Open or endoscopic total extraperitoneal inguinal hernia repair? A systematic review.
Although a large number of surgeons currently perform endoscopic hernia surgery using a total extraperitoneal (TEP) approach, reviews published to date are based mainly on trials that compare laparoscopic transabdominal preperitoneal (TAPP) repair with various types of open inguinal hernia repair. A qualitative analysis of randomized trials comparing TEP with open mesh or sutured repair. In this review, 4,231 patients were included in 23 trials. In 10 of 15 trials, TEP repair was associated with longer surgery time than open repair. A shorter postoperative hospital stay after TEP repair than after open repair was reported in 6 of 11 trials. In 8 of 9 trials, the time until return to work was significantly shorter after TEP repair. Hospital costs were significantly higher for TEP than for open repair in all four trials that included an economic evaluation. Most trials (n = 14) reported no differences in subsequent recurrence rates between TEP and open repair. The findings showed that endoscopic TEP repair is associated with longer surgery time, shorter postoperative hospital stay, earlier return to work, and recurrence rates similar to those for open inguinal hernia repair. The procedure involves greater expenses for hospitals, but appears to be cost effective from a societal perspective. The TEP technique is a serious option for mesh repair of primary hernias.


Exciton size and quantum transport in nanoplatelets.
Two-dimensional nanoplatelets (NPLs) are an exciting class of materials with promising optical and energy transport properties. The possibility of efficient energy transport between nanoplatelets raises questions regarding the nature of energy transfer in these thin, laterally extended systems. A challenge in understanding exciton transport is the uncertainty regarding the size of the exciton. Depending on the material and defects in the nanoplatelet, an exciton could plausibly extend over an entire plate or localize to a small region. The variation in possible exciton sizes raises the question how exciton size impacts the efficiency of transport between nanoplatelet structures. Here, we explore this issue using a quantum master equation approach. This method goes beyond the assumptions of Förster theory to allow for quantum mechanical effects that could increase energy transfer efficiency. The model is extremely flexible in describing different systems, allowing us to test the effect of varying the spatial extent of the exciton. We first discuss qualitative aspects of the relationship between exciton size and transport and then conduct simulations of exciton transport between NPLs for a range of exciton sizes and environmental conditions. Our results reveal that exciton size has a strong effect on energy transfer efficiency and suggest that manipulation of exciton size may be useful in designing NPLs for energy transport.


Self-help and guided self-help for eating disorders.
Anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder (BED) and eating disorder not otherwise specified (EDNOS) are common and disabling disorders. Many patients experience difficulties accessing specialist psychological treatments. Pure self-help (PSH: self-help material only) or guided self-help (GSH: self-help material with therapist guidance), may bridge this gap. Evaluate evidence from randomised controlled trials (RCTs) / controlled clinical trials (CCTs) for the efficacy of PSH/GSH with respect to eating disorder symptoms, compared with waiting list or placebo/attention control, other psychological or pharmacological treatments (or combinations/augmentations) in people with eating disorders. Evaluate evidence for the efficacy of PSH/GSH regarding comorbid symptomatology and costs. CCDANCTR-Studies and CCDANCTR-References were searched in November 2005, other electronic databases were searched, relevant journals and grey literature were checked, and personal approaches were made to authors. Published/unpublished RCTs/CCTs evaluating PSH/GSH for any eating disorder. Data was extracted using a customized spreadsheet. Relative Risks (RR) were calculated from dichotomous data and weighted/standardized mean differences (WMD/SMD) from continuous data, using a random effects model. Twelve RCTs and three CCTs were identified, all focusing on BN, BED, EDNOS or combinations of these, in adults, using manual-based PSH/GSH across various settings. Primary comparisons:At end of treatment, PSH/GSH did not significantly differ from waiting list in abstinence from bingeing (RR 0.72, 95% CI 0.47 to 1.09), or purging (RR 0.86, 95% CI 0.68 to 1.08), although these treatments produced greater improvement on other eating disorder symptoms, psychiatric symptomatology and interpersonal functioning but not depression. Compared to other formal psychological therapies, PSH/GSH did not differ significantly at end of treatment or follow-up in improvement on bingeing and purging (RR 0.99, 95% CI 0.75 to 1.31), other eating disorder symptoms, level of interpersonal functioning or depression. There were no significant differences in treatment dropout. Secondary comparisons:One small study in BED found that cognitive-behavioural GSH compared to a non-specific control treatment produced significantly greater improvements in abstinence from bingeing and other eating disorder symptoms. Studies comparing PSH with GSH found no significant differences between treatment groups at end of treatment or follow-up. Comparison between different types of PSH/GSH found significant differences on eating disorder symptoms but not on bingeing/purging abstinence rates. PSH/GSH may have some utility as a first step in treatment and may have potential as an alternative to formal therapist-delivered psychological therapy. Future research should focus on producing large well-conducted studies of self-help treatments in eating disorders including health economic evaluations, different types and modes of delivering self-help (e.g. computerised versus manual-based) and different populations and settings.


A Neural Model of Mind Wandering.
The role of the default-mode network (DMN) in the emergence of mind wandering and task-unrelated thought has been studied extensively. In parallel work, mind wandering has been associated with neuromodulation via the locus coeruleus (LC) norepinephrine (LC-NE) system. Here we propose a neural model that links the two systems in an integrative framework. The model attempts to explain how dynamic changes in brain systems give rise to the subjective experience of mind wandering. The model implies a neural and conceptual distinction between an off-focus state and an active mind-wandering state and provides a potential neural grounding for well-known cognitive theories of mind wandering. Finally, the proposed neural model of mind wandering generates precise, testable predictions at neural and behavioral levels.


Dose-dependent effects of walnuts on motor and cognitive function in aged rats.
Aged rats show decrements in performance on motor and cognitive tasks that require the use of spatial learning and memory. Previously we have shown that these deficits can be reversed by the polyphenolics in fruits and vegetables. Walnuts, which contain the n-3 fatty acids a-linolenic acid and linoleic acid, are a dietary source of polyphenols, antioxidants and lipids. Thus, the present study examined the effects of walnut supplementation on motor and cognitive ability in aged rats. Fischer 344 rats, aged 19 months, were fed a control, or a 2, 6 or 9% walnut diet for 8 weeks before motor and cognitive testing. Results for the motor testing showed that the 2% walnut diet improved performance on rod walking, while the 6% walnut diet improved performance on the medium plank walk; the higher dose of the 9% walnut diet did not improve psychomotor performance and on the large plank actually impaired performance. All of the walnut diets improved working memory in the Morris water maze, although the 9% diet showed impaired reference memory. These findings show for the first time that moderate dietary walnut supplementation can improve cognitive and motor performance in aged rats.


