Health Gains and Financial Protection Provided by the Ethiopian Mental Health Strategy: an Extended Cost-Effectiveness Analysis.
Mental and neurological (MN) health care has long been neglected in low-income settings. This paper estimates health and non-health impacts of fully publicly financed care for selected key interventions in the National Mental Health Strategy in Ethiopia for depression, bipolar disorder, schizophrenia and epilepsy. A methodology of extended cost-effectiveness analysis (ECEA) is applied to MN health care in Ethiopia. The impact of providing a package of selected MN interventions free of charge in Ethiopia is estimated for: epilepsy (75% coverage, phenobarbital), depression (30% coverage, fluoxetine, cognitive therapy and proactive case management), bipolar affective disorder (50% coverage, valproate and psychosocial therapy) and schizophrenia (75% coverage, haloperidol plus psychosocial treatment). Multiple outcomes are estimated and disaggregated across wealth quintiles: (1) healthy-life-years (HALYs) gained; (2) household out-of-pocket (OOP) expenditures averted; (3) expected financial risk protection (FRP); and (4) productivity impact. The MN package is expected to cost US$177 million and gain 155,000 HALYs (epilepsy US$37m and 64,500 HALYs; depression US$65m and 61,300 HALYs; bipolar disorder US$44m and 20,300 HALYs; and schizophrenia US$31m and 8,900 HALYs) annually. The health benefits would be concentrated among the poorest groups for all interventions. Universal public finance averts little household OOP expenditures and provides minimal FRP because of the low current utilization of these MN services in Ethiopia. In addition, economic benefits of US$ 51 million annually are expected from depression treatment in Ethiopia as a result of productivity gains, equivalent to 78% of the investment cost. The total MN package in Ethiopia is estimated to cost equivalent to US$1.8 per capita and yields large progressive health benefits. The expected productivity gain is substantially higher than the expected FRP. The ECEA approach seems to fit well with the current policy challenges and captures important equity concerns of scaling up MN programmes.


Assessment of K-Ras mutant frequency and micronucleus incidence in the mouse duodenum following 90-days of exposure to Cr(VI) in drinking water.
Chronic exposure to high concentrations of hexavalent chromium [Cr(VI)] as sodium dichromate dihydrate (SDD) in drinking water induces duodenal tumors in mice, but the mode of action (MOA) for these tumors has been a subject of scientific debate. To evaluate the tumor-site-specific genotoxicity and cytotoxicity of SDD in the mouse small intestine, tissue pathology and cytogenetic damage were evaluated in duodenal crypt and villus enterocytes from B6C3F1 mice exposed to 0.3-520mg/L SDD in drinking water for 7 and 90 days. Allele-competitive blocker PCR (ACB-PCR) was used to investigate the induction of a sensitive, tumor-relevant mutation, specifically in vivo K-Ras codon 12 GAT mutation, in scraped duodenal epithelium following 90 days of drinking water exposure. Cytotoxicity was evident in the villus as disruption of cellular arrangement, desquamation, nuclear atypia and blunting. Following 90 days of treatment, aberrant nuclei, occurring primarily at villi tips, were significantly increased at ≥60mg/L SDD. However, in the crypt compartment, there were no dose-related effects on mitotic and apoptotic indices or the formation of aberrant nuclei indicating that Cr(VI)-induced cytotoxicity was limited to the villi. Cr(VI) caused a dose-dependent proliferative response in the duodenal crypt as evidenced by an increase in crypt area and increased number of crypt enterocytes. Spontaneous K-Ras codon 12 GAT mutations in untreated mice were higher than expected, in the range of 10(-2) to 10(-3); however no treatment-related trend in the K-Ras codon 12 GAT mutation was observed. The high spontaneous background K-Ras mutant frequency and Cr(VI) dose-related increases in crypt enterocyte proliferation, without dose-related increase in K-Ras mutant frequency, micronuclei formation, or change in mitotic or apoptotic indices, are consistent with a lack of genotoxicity in the crypt compartment, and a MOA involving accumulation of mutations late in carcinogenesis as a consequence of sustained regenerative proliferation.


Bilirubin analogues as model compounds for exciton coupling.
A series of phycobilin analogues have been investigated in terms of coupled excitonic systems. These compounds consist of a monomer, a tetrapyrrole structurally similar to bilirubin (bR), and two conjugated bR analogues. Spectroscopic and computational methods have been used to investigate the degree of interchromophore coupling. We find the synthesised bR analogue shows stronger excitonic coupling than bR, owing to a different molecular geometry. The excitonic coupling in the conjugated molecules can be controlled by modifying the bridge side-group. New computed energy levels for bR using the DFT/MRCI method are also presented, which improve on published values and re-assign the character of excited singlet states.


Decreased smoking disparities among Vietnamese and Cambodian communities - Racial and Ethnic Approaches to Community Health (REACH) project, 2002-2006.
Since 1964, smoking prevalence in the United States has declined because of nationwide intervention efforts. However, smoking interventions have not been implemented uniformly throughout all communities. Some of the highest smoking rates in the United States have been reported among Southeast Asian men, and socioeconomic status has been strongly associated with smoking. To compare the effect in reducing racial and ethnic disparities between men in Southeast Asian (Vietnamese and Cambodian) communities and men residing in the same states, CDC analyzed 2002-2006 data from The Racial and Ethnic Approaches to Community Health (REACH) project. The prevalence of current smoking significantly decreased and the quit ratio (percentage of ever smokers who have quit) significantly increased in REACH Vietnamese and Cambodian communities, but changes were minimal among all men in California or all men in Massachusetts (where these communities were located). The smoking rate also declined significantly, and the quit ratio showed an upward trend in U.S. men overall; however, the changes were significantly greater in REACH communities than in the nation. Stratified analyses showed decreasing trends of smoking and increasing trends of quit ratio in persons of both high and low education levels in Vietnamese REACH communities. The relative disparities in the prevalence of smoking and in the quit ratio decreased or were eliminated between less educated Vietnamese and less educated California men and between Cambodian and Massachusetts men regardless of education level. Eliminating health disparities related to tobacco use is a major public health challenge facing Asian communities. The decline in smoking prevalence at the population level in the three REACH Vietnamese and Cambodian communities as described in this report might serve as a model for promising interventions in these populations. The results highlight the potential effectiveness of community-level interventions, such as forming community coalitions, use of local media, and enhancing communities' capacity for systems change. The Office of Minority Health and Health Equity selected this intervention analysis and discussion to provide an example of a program that might be effective for reducing tobacco use-related health disparities in the United States.


Robust mapping of electrical properties of graphene from terahertz time-domain spectroscopy with timing jitter correction.
We demonstrate a method for reliably determining the electrical properties of graphene including the carrier scattering time and carrier drift mobility from terahertz time- domain spectroscopy measurements (THz-TDS). By comparing transients originating from directly transmitted pulses and the echoes from internal reflections in a substrate, we are able to extract electrical properties irrespective of random time delays between pulses emitted in a THz-TDS setup. If such time delays are not accounted for they can significantly influence the extracted properties of the material. The technique is useful for a robust determination of electrical properties from THz-TDS measurements and is compatible with substrate materials where transients from internal reflections are well-separated in time.


Shifts in seawater chemistry disrupt trophic links within a simple shoreline food web.
Marine intertidal systems have long served as focal environments for ecological research, yet these environments are changing due to the entry of human-produced carbon dioxide into seawater, which causes 'ocean acidification' (OA). One component of OA is a decline in seawater pH, an alteration known to disrupt organism behaviors underlying predator-prey interactions. To date, however, studies examining OA's effects on feeding relationships consider predominantly simple direct interactions between consumers and their food sources. Here, we extended these established approaches to test how decreased seawater pH might alter cascading effects that span tiered linkages in trophic networks. We employed a model shoreline food web incorporating a sea star predator (Leptasterias hexactis), an herbivorous snail prey (Tegula funebralis), and a common macroalgal resource for the prey (Mazzaella flaccida). Results demonstrate direct negative effects of low pH on anti-predator behavior of snails, but also weakened indirect interactions, driven by increased snail consumption of macroalgae even as sea stars ate more snails. This latter outcome arose because low pH induced 'foolhardy' behaviors in snails, whereby their flight responses were supplanted by other activities that allowed for foraging. These findings highlight the potential for human-induced changes in seawater chemistry to perturb prey behaviors and trophic dynamics with accompanying community-level consequences.


A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment.
The survival of older patients with acute myeloid leukemia has not improved. Few clinical trials have been available for older patients who are not considered fit for an intensive chemotherapy approach. Between December 1998 and November 2003, as part of National Cancer Research Institute Acute Myeloid Leukemia 14 Trial, 217 patients, who were deemed unfit for intensive chemotherapy were randomized to receive low-dose cytarabine (Ara-C) (20 mg twice daily for 10 days) or hydroxyurea with or without all-trans retinoic acid (ATRA). Low-dose ara-C produced a better remission rate (18% vs 1%; odds ratio [OR], 0.15; 95% confidence interval [95% CI], 0.06-0.37; P = .00006) and better overall survival (OR, 0.60; 95% CI, 0.44-0.81; P = .0009), which was accounted for by the achievement of complete remission (CR) (duration of CR: 80 weeks vs 10 weeks for patients with no CR). Patients who had adverse cytogenetics did not benefit. ATRA had no effect. Toxicity scores or supportive care requirements did not differ between the treatment arms. Older, less fit patients have a poor outcome, and few trials have been conducted in this patient group. Low-dose ara-C treatment was superior to best supportive care and hydroxyurea because it had greater success in achieving CR, and it could represent standard care against which new treatments may be compared in this patient group.


Sleeping while disabled, disabled while sleeping.
This essay considers areas in which the study of sleep and sleep disorders might profit from the perspective of disability studies, as practiced in the humanities and social sciences. This interdisciplinary perspective considers the social and cultural dimensions of bodily and mental states and conditions that a particular society deems abnormal or impaired, as well as the lived consequences of those determinations. Some sleep disorders are considered disabilities, but almost all disabilities entail some disruption from normal sleeping patterns--whether because of physical pain, exhaustion, and emotional stress of facing obstacles in work and other areas of waking life, or challenging sleeping environments in which many disabled people live. Despite these disruptions, finding adequate nighttime care is often difficult for people with disabilities, and consequently, night is often when social isolation and vulnerability are most profound. In addition, caretakers themselves often find their own sleep profoundly disrupted, whether this occurs in a family setting or an institutional space. Finally, the essay suggests that a disability studies perspective can help us to see that disordered sleep--whether primary or secondary to a disabling condition--can both impact and be shaped by social relationships.


