore, we performed studies that suggest that the hyperpolarization is G-protein mediated and results from activation of a TEA-sensitive, calcium-dependent potassium conductance. The sensitivity of this conductance to thapsigargin further suggests that this response requires the release of calcium from intracellular stores. In summary, these data suggest a role for glutamate as an inhibitory transmitter in the BLA during periods of metabotropic glutamate receptor activation. In nuclei such as the BLA that are exquisitely sensitive to seizure induction, an inhibitory response to glutamate may act to delay the onset of epileptogenesis.


The efficacy and safety of hydroxychloroquine for COVID-19 prophylaxis: A systematic review and meta-analysis of randomized trials.
Populations such as healthcare workers (HCW) that are unable to practice physical distancing are at high risk of acquiring Coronavirus disease-2019 (COVID-19). In these cases pharmacological prophylaxis would be a solution to reduce severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) transmission. Hydroxychloroquine has in vitro antiviral properties against SARS CoV-2. We therefore sought to determine the efficacy and safety of hydroxychloroquine as prophylaxis for COVID-19. We electronically searched EMBASE, MEDLINE, the Cochrane COVID-19 Register of Controlled Trials, Epistemonikos COVID-19, clinicaltrials.gov, and the World Health Organization International Clinical Trials Registry Platform up to September 28th, 2020 for randomized controlled trials (RCTs). We calculated pooled relative risks (RRs) for dichotomous outcomes with the corresponding 95% confidence intervals (CIs) using a random-effect model. We identified four RCTs (n = 4921) that met our eligibility criteria. The use of hydroxychloroquine, compared to placebo, did not reduce the risks of developing COVID-19 (RR 0.82, 95% CI 0.65 to 1.04, moderate certainty), hospitalization (RR 0.72, 95% CI 0.34 to 1.50, moderate certainty), or mortality (RR 3.26, 95% CI 0.13 to 79.74, low certainty), however, hydroxychloroquine use increased the risk of adverse events (RR 2.76, 95% CI 1.38 to 5.55, moderate certainty). Although pharmacologic prophylaxis is an attractive preventive strategy against COVID-19, the current body of evidence failed to show clinical benefit for prophylactic hydroxychloroquine and showed a higher risk of adverse events when compared to placebo or no prophylaxis.


Restraining order for dendritic cells: all quiet on the fetal front.
The paradoxical ability to launch effective immunity against pathogens while avoiding the horror autotoxicus of autoimmunity is one of the most remarkable features of the mammalian immune system. This assumes a particular evolutionary significance at the maternal/fetal interface, where avoidance of immune reactivity to the fetus is vital to the propagation of the species itself. Several mechanisms of suppressing maternal immunity against the fetus have been described. The article by Collins et al. in this issue of the JCI describes a novel mechanism of avoiding immune surveillance in which the migratory capacity of dendritic cells at the maternal/fetal interface is restrained (see the related article beginning on page 2062).


Unacylated ghrelin is not a functional antagonist but a full agonist of the type 1a growth hormone secretagogue receptor (GHS-R).
Recent findings demonstrate that the effects of ghrelin can be abrogated by co-administered unacylated ghrelin (UAG). Since the general consensus is that UAG does not interact with the type 1a growth hormone secretagogue receptor (GHS-R), a possible mechanism of action for this antagonistic effect is via another receptor. However, functional antagonism of the GHS-R by UAG has not been explored extensively. In this study we used human GHS-R and aequorin expressing CHO-K1 cells to measure [Ca(2+)](i) following treatment with UAG. UAG at up to 10(-5)M did not antagonize ghrelin induced [Ca(2+)](i). However, UAG was found to be a full agonist of the GHS-R with an EC(50) of between 1.6 and 2 microM using this in vitro system. Correspondingly, UAG displaced radio-labeled ghrelin from the GHS-R with an IC(50) of 13 microM. In addition, GHS-R antagonists were found to block UAG induced [Ca(2+)](i) with approximately similar potency to their effect on ghrelin activation of the GHS-R, suggesting a similar mode of action. These findings demonstrate in a defined system that UAG does not antagonize activation of the GHS-R by ghrelin. But our findings also emphasize the importance of assessing the concentration of UAG used in both in vitro and in vivo experimental systems that are aimed at examining GHS-R independent effects. Where local concentrations of UAG may reach the high nanomolar to micromolar range, assignment of GHS-R independent effects should be made with caution.


Promoting marriage as welfare policy: looking at a public role in private lives.
This paper discusses the interest in and politics surrounding government's using welfare reform legislation to carve out a stronger role in promoting marriage. It examines trends in family formation, their impact on society, and the effect of single parenting, divorce, and step-parenting on child well-being. The paper also looks at the treatment of marriage in current government programs, new state activities to promote marriage, proposals for a stronger government role, and marriage experts' expectations for the success of marriage education programs.


Infant mortality by cause of death: main and interaction effects.
We examine infant mortality among the 1980-1982 live birth cohorts in the state of Florida, specific to five categories of underlying cause of death: infections, perinatal conditions, delivery complications, congenital malformations, and sudden infant death syndrome. The gross and net effects of eight categorical and continuous independent variables, along with 11 first-order interactions, are examined with microlevel data through the use of multinomial logit regression. Findings suggest the complexity of variable effects by cause of death and indicate the simultaneous importance of biological and social factors. It is important that the pattern of interactions suggests an overall dependence of infant life chances on social circumstances. It also suggests that these effects are attenuated for some variables and causes of death at lower birth weights, probably due to advances in health care organization, access, and technology.


Molecular mechanisms of experience-dependent plasticity in visual cortex.
A remarkable amount of our current knowledge of mechanisms underlying experience-dependent plasticity during cortical development comes from study of the mammalian visual cortex. Recent advances in high-resolution cellular imaging, combined with genetic manipulations in mice, novel fluorescent recombinant probes, and large-scale screens of gene expression, have revealed multiple molecular mechanisms that underlie structural and functional plasticity in visual cortex. We situate these mechanisms in the context of a new conceptual framework of feed-forward and feedback regulation for understanding how neurons of the visual cortex reorganize their connections in response to changes in sensory inputs. Such conceptual advances have important implications for understanding not only normal development but also pathological conditions that afflict the central nervous system.


Involvement of energy metabolism in the production of 'bystander effects' by radiation.
These experiments were done to determine if interference with energy metabolism and REDOX biochemistry during low LET radiation exposure would alter the ability of medium harvested from the irradiated cells to induce a bystander effect in unirradiated cells. Human keratinocyte cells and CHO-K1 mutant cell lines were irradiated using cobalt 60. Clonogenic assays were used to determine the reproductive death of the cells exposed to direct irradiation or medium from irradiated cells. The persistence in progeny was also examined. Use of apoptosis inhibitors or medium from the LDH or G6PD null cell lines, reduced or prevented the bystander effect. Transfection with G6PD recovered the effect. Treatment with anti-oxidant substances, L-lactate and L-deprenyl prevented bystander factor associated cell kill. The lactate analogue, oxamate, was less effective. Data from experiments where media harvested from the different cell lines was exchanged suggest that signal production and cellular response may involve different mechanisms. The effects on exposed cells were transmitted to progeny which also showed excessive levels of cell death for several generations. The results suggest that energy/REDOX metabolism may be involved in the expression of a radiation induced bystander response. Given the aberrant energy metabolism in tumour cells, this may have implications for dose escalation in radiotherapy.