Right coronary wall CMR in the older asymptomatic advance cohort: positive remodeling and associations with type 2 diabetes and coronary calcium.
Coronary wall cardiovascular magnetic resonance (CMR) is a promising noninvasive approach to assess subclinical atherosclerosis, but data are limited in subjects over 60 years old, who are at increased risk. The purpose of the study was to evaluate coronary wall CMR in an asymptomatic older cohort. Cross-sectional images of the proximal right coronary artery (RCA) were acquired using spiral black-blood coronary CMR (0.7 mm resolution) in 223 older, community-based patients without a history of cardiovascular disease (age 60-72 years old, 38% female). Coronary measurements (total vessel area, lumen area, wall area, and wall thickness) had small intra- and inter-observer variabilities (r = 0.93~0.99, all p < 0.0001), though one-third of these older subjects had suboptimal image quality. Increased coronary wall thickness correlated with increased coronary vessel area (p < 0.0001), consistent with positive remodeling. On multivariate analysis, type 2 diabetes was the only risk factor associated with increased coronary wall area and thickness (p = 0.03 and p = 0.007, respectively). Coronary wall CMR measures were also associated with coronary calcification (p = 0.01-0.03). Right coronary wall CMR in asymptomatic older subjects showed increased coronary atherosclerosis in subjects with type 2 diabetes as well as coronary calcification. Coronary wall CMR may contribute to the noninvasive assessment of subclinical coronary atherosclerosis in older, at-risk patient groups.


The PIAS homologue Siz2 regulates perinuclear telomere position and telomerase activity in budding yeast.
Budding yeast telomeres are reversibly bound at the nuclear envelope through two partially redundant pathways that involve the Sir2/3/4 silencing complex and the Yku70/80 heterodimer. To better understand how this is regulated, we studied the role of SUMOylation in telomere anchoring. We find that the PIAS-like SUMO E3 ligase Siz2 sumoylates both Yku70/80 and Sir4 in vivo and promotes telomere anchoring to the nuclear envelope. Remarkably, loss of Siz2 also provokes telomere extension in a telomerase-dependent manner that is epistatic with loss of the helicase Pif1. Consistent with our previously documented role for telomerase in anchorage, normal telomere anchoring in siz2 Δ is restored by PIF1 deletion. By live-cell imaging of a critically short telomere, we show that telomeres shift away from the nuclear envelope when elongating. We propose that SUMO-dependent association with the nuclear periphery restrains bound telomerase, whereas active elongation correlates with telomere release.


Antiviral CD8+ T Cells Restricted by Human Leukocyte Antigen Class II Exist during Natural HIV Infection and Exhibit Clonal Expansion.
CD8+ T cell recognition of virus-infected cells is characteristically restricted by major histocompatibility complex (MHC) class I, although rare examples of MHC class II restriction have been reported in Cd4-deficient mice and a macaque SIV vaccine trial using a recombinant cytomegalovirus vector. Here, we demonstrate the presence of human leukocyte antigen (HLA) class II-restricted CD8+ T cell responses with antiviral properties in a small subset of HIV-infected individuals. In these individuals, T cell receptor β (TCRβ) analysis revealed that class II-restricted CD8+ T cells underwent clonal expansion and mediated killing of HIV-infected cells. In one case, these cells comprised 12% of circulating CD8+ T cells, and TCRα analysis revealed two distinct co-expressed TCRα chains, with only one contributing to binding of the class II HLA-peptide complex. These data indicate that class II-restricted CD8+ T cell responses can exist in a chronic human viral infection, and may contribute to immune control.


A validation framework for neuroimaging software: The case of population receptive fields.
Neuroimaging software methods are complex, making it a near certainty that some implementations will contain errors. Modern computational techniques (i.e., public code and data repositories, continuous integration, containerization) enable the reproducibility of the analyses and reduce coding errors, but they do not guarantee the scientific validity of the results. It is difficult, nay impossible, for researchers to check the accuracy of software by reading the source code; ground truth test datasets are needed. Computational reproducibility means providing software so that for the same input anyone obtains the same result, right or wrong. Computational validity means obtaining the right result for the ground-truth test data. We describe a framework for validating and sharing software implementations, and we illustrate its usage with an example application: population receptive field (pRF) methods for functional MRI data. The framework is composed of three main components implemented with containerization methods to guarantee computational reproducibility. In our example pRF application, those components are: (1) synthesis of fMRI time series from ground-truth pRF parameters, (2) implementation of four public pRF analysis tools and standardization of inputs and outputs, and (3) report creation to compare the results with the ground truth parameters. The framework was useful in identifying realistic conditions that lead to imperfect parameter recovery in all four pRF implementations, that would remain undetected using classic validation methods. We provide means to mitigate these problems in future experiments. A computational validation framework supports scientific rigor and creativity, as opposed to the oft-repeated suggestion that investigators rely upon a few agreed upon packages. We hope that the framework will be helpful to validate other critical neuroimaging algorithms, as having a validation framework helps (1) developers to build new software, (2) research scientists to verify the software's accuracy, and (3) reviewers to evaluate the methods used in publications and grants.