Should Researchers Offer Results to Family Members of Cancer Biobank Participants? A Mixed-Methods Study of Proband and Family Preferences.
Genomic analysis may reveal both primary and secondary findings with direct relevance to the health of probands' biological relatives. Researchers question their obligations to return findings not only to participants but also to family members. Given the social value of privacy protection, should researchers offer a proband's results to family members, including after the proband's death? Preferences were elicited using interviews and a survey. Respondents included probands from two pancreatic cancer research resources, plus biological and nonbiological family members. Hypothetical scenarios based on actual research findings from the two cancer research resources were presented; participants were asked return of results preferences and justifications. Interview transcripts were coded and analyzed; survey data were analyzed descriptively. Fifty-one individuals (17 probands, 21 biological relatives, 13 spouses/partners) were interviewed. Subsequently, a mailed survey was returned by 464 probands, 1,040 biological family members, and 399 spouses/partners. This analysis highlights the interviews, augmented by survey findings. Probands and family members attribute great predictive power and lifesaving potential to genomic information. A majority hold that a proband's genomic results relevant to family members' health ought to be offered. While informants endorse each individual's choice whether to learn results, most express a strong moral responsibility to know and to share, particularly with the younger generation. Most have few concerns about sharing genetic information within the family; rather, their concerns focus on the health consequences of not sharing. Although additional studies in diverse populations are needed, policies governing return of genomic results should consider how families understand genomic data, how they value confidentiality within the family, and whether they endorse an ethics of sharing. A focus on respect for individual privacy-without attention to how the broad social and cultural context shapes preferences within families-cannot be the sole foundation of policy.


Greater involvement of people living with HIV in health care.
Greater Involvement of People Living with HIV/AIDS represents a mobilising and an organising principle for the involvement of people living with HIV in program and policy responses. People with HIV have been at the forefront of designing and implementing effective HIV treatment, care and prevention activities. However, governments and health systems have yet to act to fully harness the potential and resources of people living with HIV in addressing the epidemic.The lives and experiences of people living with HIV highlight the need for a shift in the existing paradigm of disease management. The high prevalence of HIV amongst health care providers in many countries, exacerbated by stigma towards those with HIV in the health care professions, is seriously undermining the capacity of health systems and signals the need to change the current nature of health care delivery. Moreover, the negative experiences of many people with HIV in relation to their health care as well as in their daily social interactions, coupled with the ever-limited current investment in treatment, care and support, demonstrate that the current system is drastically failing the majority of people with HIV. Current health management systems urgently need to be more effectively maximised, to increase the quality of standards of health care systems and services in resource poor countries. An integrated approach to health care based on a human rights framework, grounded in community realities and delivered in partnership and solidarity with people living with HIV, offers the most viable approach to overcoming the crisis of HIV in the health care system.


Massively parallel MRI detector arrays.
Originally proposed as a method to increase sensitivity by extending the locally high-sensitivity of small surface coil elements to larger areas via reception, the term parallel imaging now includes the use of array coils to perform image encoding. This methodology has impacted clinical imaging to the point where many examinations are performed with an array comprising multiple smaller surface coil elements as the detector of the MR signal. This article reviews the theoretical and experimental basis for the trend towards higher channel counts relying on insights gained from modeling and experimental studies as well as the theoretical analysis of the so-called "ultimate" SNR and g-factor. We also review the methods for optimally combining array data and changes in RF methodology needed to construct massively parallel MRI detector arrays and show some examples of state-of-the-art for highly accelerated imaging with the resulting highly parallel arrays.


Multiple routes of pesticide exposure for honey bees living near agricultural fields.
Populations of honey bees and other pollinators have declined worldwide in recent years. A variety of stressors have been implicated as potential causes, including agricultural pesticides. Neonicotinoid insecticides, which are widely used and highly toxic to honey bees, have been found in previous analyses of honey bee pollen and comb material. However, the routes of exposure have remained largely undefined. We used LC/MS-MS to analyze samples of honey bees, pollen stored in the hive and several potential exposure routes associated with plantings of neonicotinoid treated maize. Our results demonstrate that bees are exposed to these compounds and several other agricultural pesticides in several ways throughout the foraging period. During spring, extremely high levels of clothianidin and thiamethoxam were found in planter exhaust material produced during the planting of treated maize seed. We also found neonicotinoids in the soil of each field we sampled, including unplanted fields. Plants visited by foraging bees (dandelions) growing near these fields were found to contain neonicotinoids as well. This indicates deposition of neonicotinoids on the flowers, uptake by the root system, or both. Dead bees collected near hive entrances during the spring sampling period were found to contain clothianidin as well, although whether exposure was oral (consuming pollen) or by contact (soil/planter dust) is unclear. We also detected the insecticide clothianidin in pollen collected by bees and stored in the hive. When maize plants in our field reached anthesis, maize pollen from treated seed was found to contain clothianidin and other pesticides; and honey bees in our study readily collected maize pollen. These findings clarify some of the mechanisms by which honey bees may be exposed to agricultural pesticides throughout the growing season. These results have implications for a wide range of large-scale annual cropping systems that utilize neonicotinoid seed treatments.


UL54-null pseudorabies virus is attenuated in mice but productively infects cells in culture.
The pseudorabies virus (PRV) UL54 homologs are important multifunctional proteins with roles in shutoff of host protein synthesis, transactivation of virus and cellular genes, and regulation of splicing and translation. Here we describe the first genetic characterization of UL54. We constructed UL54 null mutations in a PRV bacterial artificial chromosome using sugar suicide and lambdaRed allele exchange systems. Surprisingly, UL54 is dispensable for growth in tissue culture but exhibits a small-plaque phenotype that can be complemented in trans by both the herpes simplex virus type 1 ICP27 and varicella-zoster virus open reading frame 4 proteins. Deletion of UL54 in the virus vJSdelta54 had no effect on the ability of the virus to shut off host cell protein synthesis but did affect virus gene expression. The glycoprotein gC accumulated to lower levels in cells infected with vJSdelta54 compared to those infected with wild-type virus, while gK levels were undetectable. Other late gene products, gB, gE, and Us9, accumulated to higher levels than those seen in cells infected with wild-type virus in a multiplicity-dependent manner. DNA replication is also reduced in cells infected with vJSdelta54. UL54 appears to regulate UL53 and UL52 at the transcriptional level as their respective RNAs are decreased in cells infected with vJSdelta54. Interestingly, vJSdelta54 is highly attenuated in a mouse model of PRV infection. Animals infected with vJSdelta54 survive twice as long as animals infected with wild-type virus, and this results in delayed accumulation of virus-specific antigens in skin, dorsal root ganglia, and spinal cord tissues.


Functional proteomics defines the molecular switch underlying FGF receptor trafficking and cellular outputs.
The stimulation of fibroblast growth factor receptors (FGFRs) with distinct FGF ligands generates specific cellular responses. However, the mechanisms underlying this paradigm have remained elusive. Here, we show that FGF-7 stimulation leads to FGFR2b degradation and, ultimately, cell proliferation, whereas FGF-10 promotes receptor recycling and cell migration. By combining mass-spectrometry-based quantitative proteomics with fluorescence microscopy and biochemical methods, we find that FGF-10 specifically induces the rapid phosphorylation of tyrosine (Y) 734 on FGFR2b, which leads to PI3K and SH3BP4 recruitment. This complex is crucial for FGFR2b recycling and responses, given that FGF-10 stimulation of either FGFR2b_Y734F mutant- or SH3BP4-depleted cells switches the receptor endocytic route to degradation, resulting in decreased breast cancer cell migration and the inhibition of epithelial branching in mouse lung explants. Altogether, these results identify an intriguing ligand-dependent mechanism for the control of receptor fate and cellular outputs that may explain the pathogenic role of deregulated FGFR2b, thus offering therapeutic opportunities.


Measurement invariance of TGMD-3 in children with and without mental and behavioral disorders.
This study evaluated whether the Test of Gross Motor Development 3 (TGMD-3) is a reliable tool to compare children with and without mental and behavioral disorders across gross motor skill domains. A total of 1,075 children (aged 3-11 years), 98 with mental and behavioral disorders and 977 without (typically developing), were included in the analyses. The TGMD-3 evaluates fundamental gross motor skills of children across two domains: locomotor skills and ball skills. Two independent testers simultaneously observed children's performances (agreement over 95%). Each child completed one practice and then two formal trials. Scores were recorded only during the two formal trials. Multigroup confirmatory factor analysis tested the assumption of TGMD-3 measurement invariance across disability groups. According to the magnitude of changes in root mean square error of approximation and comparative fit index between nested models, the assumption of measurement invariance across groups was valid. Loadings of the manifest indicators on locomotor and ball skills were significant (p < .001) in both groups. Item response theory analysis showed good reliability results across locomotor and the ball skills full latent traits. The present study confirmed the factorial structure of TGMD-3 and demonstrated its feasibility across normally developing children and children with mental and behavioral disorders. These findings provide new opportunities for understanding the effect of specific intervention strategies on this population. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Carotid artery stenting for vulnerable plaques on MR angiography and ultrasonography: utility of dual protection and blood aspiration method.
Carotid artery stenting (CAS) for internal carotid artery (ICA) stenosis with vulnerable plaques is controversial. We analyzed the effect of a dual protection and blood aspiration method during CAS in patients with vulnerable plaques. A total of 111 patients with ICA stenosis underwent CAS using the dual protection (simultaneous flow reversal and distal filter) and blood aspiration method. In 103 of 111 patients, preoperative carotid plaque was estimated by both 3 T MRI and ultrasonography (US). ICA plaques with a high intensity signal on time-of-flight-MR angiography (TOF-MRA) and/or mobile component on US were defined as vulnerable plaques. We assessed major adverse events (MAE) (ie, major stroke, myocardial infarction, and death) and hyperintense spots on diffusion-weighted images (DWI) after CAS. We then evaluated the visible debris captured by dual protection and blood aspiration during CAS. The preoperative ICA plaque on TOF-MRA and US was judged to be vulnerable in 48.5% (50/103 patients). The success rate of the CAS procedure was 100% with no MAE within 30 days. DWI showed small hyperintense spots in 18% (9/50 patients) and 18.9% (10/53 patients) in the vulnerable and non-vulnerable plaque groups, respectively. Visible debris was captured in 68% (34/50 patients) and 45.3% (24/53 patients) in the vulnerable and non-vulnerable plaque groups, respectively (p=0.0286). The combination of dual protection and blood aspiration could provide effective distal embolic protection although vulnerable plaques on TOF-MRA and US had a high incidence of debris during CAS. Thus, CAS using dual protection and blood aspiration is safe in patients with vulnerable plaques.