APRANK: Computational Prioritization of Antigenic Proteins and Peptides From Complete Pathogen Proteomes.
Availability of highly parallelized immunoassays has renewed interest in the discovery of serology biomarkers for infectious diseases. Protein and peptide microarrays now provide a rapid, high-throughput platform for immunological testing and validation of potential antigens and B-cell epitopes. However, there is still a need for tools to prioritize and select relevant probes when designing these arrays. In this work we describe a computational method called APRANK (Antigenic Protein and Peptide Ranker) which integrates multiple molecular features to prioritize potentially antigenic proteins and peptides in a given pathogen proteome. These features include subcellular localization, presence of repetitive motifs, natively disordered regions, secondary structure, transmembrane spans and predicted interaction with the immune system. We trained and tested this method with a number of bacteria and protozoa causing human diseases: Borrelia burgdorferi (Lyme disease), Brucella melitensis (Brucellosis), Coxiella burnetii (Q fever), Escherichia coli (Gastroenteritis), Francisella tularensis (Tularemia), Leishmania braziliensis (Leishmaniasis), Leptospira interrogans (Leptospirosis), Mycobacterium leprae (Leprae), Mycobacterium tuberculosis (Tuberculosis), Plasmodium falciparum (Malaria), Porphyromonas gingivalis (Periodontal disease), Staphylococcus aureus (Bacteremia), Streptococcus pyogenes (Group A Streptococcal infections), Toxoplasma gondii (Toxoplasmosis) and Trypanosoma cruzi (Chagas Disease). We have evaluated this integrative method using non-parametric ROC-curves and made an unbiased validation using Onchocerca volvulus as an independent data set. We found that APRANK is successful in predicting antigenicity for all pathogen species tested, facilitating the production of antigen-enriched protein subsets. We make APRANK available to facilitate the identification of novel diagnostic antigens in infectious diseases.


1-(4-Chlorophenyl)-2-methyl-4-nitro-5-(1-piperidyl)-1H-imidazole.
The only specific interactions that influence the crystal packing of the title compound, C15H17ClN4O2, are weak C-H...N and C-H...Cl hydrogen bonds, even though there is a possibility of, for example, pi-pi stacking or halogen bonding. The dihedral angle between the mean planes of the imidazole and benzene rings is 59.82 (5) degrees . The length of the C-N bond connecting the imidazole and piperidine fragments is correlated with the degree of pyramidalization of the piperidine N atom.


A case control study of cemented acetabular total hip arthroplasty components in patients less than 50 with 5-year minimum follow-up.
This study investigates the outcomes of cemented sockets in young patients (<50 years) requiring a total hip replacement (THR) compared to older patients (>50 years) having the same procedure, under the same surgeon between June 2005 and May 2009. Prosthesis survivorship rates, patient outcomes and radiological findings were compared between a consecutive series of 56 young patients (mean 42, range 25-49) and 56 older patients (mean 69, range 53-81) that underwent a primary THR using a cemented Stryker® Exeter™ Contemporary™ flanged cup. The minimum follow-up was 5 years. No significant difference was observed between the groups' Oxford Hip Scores (p = 0.078) or satisfaction scores (p = 0.67). Worst case scenario analysis for revision, failure or lost to follow-up showed 94.6% survival in the <50 year olds and 92.9% survival in the >50 year olds at 5 years. This study demonstrates no significant difference in patient outcomes, survivorship or radiographic findings at a minimum of 5 years between patients <50 years old and those >50 years old undergoing THR with a cemented socket. We believe the current trend towards uncemented cups may be driven by marketing rather than by evidence of improved outcomes. Cemented sockets provide very good outcomes for patients of all ages.


Immunotherapy and Immunochemotherapy in Visceral Leishmaniasis: Promising Treatments for this Neglected Disease.
self-healing or chronic cutaneous leishmaniasis or post-kala-azar dermal leishmaniasis; mucosal leishmaniasis; visceral leishmaniasis (VL), which is fatal if left untreated. The epidemiology and clinical features of VL vary greatly due to the interaction of multiple factors including parasite strains, vectors, host genetics, and the environment. Human immunodeficiency virus infection augments the severity of VL increasing the risk of developing active disease by 100-2320 times. An effective vaccine for humans is not yet available. Resistance to chemotherapy is a growing problem in many regions, and the costs associated with drug identification and development, make commercial production for leishmaniasis, unattractive. The toxicity of currently drugs, their long treatment course, and limited efficacy are significant concerns. For cutaneous disease, many studies have shown promising results with immunotherapy/immunochemotherapy, aimed to modulate and activate the immune response to obtain a therapeutic cure. Nowadays, the focus of many groups centers on treating canine VL by using vaccines and immunomodulators with or without chemotherapy. In human disease, the use of cytokines like interferon-γ associated with pentavalent antimonials demonstrated promising results in patients that did not respond to conventional treatment. In mice, immunomodulation based on monoclonal antibodies to remove endogenous immunosuppressive cytokines (interleukin-10) or block their receptors, antigen-pulsed syngeneic dendritic cells, or biological products like Pam3Cys (TLR ligand) has already been shown as a prospective treatment of the disease. This review addresses VL treatment, particularly immunotherapy and/or immunochemotherapy as an alternative to conventional drug treatment in experimental models, canine VL, and human disease.


Arabidopsis ENDOMEMBRANE PROTEIN 12 contributes to the endoplasmic reticulum stress response by regulating K/HDEL receptor trafficking.
ENDOMEMBRANE PROTEIN 70 (EMP70) proteins constitute a 12-member superfamily in Arabidopsis thaliana, and are the most abundant protein species in plant Golgi proteomes. However, the physiological functions of EMPs in plants remain largely unknown. Here we have demonstrated that two AtEMP12 T-DNA insertion mutants are sensitive to ER (endoplasmic reticulum) stress as induced by tunicamycin and dithiothreitol treatments. Interestingly, the unfolded protein response (UPR) is constitutively activated in the knockout mutant emp12-1 under normal growth conditions, suggesting that the activation is a result of insufficient chaperones in the ER to aid protein folding. Indeed, we have further shown that BiP is secreted into the apoplast in emp12-1, while the K/HDEL receptor ERD2a, which regulates BiP trafficking, is exclusively localized in the ER in emp12-1, instead of its known ER-Golgi dual-localization. Given an enhanced retrograde transport of ERD2a, along with less dimerized receptor formed in the absence of EMP12, ERD2a may be prematurely returned to the ER without its bound ligands. Therefore, we propose that EMP12 may act as a novel regulator of the K/HDEL receptor to ensure an effective retrograde transport of K/HDEL ligands.


First-principles free-energy analysis of helix stability: the origin of the low entropy in pi helices.
The temperature dependence of the stability of infinite poly-L-alanine alpha, pi, and 310 helices with respect to the fully extended structure (FES) is calculated using density functional theory and the harmonic approximation. We find that the vibrational entropy strongly reduces the stability of the helical conformations with respect to the FES. By mapping the ab initio data on an approximate mechanical model, we show that this effect is exclusively due to the formation of hydrogen bonds, whereas changes in the backbone stiffness are practically negligible. We furthermore observe that the temperature dependence is largest for the pi helix and smallest for the 310 helix and demonstrate that these trends are a generic behavior related to the geometric peculiarities of the respective helical conformations and independent of the specific amino acid sequence.