Dynamics of reductive genome evolution in mitochondria and obligate intracellular microbes.
Reductive evolution in mitochondria and obligate intracellular microbes has led to a significant reduction in their genome size and guanine plus cytosine content (GC). We show that genome shrinkage during reductive evolution in prokaryotes follows an exponential decay pattern and provide a method to predict the extent of this decay on an evolutionary timescale. We validated predictions by comparison with estimated extents of genome reduction known to have occurred in mitochondria and Buchnera aphidicola, through comparative genomics and by drawing on available fossil evidences. The model shows how the mitochondrial ancestor would have quickly shed most of its genome, shortly after its incorporation into the protoeukaryotic cell and prior to codivergence subsequent to the split of eukaryotic lineages. It also predicts that the primary rickettsial parasitic event would have occurred between 180 and 425 million years ago (MYA), an event of relatively recent evolutionary origin considering the fact that Rickettsia and mitochondria evolved from a common alphaproteobacterial ancestor. This suggests that the symbiotic events of Rickettsia and mitochondria originated at different time points. Moreover, our model results predict that the ancestor of Wigglesworthia glossinidia brevipalpis, dated around the time of origin of its symbiotic association with the tsetse fly (50-100 MYA), was likely to have been an endosymbiont itself, thus supporting an earlier proposition that Wigglesworthia, which is currently a maternally inherited primary endosymbiont, evolved from a secondary endosymbiont.


Management of community-acquired pneumonia in adults.
To revise the existing South African community-acquired pneumonia guideline in the light of the following factors: * Increasing antibiotic resistance * Introduction of new antibiotics * International trends based on evidence published since the previous guideline. The main aim of the guideline is to recommend an initial choice of antibiotics in patients with community-acquired pneumonia encompassing the following subgroups: * Adults without co-morbid illness * The elderly and/or those with associated co-morbid illness, including patients with concomitant human immunodeficiency virus (HIV) infection, and * Patients with severe pneumonia. Studies comparing patient outcome obtained with the various treatment regimens have been reviewed. The choice of antibiotic is based on the most commonly isolated pathogens, with cost as a consideration. The empiric antibiotic therapy covers all commonly encountered organisms in patients with community-acquired pneumonia and is likely to achieve the best prognosis. Working group of clinicians and clinical microbiologists, following detailed literature review, particularly of studies performed in South Africa. Benefits, harms and costs. The guideline pays particular attention to cost-effectiveness in South Africa and promotes rational antibiotic prescribing with the aim of limiting emergence of antibiotic resistance. These include details of likely pathogens, an appropriate diagnostic approach, indicators of severity of illness, need for hospitalisation and antibiotic treatment options. The guideline was updated by a working group of the South African Thoracic Society, which included members of the Critical Care Society of Southern Africa, and the Federation of Infectious Diseases Societies of Southern Africa. Reference was made to the recently updated international guidelines from the UK, Europe, Canada and the USA. The guideline is endorsed by the South African Thoracic Society, the Federation of Infectious Diseases Societies of Southern Africa, and the Critical Care Society of Southern Africa.


Elongation of primed DNA templates by eukaryotic DNA polymerases.
The combined action of DNA polymerase alpha and DNA polymerase beta leads to the synthesis of full-length linear DNA strands with phi X174 DNA templates containing an RNA primer. The reaction can be carried out in two stages. In the first stage, DNA polymerase alpha catalyzes the synthesis of a chain that averaged 230 deoxynucleotides long and was covalently linked to the RNA primer. In the second stage, DNA polymerase beta elongates the DNA strand covalently attached to the RNA primer to full length. With DNA primers, DNA polymerase alpha catalyzes only limited deoxynucleotide addition whereas DNA polymerase beta alone elongates DNA primed templates to full length. DNA polymerase beta can also stimulate the synthesis of adenovirus DNA in vitro in the presence of a cytosol extract from adenovirus-infected cells. In all of these systems, dNMP incorporation catalyzed by DNA polymerase beta was sensitive to N-ethylmaleimide; however, this polymerase activity was resistant to N-ethylmaleimide with poly(rA) x (dT) as the primer template.


Malignant transformation of multipotent muscle-derived cells by concurrent differentiation signals.
Recent studies have shown that germ-line determination occurs early in development and that extracellular signaling can alter this fate. This denial of a cell's fate by counteracting its intrinsic signaling pathways through extrinsic stimulation is believed to be associated with oncogenesis. Using specific populations of multipotent skeletal muscle-derived stem cells (MDSCs), we have been able to generate tumors by subjecting cells with specific lineage predilections to concomitant differentiation signals. More specifically, when a stem cell that had a predilection toward osteogenesis was implanted into a skeletal muscle, tumors formed in 25% of implanted mice. When cells predilected to undergo myogenesis were pretreated with bone morphogenetic protein 4 (BMP4) for 4 days prior to implantation, they formed tumors in 25% of mice. These same myogenic predilected cells, when transduced to express BMP4 and implanted into either a long-bone or cranial defect, formed bone, but they formed tumors in 100% of mice when implanted into the skeletal muscle. The tumors generated in this latter study were serially transplantable as long as they retained BMP4 expression. Furthermore, when we impeded the ability of the cells to undergo myogenic differentiation using small interfering RNA to the myogenic regulator MyoD1, we stopped transformation. Based on our findings, we postulate that specific MDSC populations can undergo concomitant signal-induced transformation and that the initial stages of transformation may be due to changes in the balance between the inherent nature of the cell and extrinsic signaling pathways. This theory represents a potential link between somatic stem cells and cancer and suggests an involvement of the niche/environment in transformation.


Islet cytotoxicity of interleukin 1. Influence of culture conditions and islet donor characteristics.
We recently demonstrated that the macrophage product interleukin 1 (IL-1) is cytotoxic to isolated pancreatic islets and hypothesized that IL-1 is responsible for beta-cell destruction in insulin-dependent diabetes mellitus (IDDM). We studied whether the variation in IDDM preponderance with age, sex, and genetic background in vivo is reflected in different susceptibility to IL-1 toxicity of islets in vitro. In addition, we studied the effect of preculture conditions that support endocrine islet cell function and decrease nonendocrine passenger-cell survival on the susceptibility of beta-cells to IL-1 because it is unknown whether IL-1 acts directly on beta-cells or via passenger cells. No differences in susceptibility to various doses of IL-1-containing mononuclear cell supernatants were found between islets isolated from newborn or adult rats, male or female rats, or rats of four inbred strains, indicating that age, sex, and genetic background do not influence the susceptibility of the beta-cell to IL-1. Preculture of islets for 1-7 days in normal atmosphere and preculture of islet clusters in 95% O2 to delete passenger cells did not affect IL-1-mediated cytotoxicity, suggesting that IL-1 acts directly on beta-cells. Increasing the glucose concentration (22 mM) in the culture medium, which is known to protect beta-cells against alloxan toxicity, reduced IL-1 toxicity. Five or 25% normal human serum as well as 5% normal rat serum, but not equivalent concentrations of human serum albumin, inhibited IL-1 toxicity, indicating the presence of IL-1 inhibitors, IL-1 antagonists, or beta-cell-protecting factors in normal serum.(ABSTRACT TRUNCATED AT 250 WORDS)


Man-In-The-Middle Attacks in Vehicular Ad-Hoc Networks: Evaluating the Impact of Attackers' Strategies.
Vehicular Ad-Hoc Network (VANET), a vital component of Intelligent Transportation Systems (ITS) technology, relies on communication between dynamically connected vehicles and static Road Side Units (RSU) to offer various applications (e.g., collision avoidance alerts, steep-curve warnings and infotainment). VANET has a massive potential to improve traffic efficiency, and road safety by exchanging critical information between nodes (vehicles and RSU), thus reducing the likelihood of traffic accidents. However, this communication between nodes is subject to a variety of attacks, such as Man-In-The-Middle (MITM) attacks which represent a major risk in VANET. It happens when a malicious node intercepts or tampers with messages exchanged between legitimate nodes. In this paper, we studied the impact on network performance of different strategies which attackers can adopt to launch MITM attacks in VANET, such as fleet or random strategies. In particular, we focus on three goals of MITM attacks-message delayed, message dropped and message tampered. The simulation results indicate that these attacks have a severe influence on the legitimate nodes in VANET as the network experience high number of compromised messages, high end-to-end delays and preeminent packet losses.


How should results from completed studies influence ongoing clinical trials? The CAFA Study experience.
Seven randomized studies during the past 5 years have evaluated or are evaluating the efficacy of warfarin or aspirin or both in decreasing the risk of embolic events in patients with nonrheumatic atrial fibrillation. By March 1990, two of the studies had been published, both of which showed a statistically significant decrease in embolic events in patients treated with warfarin and a low rate of major bleeding events. The investigators associated with the other ongoing studies were forced to consider how these results should affect the decision to recruit and continue follow-up of patients in their own studies. The Steering Committee of the Canadian Atrial Fibrillation Anticoagulation (CAFA) study thought the newly published results from other studies were valid, clinically important, and generalizable. The committee considered the following options for the CAFA study: continue patient recruitment as planned, provide the data available in CAFA to its External Safety and Efficacy Monitoring Committee for analysis to determine whether the CAFA data already showed a benefit of warfarin, stop patient recruitment but continue to follow patients in the group to which they were assigned, stop the trial immediately and perform a final analysis, and attempt to perform a meta-analysis of all data available from all trials. The Steering Committee of CAFA decided that the evidence of benefit with warfarin, from the two published studies, was sufficiently compelling as to stop recruitment into CAFA without any preliminary examination of the CAFA data.