Responses of Nasonovia ribisnigri (Homoptera: Aphididae) to susceptible and resistant lettuce.
Nymphs and alates of aphid Nasonovia ribisnigri (Mosley) (Homoptera: Aphididae) were tested on 10 lettuce cultivars with N. ribisnigri resistance gene Nr and 18 cultivars without the resistance gene in various bioassays. Bioassays used whole plants, leaf discs, or leaf cages to determine susceptibility of commercial lettuce cultivars to N. ribisnigri infestation and to evaluate screening methods for breeding lettuce resistance to N. ribisnigri. Resistant and susceptible plants were separated in 3 d when using whole plant bioassays. Long-term (> or =7 d) no-choice tests using leaf cages or whole plants resulted in no survival of N. ribisnigri on resistant plants, indicating great promise of the Nr gene for management of N. ribisnigri. Effective screening was achieved in both no-choice tests where resistant or susceptible intact plants were tested separately in groups or individually and in choice tests where susceptible and resistant plants were intermixed. Leaf discs bioassays were not suitable for resistance screening. All lettuce cultivars without the resistance gene were suitable hosts for N. ribisnigri, indicating the great importance of this pest to lettuce production and the urgency in developing resistant lettuce cultivars to manage N. ribisnigri.


Micro-invasive interventions for managing proximal dental decay in primary and permanent teeth.
Proximal dental lesions, limited to dentine, are traditionally treated by invasive (drill and fill) means. Non-invasive alternatives (e.g. fluoride varnish, flossing) might avoid substance loss but their effectiveness depends on patients' adherence. Recently, micro-invasive approaches for treating proximal caries lesions have been tried. These interventions install a barrier either on top (sealing) or within (infiltrating) the lesion. Different methods and materials are currently available for micro-invasive treatments, such as sealing via resin sealants, (polyurethane) patches/tapes, glass ionomer cements (GIC) or resin infiltration. To evaluate the effects of micro-invasive treatments for managing proximal caries lesions in primary and permanent dentition in children and adults. We searched the following databases to 31 December 2014: the Cochrane Oral Health Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via OVID, EMBASE via OVID, LILACs via BIREME Virtual Health Library, Web of Science Conference Proceedings, ZETOC Conference Proceedings, Proquest Dissertations and Theses, ClinicalTrials.gov, OpenGrey and the World Health Organization (WHO) International Clinical Trials Registry Platform. We searched the metaRegister of Controlled Trials to 1 October 2014. There were no language or date restrictions in the searches of the electronic databases. We included randomised controlled trials of at least six months' duration that compared micro-invasive treatments for managing non-cavitated proximal dental decay in primary teeth, permanent teeth or both, versus non-invasive measures, invasive means, no intervention or placebo. We also included studies that compared different types of micro-invasive treatments. Two review authors independently screened search results, extracted data and assessed the risk of bias. We used standard methodological procedures expected by Cochrane to evaluate risk of bias and synthesise data. We conducted meta-analyses with the random-effects model, using the Becker-Balagtas method to calculate the odds ratio (OR) for lesion progression. We assessed the quality of the evidence using GRADE methods. We included eight trials, which randomised 365 participants. The trials all used a split-mouth design, some with more than one pair of lesions treated within the same participant. Studies took place in university or dental public health clinics in Brazil, Colombia, Denmark, Germany, Thailand, Greenland and Chile. Six studies evaluated the effects of micro-invasive treatments in the permanent dentition and two studies on the primary dentition, with caries risk ranging from low to high. Investigators measured caries risk in different studies either by caries experience alone or by using the Cariogram programme, which combines eight contributing factors, including caries experience, diet, saliva and other factors related to caries. The follow-up period in the trials ranged from one to three years. All studies used lesion progression as the primary outcome, evaluating it by different methods of reading radiographs. Four studies received industry support to carry out the research, with one of them being carried out by inventors of the intervention.We judged seven studies to be at high overall risk of bias, primarily due to lack of blinding of participants and personnel. We evaluated intervention effects for all micro-invasive therapies and analysed subgroups according to the different treatment methods reported in the included studies.Our meta-analysis, which pooled the most sensitive set of data (in terms of measurement method) from studies presenting data in a format suitable for meta-analysis, showed that micro-invasive treatment significantly reduced the odds of lesion progression compared with non-invasive treatment (e.g fluoride varnish) or oral hygiene advice (e.g to floss) (OR 0.24, 95% CI 0.14 to 0.41; 602 lesions; seven studies; I(2) = 32%). There was no evidence of subgroup differences (P = 0.36).The four studies that measured adverse events reported no adverse events after micro-invasive treatment. Most studies did not report on any further outcomes.We assessed the quality of evidence for micro-invasive treatments as moderate. It remains unclear which micro-invasive treatment is more advantageous, or if certain clinical conditions or patient characteristics are better suited for micro-invasive treatments than others. The available evidence shows that micro-invasive treatment of proximal caries lesions arrests non-cavitated enamel and initial dentinal lesions (limited to outer third of dentine, based on radiograph) and is significantly more effective than non-invasive professional treatment (e.g. fluoride varnish) or advice (e.g. to floss). We can be moderately confident that further research is unlikely to substantially change the estimate of effect. Due to the small number of studies, it does remain unclear which micro-invasive technique offers the greatest benefit, or whether the effects of micro-invasive treatment confer greater or lesser benefit according to different clinical or patient considerations.


Lymphocyte inhibitor of TRAIL (TNF-related apoptosis-inducing ligand): a new receptor protecting lymphocytes from the death ligand TRAIL.
Apoptosis can be triggered by the engagement of cell surface receptors by their ligands. A growing number of receptors belonging to the TNF receptor family have been identified that contain a conserved cytoplasmic death domain. These include Fas, TNF-R1, lymphocyte-associated receptor of death (LARD), DR4, and TNF-related apoptosis-inducing ligand receptor inducer of cell killing-2 (TRICK2). The latter two are receptors for the cytotoxic ligand TNF-related apoptosis-inducing ligand (TRAIL), and one of the paradoxes raised by the cloning of these molecules was why do most cells not die upon contact with the widely expressed TRAIL molecule? This is a particular problem for lymphocytes that express DR4 and TRICK2 and are in constant circulation through TRAIL-expressing tissues. We have cloned LIT (lymphocyte inhibitor of TRAIL), which lacks a death domain. LIT is expressed predominantly on PBL, where it can competitively inhibit TRAIL-induced apoptosis through DR4/TRICK2, and may function to modulate lymphocyte sensitivity to TRAIL.