Proficient brain for optimal performance: the MAP model perspective.
Background. The main goal of the present study was to explore theta and alpha event-related desynchronization/synchronization (ERD/ERS) activity during shooting performance. We adopted the idiosyncratic framework of the multi-action plan (MAP) model to investigate different processing modes underpinning four types of performance. In particular, we were interested in examining the neural activity associated with optimal-automated (Type 1) and optimal-controlled (Type 2) performances. Methods. Ten elite shooters (6 male and 4 female) with extensive international experience participated in the study. ERD/ERS analysis was used to investigate cortical dynamics during performance. A 4 × 3 (performance types × time) repeated measures analysis of variance was performed to test the differences among the four types of performance during the three seconds preceding the shots for theta, low alpha, and high alpha frequency bands. The dependent variables were the ERD/ERS percentages in each frequency band (i.e., theta, low alpha, high alpha) for each electrode site across the scalp. This analysis was conducted on 120 shots for each participant in three different frequency bands and the individual data were then averaged. Results. We found ERS to be mainly associated with optimal-automatic performance, in agreement with the "neural efficiency hypothesis." We also observed more ERD as related to optimal-controlled performance in conditions of "neural adaptability" and proficient use of cortical resources. Discussion. These findings are congruent with the MAP conceptualization of four performance states, in which unique psychophysiological states underlie distinct performance-related experiences. From an applied point of view, our findings suggest that the MAP model can be used as a framework to develop performance enhancement strategies based on cognitive and neurofeedback techniques.


From dynamic self-organization to avalanching instabilities in soft-granular threads.
We study the dynamics of threads of monodisperse droplets, including droplet chains and multi-chains, in which the droplets are interconnected by capillary bridges of another immiscible liquid phase. This system represents wet soft-granular matter - a class of granular materials in which the grains are soft and wetted by thin fluid films-with other examples including wet granular hydrogels or foams. In contrast to wet granular matter with rigid grains (e.g., wet sand), studied previously, the deformability of the grains raises the number of available metastable states and facilitates rearrangements which allow for reorganization and self-assembly of the system under external drive, e.g., applied via viscous forces. We use a co-flow configuration to generate a variety of unique low-dimensional regular granular patterns, intermediate between 1D and 2D, ranging from linear chains and chains with periodically occurring folds to multi-chains and segmented structures including chains of finite length. In particular, we observe that the partially folded chains self-organize via limit cycle of displacements and rearrangements occurring at a frequency self-adapted to the rate of build-up of compressive strain in the chain induced by the viscous forces. Upon weakening of the capillary arrest of the droplets, we observe spontaneous fluidization of the quasi-solid structures and avalanches of rearrangements. We identify two types of fluidization-induced instabilities and rationalize them in terms of a competition between advection and propagation. While we use aqueous droplets as the grains we demonstrate that the reported mechanisms of adaptive self-assembly apply to other types of soft granular systems including foams and microgels. We discuss possible application of the reported quasi-1D compartmentalized structures in tissue engineering, bioprinting and materials science.


Methotrexate treatment of rheumatoid arthritis: is a fortnightly maintenance schedule enough?
In 15 patients with rheumatoid arthritis who were in clinical remission the weekly regimen of methotrexate treatment was changed to fortnightly without a change in dose. A total of 13 patients completed a 12 month trial. No change in clinical or laboratory parameters occurred. There was no change in the use of analgesics or non-steroidal anti-inflammatory drugs and the patients remained in remission. Two patients had to be withdrawn after two and four months respectively because of a flare in disease activity. It is suggested that in most patients with rheumatoid arthritis who are treated with methotrexate and whose disease activity is stable a fortnightly regimen can be permitted without affecting drug efficacy.


Prevalence and risk factors associated with sexually transmitted infections (STIs) among women of reproductive age in Swaziland.
Sexually transmitted infections (STIs) remain an important public health problem with approximately half a billion new cases annually among persons aged 15-49 years. Epidemiological data on STIs among women of reproductive age in Swaziland are limited. The availability of epidemiological data on STIs and associated risk factors in this population is essential for the development of successful prevention, diagnosis and management strategies in the country. The study aimed to determine the prevalence and risk factors associated with STIs. A total of 655 women aged 15-49 years were systematically enrolled from five health facilities using a cross-sectional study design. Cervical specimen were tested using GeneXpert CT/NG Assays for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG), GeneXpertTV Assay for Trichomonas vaginalis (TV), and GeneXpert HPV Assays for hr-HPV. Blood samples were tested using Alere Determine HIV-1/2Ag/Ab Combo and Trinity Biotech Uni-Gold Recombigen HIV test for confirmation for HIV, and Rapid Plasma Reagin and TPHA test for confirmation for Treponema pallidum (syphilis). Genital warts were assessed prior to specimen collection. Survey weighted analyses were done to estimate the population burden of STIs. The four most common curable STIs: CT, NG, TV, Treponema pallidum (syphilis), as well as genital warts were considered in this study. The overall weighted prevalence of any of these five STIs was 19.4% (95% CI: 14.9-24.8), corresponding to 72 990 women with STIs in Swaziland. The estimated prevalences were 7.0% (95% CI: 4.1-11.2) for CT, 6.0% (95% CI: 3.8-8.8) for NG, 8.4% (95% CI: 5.4-12.8) for TV, 1.4% (95% CI: 1.1-10.2) for syphilis and 2.0% (95% CI: 1.0-11.4) for genital warts. The overall weighted HIV prevalence was 42.7% (95%CI: 35.7-46.2). Among hr-HPV positive women, 18.8% (95% CI: 13.1-26.3) had one STI, while 6.3% (95% CI: 3.3-11.7) had multiple STIs. Risk factors associated with STIs were being employed (OR = 2.2, 95% CI: 1.0-4.7), self-employed (OR = 2.8, 95% CI: 1.5-5.5) and being hr-HPV positive (OR = 2.0, 95% CI: 1.3-3.1). Age (0.9, 95% CI: 0.8-0.9), being married (OR = 0.4, 95% CI: 0.3-0.7) and not using condoms with regular partners (OR = 0.5, 95% CI: 0.3-0.9) were inversely associated with STIs. STIs are highly prevalent among women of reproductive age in Swaziland. Thus, a comprehensive STIs screening, surveillance and treatment programme would be justified and could potentially lower the burden of STIs in the country.


Prevalence of and factors associated with burnout among health care professionals in Arab countries: a systematic review.
Burnout among healthcare professionals is one of the key challenges affecting health care practice and quality of care. This systematic review aims to (1) estimate the prevalence of burnout among health care professionals (HCP) in Arab countries; and (2) explore individual and work-related factors associated with burnout in this population. Multiple electronic databases were searched for studies published in English or Arabic from January 1980 to November 2014 assessing burnout (using the Maslach Burnout Inventory; MBI) amongst health care professionals (HCP) in Arab countries. Nineteen studies (N = 4108; 49.3% females) conducted on HCP in Bahrain, Egypt, Jordan, Lebanon, Palestine, Saudi Arabia and Yemen were included in this review. There was a wide range of prevalence estimates for the three MBI subscales, high Emotional Exhaustion (20.0-81.0%), high Depersonalization (9.2-80.0%), and low Personal Accomplishment (13.3-85.8%). Gender, nationality, service duration, working hours, and shift patterns were all significantly associated with burnout. Within the constraints of the study and the range of quality papers available, our review revealed moderate-to-high estimates of self-reported burnout among HCP in Arab countries that are similar to prevalence estimates in non-Arabic speaking westernized developed countries. In order to develop culturally appropriate interventions, further research using longitudinal designs is needed to confirm the risk factors for burnout in specific HCP settings and specialties in Arab countries.


Catalysis beyond frontier molecular orbitals: Selectivity in partial hydrogenation of multi-unsaturated hydrocarbons on metal catalysts.
The mechanistic understanding and control over transformations of multi-unsaturated hydrocarbons on transition metal surfaces remains one of the major challenges of hydrogenation catalysis. To reveal the microscopic origins of hydrogenation chemoselectivity, we performed a comprehensive theoretical investigation on the reactivity of two α,β-unsaturated carbonyls-isophorone and acrolein-on seven (111) metal surfaces: Pd, Pt, Rh, Ir, Cu, Ag, and Au. In doing so, we uncover a general mechanism that goes beyond the celebrated frontier molecular orbital theory, rationalizing the C═C bond activation in isophorone and acrolein as a result of significant surface-induced broadening of high-energy inner molecular orbitals. By extending our calculations to hydrogen-precovered surface and higher adsorbate surface coverage, we further confirm the validity of the "inner orbital broadening mechanism" under realistic catalytic conditions. The proposed mechanism is fully supported by our experimental reaction studies for isophorone and acrolein over Pd nanoparticles terminated with (111) facets. Although the position of the frontier molecular orbitals in these molecules, which are commonly considered to be responsible for chemical interactions, suggests preferential hydrogenation of the C═O double bond, experiments show that hydrogenation occurs at the C═C bond on Pd catalysts. The extent of broadening of inner molecular orbitals might be used as a guiding principle to predict the chemoselectivity for a wide class of catalytic reactions at metal surfaces.


Latent geometry of bipartite networks.
Despite the abundance of bipartite networked systems, their organizing principles are less studied compared to unipartite networks. Bipartite networks are often analyzed after projecting them onto one of the two sets of nodes. As a result of the projection, nodes of the same set are linked together if they have at least one neighbor in common in the bipartite network. Even though these projections allow one to study bipartite networks using tools developed for unipartite networks, one-mode projections lead to significant loss of information and artificial inflation of the projected network with fully connected subgraphs. Here we pursue a different approach for analyzing bipartite systems that is based on the observation that such systems have a latent metric structure: network nodes are points in a latent metric space, while connections are more likely to form between nodes separated by shorter distances. This approach has been developed for unipartite networks, and relatively little is known about its applicability to bipartite systems. Here, we fully analyze a simple latent-geometric model of bipartite networks and show that this model explains the peculiar structural properties of many real bipartite systems, including the distributions of common neighbors and bipartite clustering. We also analyze the geometric information loss in one-mode projections in this model and propose an efficient method to infer the latent pairwise distances between nodes. Uncovering the latent geometry underlying real bipartite networks can find applications in diverse domains, ranging from constructing efficient recommender systems to understanding cell metabolism.


Ghrelin and motilin in the gastrointestinal system.
Human ghrelin and human motilin, belonging to the ghrelin/motilin-related peptide family, share 36% amino acid sequence identity, while the human ghrelin receptor exhibits a remarkable 50% overall identity with the human motilin receptor. In addition to their structural resemblance, ghrelin and motilin are the only two mammalian hormones known to decrease in the postprandial period. Ghrelin and motilin participate in initiating the migrating motor complex in the stomach, and stimulate gastrointestinal motility, accelerate gastric emptying, and induce "gastric hunger". In addition to modulating the release of growth hormone and gut motility, ghrelin plays a crucial role in the secretion and protection of the stomach and colon. Ghrelin mimetics and motilin agonists are currently being developed to reverse gastrointestinal hypomotility disorders. With additional appetite-enhancing, adiposity-promoting, and anti-inflammatory effects, ghrelin and rikkunshito (a traditional Japanese herb enhancing acyl ghrelin signaling) are superior to motilin in the treatment of cancer-related anorexia and cachexia, post-chemotherapy symptoms, rheumatological diseases, age-related frailty, as well as post-operative, septic, and post-burn gut ileus.


Gender discrepancies in the level of disease progression in hospitalized patients with diabetes.
Diabetes is a widely recognized and common cause of mortality, morbidity, and excess cost in the health care system. Type 2 diabetes is specifically on the rise, particularly in association with the increasing obesity rate. Substantial literature has examined differences in behavior across genders and potential effect on disease. However, based on a literature review, little has been done to evaluate differences in patterns of diabetes related to inpatient care across genders and to link these differences with potential explanations related to differences in care-seeking behavior, treatment compliance, and lifestyle choices. This review and analysis of national inpatient data demonstrates substantial differences associated with gender in patterns of hospital-based care in patients with type 2 diabetes. Men are more likely to be admitted for diabetes-related conditions and to present with blood sugars at extreme levels, including acutely elevated and dangerous blood sugar levels. When considering these findings in conjunction with the existing literature, it can be concluded that these differences are primarily reflective of variances in care-seeking behavior and long-term adherence to prescribed medications. Policies that promote expansion of health care benefits to include coverage for men at risk for type 2 diabetes, aggressive education and treatment programs, and expanded prescription drug coverage are necessary to reduce gender discrepancies in patterns of hospitalization and to improve outcomes.


Nephelometer optical response model for the interpretation of atmospheric aerosol measurements.
A numerical model evaluating the response of a typical integrating nephelometer is described. The model incorporates the actual scattering geometry as well as the effects of a finite light source, detector size, and a nonideal Lambertian diffuser. An angular scattering weighting function is introduced to provide a tractable approach in numerical calculations and easy application. Using established size distribution ensembles associated with a few representative aerosol types, we compare the calculated response of a real nephelometer with that of an ideal, or perfect, nephelometer. The results indicate that, frequently, the nephelometer-produced aerosol-scattering coefficient is of the order of 10-20% too small; but for some naturally occurring aerosols, the difference may be as large as 40-50%. For a multiple-wavelength nephelometer, the response model can be employed to estimate the expected error in the aerosol-scattering coefficients directly from the measurements themselves.


Oral N-carbamylglutamate supplementation increases protein synthesis in skeletal muscle of piglets.
This study investigated the potential mechanisms by which oral supplementation of N-carbamylglutamate (NCG), an analogue of endogenous N-acetylglutamate (an activator of arginine synthesis) increases growth rate in sow-reared piglets. Two piglets of equal body weight (BW) and of the same gender from each lactating sow were allotted to receive oral administration of 0 (control) or 50 mg of NCG/kg BW every 12 h for 7 d. Piglets (n=32; BW=3 kg) were studied in the food-deprived or fed state following the 7 d of treatment. Overnight food-deprived piglets were given NCG or water (control) at time 0 and 60 min. Piglets studied in the fed state were gavage-fed sow's milk with their respective NCG treatment at 0 and 60 min. At 60 min, the piglets were administered a flooding dose of [3H]phenylalanine and killed at 90 min to measure tissue protein synthesis. Piglets treated with NCG gained 28% more weight than control pigs (P<0.001) over the 7-d period. Fed pigs had greater rates of protein synthesis in longissimus dorsi and gastrocnemius muscles and duodenum compared with food-deprived pigs (P<0.001). Absolute protein synthesis rates in longissimus dorsi (P=0.050) and gastrocnemius (P=0.068) muscles were 30 and 21% greater, respectively, in NCG-treated compared with control pigs. Piglets supplemented with NCG also had greater plasma concentrations of arginine and somatotropin than control pigs (P<0.001). The results suggest that oral NCG supplementation increases plasma arginine and somatotropin levels, leading to an increase in growth rate and muscle protein synthesis in nursing piglets.


Site-1 protease-derived soluble (pro)renin receptor targets vasopressin receptor 2 to enhance urine concentrating capability.
The antidiuretic hormone vasopressin (AVP), acting through its type 2 receptor (V2R) in the collecting duct (CD), critically controls urine concentrating capability. Here, we report that site-1 protease-derived (S1P-derived) soluble (pro)renin receptor (sPRR) participates in regulation of fluid homeostasis via targeting V2R. In cultured inner medullary collecting duct (IMCD) cells, AVP-induced V2R expression was blunted by a PRR antagonist, PRO20; a PRR-neutralizing antibody; or a S1P inhibitor, PF-429242. In parallel, sPRR release was increased by AVP and reduced by PF-429242. Administration of histidine-tagged sPRR, sPRR-His, stimulated V2R expression and also reversed the inhibitory effect of PF-429242 on the expression induced by AVP. PF-429242 treatment in C57/BL6 mice impaired urine concentrating capability, which was rescued by sPRR-His. This observation was recapitulated in mice with renal tubule-specific deletion of S1P. During the pharmacological or genetic manipulation of S1P alone or in combination with sPRR-His, the changes in urine concentration were paralleled with renal expression of V2R and aquaporin-2 (AQP2). Together, these results support that S1P-derived sPRR exerts a key role in determining renal V2R expression and, thus, urine concentrating capability.


Feasibility and Efficacy of Intra-Arterial Administration of Mesenchymal Stem Cells in an Animal Model of Double Toxin-Induced Multiple System Atrophy.
Multiple system atrophy (MSA) is a sporadic neurodegenerative disease of the central and autonomic nervous system. Because no drug treatment consistently benefits MSA patients, neuroprotective strategy using mesenchymal stem cells (MSCs) has a lot of concern for the management of MSA. In this study, we investigated the safety and efficacy of intra-arterial administration of MSCs via internal carotid artery (ICA) in an animal model of MSA. The study was composed of feasibility test using a ×10 and ×50 of a standard dose of MSCs (4 × 107 MSCs) and efficacy test using a ×0.2, ×2, and ×20 of the standard dose. An ultrasonic flow meter and magnetic resonance imaging (MRI) showed that no cerebral ischemic lesions with patent ICA blood flow was were observed in animals receiving a ×10 of the standard dose of MSCs. However, no MSA animals receiving a ×50 of the standard dose survived. In efficacy test, animals injected with a ×2 of the standard dose increased nigrostriatal neuronal survival relative to a ×0.2 or ×20 of the standard dose. MSA animals receiving MSCs at ×0.2 and ×2 concentrations of the standard dose exhibited a significant reduction in rotation behavior relative to ×20 of the standard dose of MSCs. Cerebral ischemic lesions on MRI were only observed in MSA animals receiving a ×20 of the standard dose. The present study revealed that if their concentration is appropriate, intra-arterial injection of MSCs is safe and exerts a neuroprotective effect on striatal and nigral neurons with a coincidental improvement in motor behavior. Stem Cells Translational Medicine 2017;6:1424-1433.


Relationship Between HIV Coinfection, Interleukin 10 Production, and Mycobacterium tuberculosis in Human Lymph Node Granulomas.
Human immunodeficiency virus type 1 (HIV)-infected persons are more susceptible to tuberculosis than HIV-uninfected persons. Low peripheral CD4+ T-cell count is not the sole cause of higher susceptibility, because HIV-infected persons with a high peripheral CD4+ T-cell count and those prescribed successful antiretroviral therapy (ART) remain more prone to active tuberculosis than HIV-uninfected persons. We hypothesized that the increase in susceptibility is caused by the ability of HIV to manipulate Mycobacterium tuberculosis-associated granulomas. We examined 71 excised cervical lymph nodes (LNs) from persons with HIV and M. tuberculosis coinfection, those with HIV monoinfection, and those with M. tuberculosis monoinfection with a spectrum of peripheral CD4+ T-cell counts and ART statuses. We quantified differences in M. tuberculosis levels, HIV p24 levels, cellular response, and cytokine presence within granulomas. HIV increased M. tuberculosis numbers and reduced CD4+ T-cell counts within granulomas. Peripheral CD4+ T-cell depletion correlated with granulomas that contained fewer CD4+ and CD8+ T cells, less interferon γ, more neutrophils, more interleukin 10 (IL-10), and increased M. tuberculosis numbers. M. tuberculosis numbers correlated positively with IL-10 and interferon α levels and fewer CD4+ and CD8+ T cells. ART reduced IL-10 production. Peripheral CD4+ T-cell depletion correlated with increased M. tuberculosis presence, increased IL-10 production, and other phenotypic changes within granulomas, demonstrating the HIV infection progressively changes these granulomas.