Passive treatment of acid mine drainage in bioreactors using sulfate-reducing bacteria: critical review and research needs.
Acid mine drainage (AMD), characterized by low pH and high concentrations of sulfate and heavy metals, is an important and widespread environmental problem related to the mining industry. Sulfate-reducing passive bioreactors have received much attention lately as promising biotechnologies for AMD treatment. They offer advantages such as high metal removal at low pH, stable sludge, very low operation costs, and minimal energy consumption. Sulfide precipitation is the desired mechanism of contaminant removal; however, many mechanisms including adsorption and precipitation of metal carbonates and hydroxides occur in passive bioreactors. The efficiency of sulfate-reducing passive bioreactors is sometimes limited because they rely on the activity of an anaerobic microflora [including sulfate-reducing bacteria (SRB)] which is controlled primarily by the reactive mixture composition. The most important mixture component is the organic carbon source. The performance of field bioreactors can also be limited by AMD load and metal toxicity. Several studies conducted to find the best mixture of natural organic substrates for SRB are reviewed. Moreover, critical parameters for design and long-term operation are discussed. Additional work needs to be done to properly assess the long-term efficiency of reactive mixtures and the metal removal mechanisms. Furthermore, metal speciation and ecotoxicological assessment of treated effluent from on-site passive bioreactors have yet to be performed.


Predictors of financial toxicity and its associations with health-related quality of life and treatment non-adherence in Turkish cancer patients.
This study aims to determine the financial toxicity (FT) level in cancer patients, identify the risk factors associated with this level, and reveal the effect of this level on patient outcomes (health-related quality of life (HRQoL) and treatment non-adherence). The data of 316 cancer patients, who were receiving inpatient treatment in an oncology hospital affiliated to a public university in Ankara, Turkey, were ≥ 18 years old, and were receiving chemotherapy for at least 3 months, were evaluated. The data were collected through a face-to-face interview. FT was measured with the COmprehensive Score for financial Toxicity (COST) Measure (v2), HRQoL was measured with the Functional Assessment of Cancer Therapy-General (FACT-G) Scale (v4), and treatment adherence was measured using a questionnaire created by conducting a literature review. Patients were found to experience FT above the moderate level (mean ± SD, 21.85 ± 12.02; median value, 24.0). Younger age, being married, low education level, low monthly household income, and receiving social/economic support for treatment were revealed to be the determinants of high FT. Moreover, as the FT score decreased (as the FT level felt increased), the HRQoL was observed to decrease, and treatment non-adherence increased. The results indicate that FT problem is also valid for cancer patients in Turkey despite the system of general health insurance. The FT was found to result from socio-economic characteristics rather than the disease and treatment-related characteristics. The significant associations revealed between FT and patient outcomes emphasize the importance of reducing the FT in cancer patients.


A review of the effect of traffic and weather characteristics on road safety.
Taking into consideration the increasing availability of real-time traffic data and stimulated by the importance of proactive safety management, this paper attempts to provide a review of the effect of traffic and weather characteristics on road safety, identify the gaps and discuss the needs for further research. Despite the existence of generally mixed evidence on the effect of traffic parameters, a few patterns can be observed. For instance, traffic flow seems to have a non-linear relationship with accident rates, even though some studies suggest linear relationship with accidents. On the other hand, increased speed limits have found to have a straightforward positive relationship with accident occurrence. Regarding weather effects, the effect of precipitation is quite consistent and leads generally to increased accident frequency but does not seem to have a consistent effect on severity. The impact of other weather parameters on safety, such as visibility, wind speed and temperature is not found straightforward so far. The increasing use of real-time data not only makes easier to identify the safety impact of traffic and weather characteristics, but most importantly makes possible the identification of their combined effect. The more systematic use of these real-time data may address several of the research gaps identified in this research.


Health Status of Ready-to-Plant Grapevine Nursery Material in Canada Regarding Young Vine Decline Fungi.
Young vine decline (YVD), caused by several taxonomically different fungi, results in the decline and death of grapevines within a few years after planting. Infection can occur in nursery mother blocks and/or at several stages in the nursery propagation process, but the final plant material may remain asymptomatic. Four nurseries that sell ready-to-plant grapevines in Canada were sampled to evaluate the health status with regard to YVD fungi, including Botryosphaeriaceae spp., Cadophora luteo-olivacea, Dactylonectria macrodidyma, Dactylonectria torresensis, Phaeoacremonium minimum, and Phaeomoniella chlamydospora. Plants representing three cultivars, 'Chardonnay', 'Merlot', and 'Pinot noir', either grafted onto '3309C' rootstock or self-rooted, were provided by the nurseries. Samples from the roots, base of the rootstock or self-rooted cultivar, graft-union, and scion were collected from each plant. DNA was extracted, and the total abundance of each fungus was quantified using Droplet Digital PCR. Results revealed that 99% of plants harbored at least one of the fungi studied, with a mean of three different fungal species that were present per grapevine. Droplet Digital PCR results showed that the abundance of the different fungi significantly varied between different sections of each plant, individual plants for each cultivar, and cultivars from the same nursery. Necrosis measurements were recorded from the base of the rootstock or self-rooted cultivars and did not correlate with fungal abundance recorded in that section for each grapevine, but necrosis was consistent across cultivars within nurseries. Five different rootstocks were compared from one nursery, and results showed no differences between rootstocks and their health status. Among all nurseries, C. luteo-olivacea was the most prevalent fungus (97% of the plants), while D. macrodidyma was the least commonly found (13% of the plants). This study shows that ready-to-plant nursery material sold in Canada is likely to be infected with several YVD fungi and that presence and abundance of fungi vary significantly among individual grapevines and nurseries.


Profile changes associated with maxillary incisor retraction in the postadolescent orthodontic patient.
Maxillary incisor retraction and associated upper lip changes were studied in 30 male and 30 female postadolescent orthodontic patients to determine if a statistically significant correlation and ratio existed between maxillary incisor and lip retraction, dependent on thickness, strain, and length of the upper lip. This analysis attempted to eliminate the effects of growth and gender. Statistically significant correlations were found in both male and female patients who had thin, highly strained lips. Although a ratio for predictive purposes was determined for each of these groups, their absolute value is questionable because no apparent pattern exists between them. Furthermore, as lip thickness increased and lip strain decreased, correlation coefficients fell to nonsignificance, making it more difficult to predict upper lip change resulting from maxillary incisor retraction in these individuals.


Beyond health aid: would an international equalization scheme for universal health coverage serve the international collective interest?
It has been argued that the international community is moving 'beyond aid'. International co-financing in the international collective interest is expected to replace altruistically motivated foreign aid. The World Health Organization promotes 'universal health coverage' as the overarching health goal for the next phase of the Millennium Development Goals. In order to provide a basic level of health care coverage, at least some countries will need foreign aid for decades to come. If international co-financing of global public goods is replacing foreign aid, is universal health coverage a hopeless endeavor? Or would universal health coverage somehow serve the international collective interest?Using the Sustainable Development Solutions Network proposal to finance universal health coverage as a test case, we examined the hypothesis that national social policies face the threat of a 'race to the bottom' due to global economic integration and that this threat could be mitigated through international social protection policies that include international cross-subsidies - a kind of 'equalization' at the international level.The evidence for the race to the bottom theory is inconclusive. We seem to be witnessing a 'convergence to the middle'. However, the 'middle' where 'convergence' of national social policies is likely to occur may not be high enough to keep income inequality in check.The implementation of the international equalization scheme proposed by the Sustainable Development Solutions Network would allow to ensure universal health coverage at a cost of US$55 in low income countries-the minimum cost estimated by the World Health Organization. The domestic efforts expected from low and middle countries are far more substantial than the international co-financing efforts expected from high income countries. This would contribute to 'convergence' of national social policies at a higher level. We therefore submit that the proposed international equalization scheme should not be considered as foreign aid, but rather as an international collective effort to protect and promote national social policy in times of global economic integration: thus serving the international collective interest.


Electromagnetic interference of analog cellular telephones with pacemakers.
The aim of this study was to verify whether there is a public health risk from the interference of analog cellular telephones with pacemakers. We used a human trunk simulator to reproduce an actual implant, and two cellular telephones working with the TACS (Total Access Communication System) standard. Results showed that the electromagnetic field radiated from the analog cellular telephones interfered with a large number of the pacemakers tested (10/25). When the telephone antenna was in close proximity to the pacemaker head, pacemaker desensitizing and sensitizing and pulse inhibition was detected at the moment of an incoming call and throughout ringing. In the worst case of pulse inhibition, the pacemaker skipped three nonconsecutive beats and then resumed its normal pacing, while the desensitizing and sensitizing phenomena persisted as long as the interfering signal was on. Pulse inhibition was also observed when the connection did not succeed. Maximum sensing threshold variation was about 186% (increase) and 62% (decrease) for desensitizing and sensitizing phenomena, respectively. It was also demonstrated that the signal emitted by analog cellular telephones during the crossing of contiguous cells could induce pacemaker pulse inhibition, but under our experimental conditions this event did not seem to pose a risk for the pacemaker patient.


Proteins that control the geometry of microtubules at the ends of cilia.
Cilia, essential motile and sensory organelles, have several compartments: the basal body, transition zone, and the middle and distal axoneme segments. The distal segment accommodates key functions, including cilium assembly and sensory activities. While the middle segment contains doublet microtubules (incomplete B-tubules fused to complete A-tubules), the distal segment contains only A-tubule extensions, and its existence requires coordination of microtubule length at the nanometer scale. We show that three conserved proteins, two of which are mutated in the ciliopathy Joubert syndrome, determine the geometry of the distal segment, by controlling the positions of specific microtubule ends. FAP256/CEP104 promotes A-tubule elongation. CHE-12/Crescerin and ARMC9 act as positive and negative regulators of B-tubule length, respectively. We show that defects in the distal segment dimensions are associated with motile and sensory deficiencies of cilia. Our observations suggest that abnormalities in distal segment organization cause a subset of Joubert syndrome cases.


Trends and Patterns of Burden of Disease and Injuries in Korea Using Disability-Adjusted Life Years.
It is extremely important to objectively take a view of population health to provide useful information to decision makers, health-sector leaders, researchers, and informed citizens. This study aims to examine the burden of disease in Korea as of 2015, and to study how the burden of disease changes with the passage of time. We used results from the Korean National Burden of Disease and Injuries Study 2015 for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive disability-adjusted life years (DALYs) by gender and age groups from 2007 to 2015. DALYs were calculated as the sum of the years of life lost (YLLs) and the years lived with disability (YLDs). In 2015, the burden of disease for Korean people was calculated at 29,476 DALYs per 100,000 population. DALYs caused by low back pain were the highest, followed by diabetes mellitus and chronic obstructive pulmonary disease. The burden of disease showed a consistently increasing trend from 2007 to 2015. Although YLLs have been on the decrease since 2011, the increase in YLDs has contributed to the overall rise in DALYs. The DALYs per 100,000 population in 2015 increased by 28.1% compared to 2007. As for the diseases for which the burden of disease is substantially increasing, it is needed to establish appropriate policies in a timely manner. The results of this study are expected to be the basis for prioritizing public health and health care policies in Korea.


Cold denaturation of yeast frataxin offers the clue to understand the effect of alcohols on protein stability.
Although alcohols are well-known to be protein denaturants when present at high concentrations, their effect on proteins at low concentrations is much less well characterized. In this paper, we present a study of the effects of alcohols on protein stability using Yfh1, the yeast ortholog of the human protein frataxin. Exploiting the unusual property of this protein of undergoing cold denaturation around 0 degrees C without any ad hoc destabilization, we determined the stability curve on the basis of both high and low temperature unfolding in the presence of three commonly used alcohols: trifluoroethanol, ethanol, and methanol. In all cases, we observed an extended temperature range of protein stability as determined by a modest increase of the high temperature of unfolding but an appreciable decrease in the low temperature of unfolding. On the basis of simple thermodynamic considerations, we are able to interpret the literature on the effects of alcohols on proteins and to generalize our findings. We suggest that alcohols, at low concentration and physiological pH, stabilize proteins by greatly widening the range of temperatures over which the protein is stable. Our results also clarify the molecular mechanism of the interaction and validate the current theoretical interpretation of the mechanism of cold denaturation.