Young people and HIV in Cambodia: meanings, contexts and sexual cultures.
Like many other countries in South East Asia, Cambodia is experiencing a rapidly developing AIDS epidemic. Groups reported as being particularly seriously affected include sex workers and their clients. Young people too may be at heightened risk: some young women find sex work a lucrative option in the context of low wages and poor employment opportunities, and some young men pay for sex either as individuals or as part of group socializing. These same young men may subsequently have sex with other partners, thus extending networks of transmission. While there is limited knowledge about the form of such sexual networks, little is known about the meanings that underpin young people's sexual relations and partnerships, the sexual identities associated with such meanings, and prevailing socio-sexual cultures. This paper reports on findings from an in-depth qualitative study conducted among two groups of young people: one urban, the other rural. Following an initial Rapid Assessment Process, data was collected via individual interviews, focus group interviews and participant observation. The research team included young people themselves. Data is presented on dominant discourses about sex and sexuality in Cambodia; contemporary patterns of sexual behaviour; sexual meanings and sexual practices; sexual relations among young people involving payment; and sexual relations not involving payment. The implications for more effective HIV prevention efforts are discussed.


Survival of Escherichia coli in common garden mulches spiked with synthetic greywater.
Reuse of domestic wastewater is increasingly practiced as a means to address global demands on fresh water. Greywater is primarily reused via subsurface irrigation of gardens, where the soil environment is seen to be an integral part of the treatment process. The fate of biological contaminants (i.e. pathogens) in the soil is reasonably well understood, but their persistence and survival in soil cover layers is largely unexplored. This study investigated the ability of Escherichia coli to survive in common soil cover layers. Three garden mulches were investigated: pea straw mulch, a bark-based mulch and a coconut husk mulch. Each mulch was treated with an E. coli solution, a synthetic greywater with E. coli, or a freshwater control. Escherichia coli was applied at 1 × 104 most probable number (MPN) per g dry weight mulch. Subsamples were temporally analysed for E. coli. The bark and coconut husk mulches showed a steady decline in E. coli numbers, while E. coli increased in the pea straw mulch for the duration of the 50 days experiment, peaking at 1·8 × 108 MPN per g dry weight mulch. This study highlighted the importance of selection of a suitable material for covering areas that are subsurface irrigated with greywater. Potential for microbial contamination is one of the limiting factors for domestic greywater reuse. Although subsurface irrigation is considered to be one of the lowest risk applications, there is still a possibility of microbes reaching the soil surface if the environmental conditions are not favourable or if soil movement inadvertently exposes the irrigation line. In these circumstances, the soil cover layer may be contaminated by greywater microbes. This study assesses the survival rates of the pathogen indicator organism Escherichia coli in three soil cover materials commonly used worldwide and makes clear recommendations to facilitate the safe reuse of domestic greywater.


Rhomboid intramembrane protease RHBDL4 triggers ER-export and non-canonical secretion of membrane-anchored TGFα.
Rhomboid intramembrane proteases are the enzymes that release active epidermal growth factor receptor (EGFR) ligands in Drosophila and C. elegans, but little is known about their functions in mammals. Here we show that the mammalian rhomboid protease RHBDL4 (also known as Rhbdd1) promotes trafficking of several membrane proteins, including the EGFR ligand TGFα, from the endoplasmic reticulum (ER) to the Golgi apparatus, thereby triggering their secretion by extracellular microvesicles. Our data also demonstrate that RHBDL4-dependent trafficking control is regulated by G-protein coupled receptors, suggesting a role for this rhomboid protease in pathological conditions, including EGFR signaling. We propose that RHBDL4 reorganizes trafficking events within the early secretory pathway in response to GPCR signaling. Our work identifies RHBDL4 as a rheostat that tunes secretion dynamics and abundance of specific membrane protein cargoes.


Child maltreatment in Puerto Rico: findings from the 2010 National Child Abuse and Neglect Data System.
Child maltreatment can have long-term adverse effects. Quantifying the scope and characteristics of child maltreatment is necessary for effective prevention in Puerto Rico. The National Child Abuse and Neglect Data System Child File contains all the reports of child maltreatment from the United States (US) and Puerto Rico. A child maltreatment victim is defined as a child whose maltreatment was substantiated or indicated by the local child protective agency. We compared reporting and victimization rates and reporting sources in Puerto Rico, with those in the US and examined characteristics of child maltreatment in Puerto Rico. During 2006-2010, a total of 31,849-40,712 cases of child maltreatment were reported annually in Puerto Rico. Victimization rates are consistently higher in Puerto Rico than in the US (10.7/1,000-14.8/1,000 in Puerto Rico vs. 10.1/1,000-12.1/1,000 in the US), despite consistently lower reporting rates. In 2010, victimization rates were highest among children aged 1-6 years. In Puerto Rico, neglect is the most common form of maltreatment, followed by emotional abuse; however, the majority of victims suffered multiple types of abuse. Reporting was more commonly anonymous in Puerto Rico (29.8%) than in the US (9.4%) and less commonly provided by professionals in Puerto Rico (37.2%) than in the US (58.7%). We identified a high prevalence of child maltreatment in Puerto Rico. A lower reporting rate, higher victimization rate, and substantial percentage of anonymous reporting indicate potential underreporting of child maltreatment in Puerto Rico. Increasing the awareness and training professionals for improved child maltreatment identification could help alleviate the problem of underreporting.


Geographical distribution and risk factors for Echinococcus granulosus infection in peri-urban wild dog populations.
The transmission of zoonotic pathogens associated with wildlife in peri-urban environments can be influenced by the interplay of numerous socioecological factors. Echinococcus granulosus is known to be common within peri-urban wild dog populations however knowledge of the factors that influence its presence is limited. We investigated the demographic distribution of adult cestode abundance (ACA: defined as the product between prevalence of infection and adult cestode infection intensity) and the role of the physical environment, climate and individual factors in determining the geographical variation of E. granulosus infection in wild dog populations from southeast Queensland and surrounds. Our results align with previous studies that show significant E. granulosus aggregation in that 15.8% of peri-urban wild dogs sampled were responsible for ∼70% of the total adult cestode infection intensity. On average, female dogs were found to have a higher ACA than male dogs, and the average ACA generally decreased with age. Significant geographical variation was found in the prevalence of E. granulosus, with a strong propensity for clustering. The average size of clusters was 22.5 km. The probability of finding E. granulosus infection significantly increased with maximum temperature, relative humidity, and rainfall, and after accounting for individual and climatic variables, the model accounted for the majority of the spatial dependence in prevalence. Our predictive map of E. granulosus prevalence in peri-urban wild dogs confirms that E. granulosus is highly endemic in the eastern Australia study area. The prediction map provides a useful tool for targeting potential disease management strategies in peri-urban areas, where broad scale management of wild dog populations is difficult to implement.


Nasal dissemination of a single-clone IgH-rearranged conjunctival MALT lymphoma through the nasolacrimal duct: A case report.
The aim of the present study was to report a rare case of single-clone, immunoglobulin heavy chain (IgH)-rearranged mucosa-associated lymphoid tissue (MALT) lymphoma in the conjunctiva, with nasal cavity dissemination through the nasolacrimal duct. A 24-year-old female was diagnosed with MALT lymphoma of the nasal cavity at the Department of Otolaryngology, Wan Fang Medical Center, Taipei Medical University (Tapei, Taiwan) in October 2008. A biopsy of the relapsing conjunctival lesion revealed a MALT lymphoma by pathological staining, while a single-clone, IgH-rearranged tumor lesion in the nasal cavity and conjunctiva was confirmed using continuous sinus computed tomography scans and polymerase chain reaction. Tumor lesions were negative for Helicobacter pylori and Chlamydia infection, but exhibited bilateral neck lymph node dissemination. A combination of radiation therapy (a total dosage of 46.8 Gray, in two phases covering the left lacrimal sac, nasal cavity and bilateral neck region) and topical ciprofloxacin plus steroid (0.3% ciprofloxacin 4 times a day and betamethasone eye ointment before sleep for 1 month) was provided as an effective therapeutic strategy, and no recurrence was found in the next 3 years. The nasolacrimal duct serves as a channel for conjunctival tumor spreading and is easily neglected. IgH-involved translocation in MALT lymphoma is a factor in the progression of the disease, and aggressive combination therapy is essential for a high-risk, disseminated IgH-rearranged MALT lymphoma.


Natural killer cell in systemic lupus erythematosus. Defects in effector lytic activity and response to interferon and interferon inducers.
Spontaneous cytotoxicity mediated by natural killer (NK) cells is impaired in several human diseases including systemic lupus erythematosus (SLE). The precise mechanism(s) by which NK activity is suppressed in patients with SLE is generally unknown. The present study was designed to focus on cellular defects per se in NK cells from patients with SLE. It was observed that the usual enhancing effect of interferon (IF) and IF inducers was markedly impaired in SLE patients. Of 24 SLE patients studied, 17 had significantly decreased NK activity relative to controls. NK activity had a significant negative correlation with clinical activity score (r = -0.56, P less than 0.005) but was not correlated with corticosteroid dose, antinuclear antibody titers, total hemolytic complement (CH50), or sedimentation rate. Furthermore, significant depressions in NK activity correlated with variations in disease activity in six patients followed serially. Depressed NK function could not be reversed by prolonged in vitro incubation at 37 degrees C or with protease treatment. Furthermore, depressed NK activity was not altered by removal of glass adherent cells nor was a suppression of NK activity in normal controls seen by the addition of SLE peripheral mononuclear cells. No reversal of depressed activity to normal levels was seen by the addition of indomethacin nor did the supernatants from SLE cell cultures cause a suppression of normal NK function. NK activity in SLE patients did not respond normally to IF inducers (poly-I:C and concanavalin A) even if the SLE patients had normal NK function. The response of SLE cells to exogenous IF was also impaired. The number of effector-target conjugates was quantitated with several target cells (K562, Yac-1, Fravel) in SLE patients and controls. A significant correlation between the proportion of glass nonadherent mononuclear cells that formed effector-target conjugates with these various targets and the magnitude of NK lysis was observed. However, SLE and normal subjects had equal numbers of effector-target conjugates independent of NK function. Release of a soluble cytotoxic factor was induced with concanavalin A, and was markedly impaired in SLE patients relative to normal controls. Thus, impaired NK cell function in SLE does not appear to be related to cell-mediated suppressive mechanisms or to the deletion of effector cells; rather, the decreased NK activity may be related to an impaired release of a soluble cytotoxic factor.