The role of LEF1 in endometrial gland formation and carcinogenesis.
Endometrial carcinoma is the most common gynecologic cancer, yet the mechanisms underlying this disease process are poorly understood. We hypothesized that Lef1 is required for endometrial gland formation within the uterus and is overexpressed in endometrial cancer. Using Lef1 knockout (KO) mice, we compared uterine gland development to wild-type (WT) controls, with respect to both morphology and expression of the Lef1 targets, cyclin D1 and MMP7. We characterized the dynamics of Lef1 protein expression during gland development and the mouse estrus cycle, by immunostaining and Western blot. Finally, we investigated the roles of cyclin D1 and MMP7 in gland and cancer formation in the mouse, and assessed the relevance of Lef1 to human cancer by comparing expression levels in cancerous and normal endometrial tissues. Lef1 upregulation in mouse endometrium correlates with the proliferative stages of the estrus cycle and gland development during the neonatal period. WT mice endometrial glands began to develop by day 5 and were easily identified by day 9, whereas Lef1 KO mice endometrial glands had not developed by day 9 although the endometrial lining was intact. We found that during gland development cyclin D1 is elevated and localized to the gland buds, and that this requires the presence of Lef1. We also noted that Lef1 protein was expressed at higher levels in endometrial cancers within mice and humans when compared to normal endometrium. Our loss-of-function data indicate that Lef1 is required for the formation of endometrial glands in the mouse uterus. Lef1 protein elevation corresponds to gland formation during development, and varies cyclically with the mouse estrus cycle, in parallel with gland regeneration. Finally, Lef1 is overexpressed in human and mouse endometrial tumors, consistent with it playing a role in gland proliferation.


Risk factors associated with the severity of injury outcome for paediatric road trauma.
Road trauma is one of the most common causes of injury for children. Yet risk factors associated with different levels of injury severity for childhood road trauma have not been examined in-depth. This study identifies crash and injury risk factors associated with the severity of non-fatal injury outcome for paediatric road trauma. A retrospective analysis was conducted of paediatric road trauma identified in linked police-reported and hospitalisation records during 1 January 2001 to 31 December 2011 in New South Wales (NSW), Australia. The linkage rate was 54%. Injury severity was calculated from diagnosis classifications in hospital records using the International Classification of Disease Injury Severity Score. Univariate and multi-variable logistic regression was conducted. There were 2412 car occupants, 1701 pedestrians and 612 pedal cyclists hospitalised where their hospital record linked to a police report. For car occupants, unauthorised vehicle drivers had twice the odds (OR: 2.21, 95%CI 1.47-3.34) and learner/provisional drivers had one and a half times higher odds (OR: 1.54, 95%CI 1.15-2.07) of a child car occupant sustaining a serious injury compared to a minor injury. For pedal cyclists and pedestrians, there were lower odds of a crash occurring during school commuting time and higher odds of a crash occurring during the weekend or on a dry road for children who sustained a serious versus a minor injury. Injury prevention initiatives, such as restraint and helmet use, that should reduce injury and/or crash severity are advocated.


Profound coordinated alterations of intratumoral NK cell phenotype and function in lung carcinoma.
Both the innate and adaptive immune systems contribute to tumor immunosurveillance in mice and humans; however, there is a paucity of direct evidence of a role for natural killer (NK) cells in this important process. In this study, we investigated the intratumoral phenotypic profile and functions of NK cells in primary human tumor specimens of non-small cell lung carcinoma (NSCLC). We used in situ methods to quantify and localize NK cells using the NKp46 marker and we characterized their phenotype in blood, tumoral, and nontumoral samples of NSCLC patients. Intratumoral NK cells displayed a profound and coordinated alteration of their phenotype, with a drastic reduction of NK cell receptor expression specifically detected in the tumoral region. According to their altered phenotype, intratumoral NK cells exhibited profound defects in the ability to activate degranulation and IFN-γ production. We found that the presence of NK cells did not impact the clinical outcome of patients with NSCLC. Finally, we showed that tumor cells heterogeneously express ligands for both activating and inhibitory NK receptors. Taken together, our results suggest that the NSCLC tumor microenvironment locally impairs NK cells, rendering them less tumorcidal and thereby supportive to cancer progression.


Genotype, Antifungal Susceptibility, and Virulence of Clinical South African Cryptococcus neoformans Strains from National Surveillance, 2005-2009.
In South Africa, Cryptococcus neoformans is the most common cause of adult meningitis. We performed multi locus sequence typing and fluconazole susceptibility testing of clinical C. neoformans isolates collected from 251 South African patients with cryptococcosis through national surveillance from 2005 to 2009. We examined the association between clinical characteristics of patients and genotype, and the effect of genotype on in-hospital mortality. We performed whole genome phylogenetic analysis of fifteen C. neoformans isolates with the molecular type VNB and tested their virulence in a Galleria mellonella model. Most isolates had the molecular type VNI (206/251, 82%), followed by VNII (25/251, 10%), VNB (15/251, 6%), and VNIV (5/251, 2%); 67 sequence types were identified. There were no differences in fluconazole minimum inhibitory concentration (MIC) values among molecular types and the majority of strains had low MIC values (MIC50 of 1 µg/mL and MIC90 of 4 µg/mL). Males were almost twice as likely of being infected with a non-VNI genotype (adjusted odds ratio [OR]: 1.65, 95% confidence interval [CI]: 0.25-10.99; p = 0.61). Compared to patients infected with a VNI genotype, those with a non-VNI genotype had a 50% reduced adjusted odds of dying in hospital (95% CI: 0.03-7.57; p = 0.62). However, for both these analyses, our estimates had wide confidence intervals spanning 1 with large p-values. Fifteen VNB strains were not as virulent in a G. mellonella larval model as the H99 reference strain. A majority of these VNB strains belonged to the VNBII clade and were very closely related by phylogenetic analysis.