Energetic context determines species and community responses to ocean acidification.
Physiological responses to ocean acidification are thought to be related to energetic trade-offs. Although a number of studies have proposed that negative responses to low pH could be minimized in situations where food resources are more readily available, evidence for such effects on individuals remain mixed, and the consequences of such effects at the community level remain untested. We explored the potential for food availability and diet quality to modify the effects of acidification on developing marine fouling communities in field-deployed mesocosms by supplementing natural food supply with one of two species of phytoplankton, differing in concentration of fatty acids. After 12 weeks, no species demonstrated the interactive effects generally predicted in the literature, where a positive overall effect of diet mitigated the negative overall effects of acidification. Rather, for some species, additional food supply appeared to bring out or exacerbate the negative effects of low pH. Community richness and structure were only altered by acidification, while space occupation and evenness reflected patterns of the most dominant species. Importantly, we find that acidification stress can increase the relative abundance of invasive species, even under resource conditions that otherwise prevented invasive species establishment. Overall, the proposed hypothesis regarding the ability for food addition to mitigate the negative effects of acidification is thus far not widely supported at species or community levels. It is clear that acidification is a strong driving force in these communities but understanding underlying energetic and competitive context is essential to developing mechanistic predictions for climate change responses.


Vitamin D levels and disease status in Texas patients with systemic lupus erythematosus.
Previous studies have suggested a relationship between low serum levels of vitamin D and lupus. Vitamin D receptor ligands can mediate immunosuppressive effects and low levels of this hormone have been proposed as contributing to the immune activation in lupus and other autoimmune diseases. We sought to investigate the prevalence of vitamin D insufficiency in our patients with lupus. Serum levels of 25-OH vitamin D were measured in 37 female patients with lupus using an enzyme-linked immunoassay. Correlations with clinical and immunologic measures were determined. Approximately 65% of the patients with lupus had values less than 80 nmol, which is accepted as the lower limit of vitamin D adequacy. In addition, 20% of the subjects had levels of 25-hydroxyvitamin D that were lower than the normal range for the assay (<47.7 nmol/L). The group of patients with these lowest levels showed disease activity measures, including global assessment scores, that were higher in the than in those with levels considered normal in the assay (P < or = 0.003). However, levels of autoantibodies including dsDNA were higher in the group with levels of vitamin D that were greater than 47.7 nmol/L (P = 0.0069). The increased disease symptoms present in patients with very low levels of vitamin D suggests a role for supplementation with exogenous vitamin D to optimize therapeutic outcomes. However, the possibility that such treatment could lead to increased autoantibody levels requires further study.


Nonpareil 3: Fast Estimation of Metagenomic Coverage and Sequence Diversity.
Estimations of microbial community diversity based on metagenomic data sets are affected, often to an unknown degree, by biases derived from insufficient coverage and reference database-dependent estimations of diversity. For instance, the completeness of reference databases cannot be generally estimated since it depends on the extant diversity sampled to date, which, with the exception of a few habitats such as the human gut, remains severely undersampled. Further, estimation of the degree of coverage of a microbial community by a metagenomic data set is prohibitively time-consuming for large data sets, and coverage values may not be directly comparable between data sets obtained with different sequencing technologies. Here, we extend Nonpareil, a database-independent tool for the estimation of coverage in metagenomic data sets, to a high-performance computing implementation that scales up to hundreds of cores and includes, in addition, a k-mer-based estimation as sensitive as the original alignment-based version but about three hundred times as fast. Further, we propose a metric of sequence diversity (Nd ) derived directly from Nonpareil curves that correlates well with alpha diversity assessed by traditional metrics. We use this metric in different experiments demonstrating the correlation with the Shannon index estimated on 16S rRNA gene profiles and show that Nd additionally reveals seasonal patterns in marine samples that are not captured by the Shannon index and more precise rankings of the magnitude of diversity of microbial communities in different habitats. Therefore, the new version of Nonpareil, called Nonpareil 3, advances the toolbox for metagenomic analyses of microbiomes. IMPORTANCE Estimation of the coverage provided by a metagenomic data set, i.e., what fraction of the microbial community was sampled by DNA sequencing, represents an essential first step of every culture-independent genomic study that aims to robustly assess the sequence diversity present in a sample. However, estimation of coverage remains elusive because of several technical limitations associated with high computational requirements and limiting statistical approaches to quantify diversity. Here we described Nonpareil 3, a new bioinformatics algorithm that circumvents several of these limitations and thus can facilitate culture-independent studies in clinical or environmental settings, independent of the sequencing platform employed. In addition, we present a new metric of sequence diversity based on rarefied coverage and demonstrate its use in communities from diverse ecosystems.


Localization and dynamics of glucocorticoid receptor at the plasma membrane of activated mast cells.
In addition to their actions in the cell nucleus, glucocorticoids exhibit rapid non-nuclear responses that are mechanistically not well understood. To explain these effects, the localization of a glucocorticoid receptor (GR) expressed in mast cells as a GFP fusion was analyzed after activation of the cells on allergenic lipid arrays. These arrays were produced on glass slides by dip-pen nanolithography (DPN) and total internal reflection (TIRF) microscopy was used to visualize the GR. A rapid glucocorticoid-independent and -dependent recruitment of the GR-GFP to the plasma cell membrane was observed following contact of the cells with the allergenic array. In addition, the mobility of the GR at the membrane was monitored by fluorescence recovery after photobleaching (FRAP) and shown to follow binding kinetics demonstrating interactions of the receptor with membrane-bound factors. Furthermore the recruitment of the GR to the cell membrane was shown to result in a glucocorticoid-mediated increase in Erk phosphorylation. This is evidenced by findings that destruction of the membrane composition of the mast cells by cholesterol depletion impairs the membrane localization of the GR and subsequent glucocorticoid-mediated enhancement of Erk phosphorylation. These results demonstrate a membrane localization and function of the GR in mast cell signaling.


Anatomical relationships between aromatase and tyrosine hydroxylase in the quail brain: double-label immunocytochemical studies.
The activation of male sexual behavior in Japanese quail (Coturnix japonica) requires the transformation of testosterone to 17beta-estradiol by the enzyme aromatase (estrogen synthetase). There are prominent sex differences in aromatase activity that may be regulated in part by sex differences in catecholaminergic activity. In this study, we investigate, with double-label immunocytochemistry methods, the anatomical relationship between the catecholamine synthesizing enzyme, tyrosine hydroxylase (TH) and aromatase (ARO) in the quail brain. The immunoreactivity observed for each antigen generally matched the previously described distribution. One exception is the observation that cells weakly labeled for aromatase were found widely distributed throughout the telencephalon. The presence of telencephalic aromatase was confirmed independently by radioenzymatic assays. There was an extensive overlap between the distribution of the two antigens in many brain areas. In all densely labeled aromatase-immunoreactive (ARO-ir) cell groups, including the preoptic medial nucleus, nucleus of the stria terminalis, mediobasal hypothalamus, and paleostriatum ventrale, ARO-ir cells were found in close association with TH-ir fibers. These TH-ir fibers often converged on an ARO-ir cell, and one or more TH-ir punctate structure(s) were found in close contact with nearly every densely labeled ARO-ir cell. In the telencephalon (mostly the neostriatum), all TH-ir fibers were found to be part of fiber groups that surrounded weakly immunoreactive aromatase cells. The few cells exhibiting an intracellular colocalization were detected in the anteroventral periventricular nucleus. These results are consistent with the hypothesis that catecholaminergic inputs regulate brain aromatase.


Disparity of isoflurane effects on left and right ventricular afterload and hydraulic power generation in swine.
The interaction between myocardial and vascular effects of anesthetics has a potential impact on how these drugs influence performance of the heart. Most studies have focused on volatile anesthetic effects on the left ventricle (LV) and systemic circulation. Whether the right ventricle (RV) and pulmonary circulation respond in a similar fashion, however, is unclear. In the present study, we therefore examined the dose-related effects of isoflurane on LV and RV contractility and total afterload and related changes to simultaneous effects on the hydraulic power generated by each chamber. Two groups of swine were studied: one received no additional treatment before isoflurane (ISO, n = 6), and the other received hexamethonium, atropine, and propranolol to produce autonomic blockade before isoflurane administration (ISO+AB, n = 4). For each experiment, measurements were made of RV and LV regional segment lengths and pressures, along with proximal aortic and pulmonary arterial (PA) blood flow and pressure during the administration of 0, 0.5, 1.0, and 1.5 minimum alveolar anesthetic concentration (MAC) isoflurane. Contractility was assessed by calculating the regional preload recruitable stroke work slope (PRSW). Afterload was characterized in both nonpulsatile and pulsatile terms by calculating aortic input impedance magnitude (Z). From these data, total arterial resistance (R), characteristic impedance (ZC), and vascular compliance (C) were determined with reference to a three-element Windkessel model of the circulation. Additionally, steady-state (WSS), oscillatory (WOS), and total (WT) hydraulic power output of each ventricle was calculated. In the ISO group, isoflurane produced a nearly threefold greater decrease of peak systolic pressure in the LV than in the RV, yet the dose-related decrease of regional PRSW was virtually the same in both chambers. In the aorta, isoflurane produced a maximal 25% reduction in R at 1.0 MAC and doubled C without a significant change in ZC. Alternatively, PA R was increased from baseline at 1.0 and 1.5 MAC, whereas ZC was increased from all other values at 1.5 MAC. PA C was not altered by isoflurane. In ISO+AB pigs, PA ZC at baseline was higher than that evident in ISO animals but was not altered by isoflurane. In contrast, baseline aortic R was lower in ISO+AB pigs but was still modestly reduced by 1.0 MAC isoflurane. In ISO animals, WT and WSS from both ventricles demonstrated dose-related decreases, but the reductions in LV WTand WSS were greater than those for the RV at all doses. Accordingly, the power requirement per unit flow decreased for the LV but remained constant for the RV. WOS for both ventricles was also reduced by isoflurane. However, the LV WOS to WT ratio increased, which indicates that more power was lost to the system by pulsation. In contrast, reductions in RV WT and WOS were nearly parallel at all isoflurane doses, and the WOS to WT ratio was unchanged. In the ISO+AB group, isoflurane-induced alterations in LV and RV power characteristics were similar to those in the ISO group. These data indicate that, despite similar effects on biventricular contractility, isoflurane exerts qualitatively different effects on RV and LV afterload, in part via alteration in autonomic nervous activity, that influence the distribution of power output between steady-state and pulsatile components. In this study, we examined the effects of isoflurane on cardiac performance in swine and found that, although the drug depresses contraction of both the left and right ventricles similarly, it has different effects on forces that oppose the ejection of blood. These findings demonstrate that the two interdependent pumps that comprise the heart can be influenced differently by anesthetic drugs.


Pre-existing neuronal pathways in the developing optic lobes of Drosophila.
We have identified a set of larval neurones in the developing adult optic lobes of Drosophila by selectively labelling cells that have undergone only a few mitoses. A cluster of three cells is located in each of the optic lobes near the insertion site of the optic stalk. Their axons fasciculate with fibres of the larval optic nerve, the Bolwig's nerve, and then form part of the posterior optic tract. These cells are likely to be first order interneurones of the larval visual system. Unlike the Bolwig's nerve, they persist into the adult stage. The possibility of a pioneering function of the larval visual system during formation of the adult optic lobe neuropil is discussed.


Controlling retinal pigment epithelium injury after experimental detachment of the retina.
Damage induced by detachment of the neural retina and the retinal pigment epithelium (RPE) can be reduced by dark adaptation. The authors evaluated the influence of the duration of dark adaptation, time of day, and modification of the melatonin-dopamine pathway on acute RPE lesions induced by mechanical detachment. BALB/c mice were studied at different times of day and different periods of dark adaptation. Some mice were treated with melatonin or sulpiride, a D2 dopamine receptor antagonist. Enucleated eyes and different saline solutions were used in experiments ex vivo. Retinal detachments in vivo were made by subretinal injections of hyaluronic acid. RPE cell damage was quantitatively evaluated with a dye exclusion procedure, and their viability was tested by preservation of tight junctions in culture. Lectin histochemistry was used to examine the interphotoreceptor matrix (IPM). Significant propidium iodide (PI) incorporation in RPE cells was detected after ex vivo separation during daytime, but it was very low when detachment took place at night after 24 to 48 hours of dark adaptation. PI exclusion was achieved during daytime after a single hour of dark adaptation when mice were pretreated with melatonin or sulpiride. Reduction of RPE cell damage was accompanied by decreased lectin binding to cone sheaths. A combination of time of day and length of dark adaptation decreased damage induced by detachment of the retina ex vivo and in vivo. Melatonin or sulpiride could replace these environmental factors. Therefore, melatonin and dopamine pathways might be involved in the control of IPM properties and retina/RPE interactions.


Boosting Up Performance of Inverted Photovoltaic Cells from Bis(alkylthien-2-yl)dithieno[2,3-d:2',3'-d']benzo[1,2-b:4',5'-b']di thiophene-Based Copolymers by Advantageous Vertical Phase Separation.
The photovoltaic cells (PVCs) from conjugated copolymers of PDTBDT-BT and PDTBDT-FBT with 5,10-bis(4,5-didecylthien-2-yl)dithieno[2,3-d:2',3'-d']benzo[1,2-b:4,5-b']dithiophene as electron donor moieties and benzothiadiazole and/or 5,6-difluorobenzothiadiazole as electron acceptor moieties are optimized by employing alcohol-soluble PFN (poly(9,9-bis(3'-(N,N-dimethylamino)propyl)-2,7-fluorene)-alt-2,7-(9,9-dioctylfluorene)) as cathode modification interlayer. The power conversion efficiencies (PCEs) of inverted PVCs (i-PVCs) from PDTBDT-BT and PDTBDT-FBT with devices configuration as ITO/PFN/active layer/MoO3/Ag are increased from 4.97% to 8.54% and 5.92% to 8.74%, in contrast to those for the regular PVCs (r-PVCs) with devices configuration as ITO/PEDOT:PSS/active layer/Ca/Al under 100 mW/cm2 AM 1.5 illumination. The optical modeling calculations and X-ray photoelectron spectroscopy (XPS) investigations reveal that the r-PVCs and i-PVCs from the copolymers exhibit similar light harvesting characteristics, and the enhancements of the PCEs of the i-PVCs from the copolymers are mainly contributed to the favorable vertical phase separation as the strongly polymer-enriched top surface layers and slightly PC71BM (phenyl-C71-butyric acid methyl ester)-enriched bottom surface layers are correspondingly connected to the anodes and cathodes of the i-PVCs, while they are opposite in the r-PVCs. As we known, it is the first time to experimentally verify that the i-PVCs with alcohol-soluble conjugated polymers cathode modification layers enjoy favorable vertical phase separation.


Genomic diversity, population structure, and migration following rapid range expansion in the Balsam poplar, Populus balsamifera.
Rapid range expansions can cause pervasive changes in the genetic diversity and structure of populations. The postglacial history of the Balsam Poplar, Populus balsamifera, involved the colonization of most of northern North America, an area largely covered by continental ice sheets during the last glacial maximum. To characterize how this expansion shaped genomic diversity within and among populations, we developed 412 SNP markers that we assayed for a range-wide sample of 474 individuals sampled from 34 populations. We complemented the SNP data set with DNA sequence data from 11 nuclear loci from 94 individuals, and used coalescent analyses to estimate historical population size, demographic growth, and patterns of migration. Bayesian clustering identified three geographically separated demes found in the Northern, Central, and Eastern portions of the species' range. These demes varied significantly in nucleotide diversity, the abundance of private polymorphisms, and population substructure. Most measures supported the Central deme as descended from the primary refuge of diversity. Both SNPs and sequence data suggested recent population growth, and coalescent analyses of historical migration suggested a massive expansion from the Centre to the North and East. Collectively, these data demonstrate the strong influence that range expansions exert on genomic diversity, both within local populations and across the range. Our results suggest that an in-depth knowledge of nucleotide diversity following expansion requires sampling within multiple populations, and highlight the utility of combining insights from different data types in population genomic studies.


Protease domain and transmembrane domain of the type VII secretion mycosin protease determine system-specific functioning in mycobacteria.
Mycobacteria use type VII secretion systems to secrete proteins across their highly hydrophobic diderm cell envelope. Pathogenic mycobacteria, such as Mycobacterium tuberculosis and Mycobacterium marinum, have up to five of these systems, named ESX-1 to ESX-5. Most of these systems contain a set of five conserved membrane components, of which the four Ecc proteins form the core membrane-embedded secretion complex. The fifth conserved membrane protein, mycosin protease (MycP), is not part of the core complex but is essential for secretion, as it stabilizes this membrane complex. Here we investigated which MycP domains are required for this stabilization by producing hybrid constructs between MycP1 and MycP5 in M. marinum and analyzed their effect on ESX-1 and ESX-5 secretion. We found that both the protease and transmembrane domain are required for the ESX system-specific function of mycosins. In addition, we observed that the transmembrane domain strongly affects MycP protein levels. We also show that the extended loops 1 and 2 in the protease domain are probably primarily involved in MycP stability, whereas loop 3 and the MycP5-specific loop 5 are dispensable. The atypical propeptide, or N-terminal extension, is required only for MycP stability. Finally, we show that the protease domain of MycPP1, encoded by the esx-P1 locus on the pRAW plasmid, is functionally redundant to the protease domain of MycP5 These results provide the first insight into the regions of mycosins involved in interaction with and stabilization of their respective ESX complexes.


Is a diagnostic category for paraphilic coercive disorder defensible?
There is a proposal to establish a paraphilic coercive disorder as a new paraphilia in the DSM-V. The empirical data do not, however, support the hypothesis that a distinct syndrome exists that comprises males who are sexually aroused by the coercive elements of rape per se. Purported evidence for this syndrome has centered on the results of phallometric studies. Higher plethysmographic responses of rapists to coercive rape scenarios may, however, be better explained by the failure of coercive elements to inhibit arousal to sexual aspects of the stimuli rather than by arousal specifically to the coercive elements. In addition, sexual fantasies about forcing sex and about struggling victims are highly correlated with sadistic fantasies and have not been shown to identify a syndrome that can be discriminated from sadism. Finally, taxometric evidence strongly supports the hypothesis that the underlying components of rape are distributed as dimensions and do not constitute a separate taxon. Consequently, the criteria purported to categorize rapists into the proposed syndrome would have to be arbitrarily determined. Not only does there seem to be little empirical justification for the creation of this new syndrome, the inclusion of this disorder among the paraphilias would have serious potential for misuse. It would imply endorsement of Paraphilia, NOS, nonconsent, which is currently inappropriately employed in civil commitment proceedings to justify commitment.


A hepatitis C virus (HCV) vaccine comprising envelope glycoproteins gpE1/gpE2 derived from a single isolate elicits broad cross-genotype neutralizing antibodies in humans.
Although a cure for HCV is on the near horizon, emerging drug cocktails will be expensive, associated with side-effects and resistance making a global vaccine an urgent priority given the estimated high incidence of infection around the world. Due to the highly heterogeneous nature of HCV, an effective HCV vaccine which could elicit broadly cross-neutralizing antibodies has represented a major challenge. In this study, we tested for the presence of cross-neutralizing antibodies in human volunteers who were immunized with recombinant glycoproteins gpE1/gpE2 derived from a single HCV strain (HCV1 of genotype 1a). Cross neutralization was tested in Huh-7.5 human hepatoma cell cultures using infectious recombinant HCV (HCVcc) expressing structural proteins of heterologous HCV strains from all known major genotypes, 1-7. Vaccination induced significant neutralizing antibodies against heterologous HCV genotype 1a virus which represents the most common genotype in North America. Of the 16 vaccinees tested, 3 were selected on the basis of strong 1a virus neutralization for testing of broad cross-neutralizing responses. At least 1 vaccinee was shown to elicit broad cross-neutralization against all HCV genotypes. Although observed in only a minority of vaccinees, our results prove the key concept that a vaccine derived from a single strain of HCV can elicit broad cross-neutralizing antibodies against all known major genotypes of HCV and provide considerable encouragement for the further development of a human vaccine against this common, global pathogen.