High-throughput metabolic state analysis: the missing link in integrated functional genomics of yeasts.
The lack of comparable metabolic state assays severely limits understanding the metabolic changes caused by genetic or environmental perturbations. The present study reports the application of a novel derivatization method for metabolome analysis of yeast, coupled to data-mining software that achieve comparable throughput, effort and cost compared with DNA arrays. Our sample workup method enables simultaneous metabolite measurements throughout central carbon metabolism and amino acid biosynthesis, using a standard GC-MS platform that was optimized for this purpose. As an implementation proof-of-concept, we assayed metabolite levels in two yeast strains and two different environmental conditions in the context of metabolic pathway reconstruction. We demonstrate that these differential metabolite level data distinguish among sample types, such as typical metabolic fingerprinting or footprinting. More importantly, we demonstrate that this differential metabolite level data provides insight into specific metabolic pathways and lays the groundwork for integrated transcription-metabolism studies of yeasts.


Antibacterial Activities and Possible Modes of Action of Acacia nilotica (L.) Del. against Multidrug-Resistant Escherichia coli and Salmonella.
Medicinal plants are frequently used for the treatment of various infectious diseases. The objective of this study was to evaluate the antibacterial activity and mode of action of Acacia nilotica and the antibiogram patterns of foodborne and clinical strains of Escherichia coli and Salmonella. The mechanism of action of acacia extracts against E. coli and Salmonella was elucidated by observing morphological damages including cell integrity and cell membrane permeability, as well as changes in cell structures and growth patterns in kill-time experiments. The clinical isolates of E. coli and Salmonella were found resistant to more of the tested antibiotics, compared to food isolates. Minimum inhibitory concentration and minimum bactericidal concentration of acacia leaf extracts were in the ranges of 1.56-3.12 mg/mL and 3.12-6.25 mg/mL, respectively, whereas pods and bark extracts showed somewhat higher values of 3.12-6.25 mg/mL and 6.25-12.5 mg/mL, respectively, against all tested pathogens. The release of electrolytes and essential cellular constituents (proteins and nucleic acids) indicated that acacia extracts damaged the cellular membrane of the pathogens. These changes corresponded to simultaneous reduction in the growth of viable bacteria. This study indicates that A. nilotica can be a potential source of new antimicrobials, effective against antibiotic-resistant strains of pathogens.


First Report of Branch Blight of Tree Peony Caused by Phoma glomerata in China.
Tree peony (Paeonia suffruticosa Andrews) is a perennial woody deciduous shrub native to China and famous for its beautiful flowers. Starting in early autumn 2010, blighted branches of tree peony were detected in the International Peony Garden in Luoyang. The disease incidence was greater than 10% and disease symptoms included bulb atrophy and twig and branch dieback. Pycnidia were embedded within the bark of diseased branches. They were small, black, ostiolate, and measured 145 to 275 × 140 to 251 μm. Pycnoconidia were single-celled, hyaline or sandy beige, rounded to ellipsoidal, and 3.9 to 10.3 × 2.3 to 7.0 μm. Pure cultures were obtained by plating the pycnoconidia on potato dextrose agar (PDA). In culture, the fungus produced a circular, white to pink colony with pyknotic and linter shaped aerial mycelium. Numerous pycnidia, initially brown and dark at maturity, were embedded in the mycelium, especially in the center of the colony, with a few of them scattered in the edge. The morphological characteristics were consistent with Phoma (2). The ITS1-5.8S-ITS2 region of three isolates were PCR amplified and sequenced with primers ITS1 and ITS4. Sequences (GenBank Accession No. JX885584) showed 99% identity with reference isolates of Peyronellaea glomerata (Corda) Goid (AB470906.1 and HQ380779.1) and Phoma glomerata (Corda) Wollenw. & Hochapfel (EU098115.1). These two species are synonyms (1). To test pathogenicity, nine healthy branches of 3-year-old potted tree peony plants were wound-inoculated with a PDA disk containing pycnidia from an actively growing colony of P. glomerata. Three control branches were inoculated with sterile PDA disks. Each inoculated branch was wrapped in a plastic bag and maintained in a greenhouse at 25 to 28°C. After 3 days, brown patches appeared on inoculated branches and extended by up to 1 cm. Pycnidia identical to those observed in the field and in storage appeared on all inoculated branches 7 days after inoculation. Control branches did not show symptoms. The pathogen was reisolated from inoculated branches, fulfilling Koch's postulates. P. glomerata was reported as the causal agent of withering of flowers and young shoots of grapevines in Yugoslavia (3). To our knowledge, P. glomerata and Botryosphaeria dothidea have always been reported together, causing branch wilting or dieback. To our knowledge, this is the first report of branch blight of tree peony caused by P. glomerata in China. References: (1) M. M. Aveskamp et al. Mycol. Soc. Am. 101:363, 2009. (2) G. H. Boerema et al. Studies in Mycology, 3, 1973. (3) A. Šaric-Sabadoš et al. Atti Ist. bot. Univ. Pavia 18:101, 1960.


HIV antibody characterization as a method to quantify reservoir size during curative interventions.
Quantitative humoral profiling of recent samples from a human immunodeficiency virus (HIV)-infected adult who was cured following a delta32/delta32 CCR5 stem cell transplant in 2007 revealed no antibodies against p24, matrix, nucleocapsid, integrase, protease, and gp120, but low levels of antibodies against reverse transcriptase, tat, and gp41. Antibody levels to these HIV proteins persisted at high and stable levels in most noncontrollers, elite controllers, and antiretroviral-treated subjects, but a rare subset of controllers had low levels of antibodies against matrix, reverse transcriptase, integrase, and/or protease. Comprehensive HIV antibody profiles may prove useful for monitoring curative interventions.


Genetic deletion of Abcc6 disturbs cholesterol homeostasis in mice.
Genetic studies link adenosine triphosphate-binding cassette transporter C6 (ABCC6) mutations to pseudoxanthoma elasticum (PXE). ABCC6 sequence variations are correlated with altered HDL cholesterol levels and an elevated risk of coronary artery diseases. However, the role of ABCC6 in cholesterol homeostasis is not widely known. Here, we report reduced serum cholesterol and phytosterol levels in Abcc6-deficient mice, indicating an impaired sterol absorption. Ratios of cholesterol precursors to cholesterol were increased, confirmed by upregulation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase (Hmgcr) expression, suggesting activation of cholesterol biosynthesis in Abcc6-/- mice. We found that cholesterol depletion was accompanied by a substantial decrease in HDL cholesterol mediated by lowered ApoA-I and ApoA-II protein levels and not by inhibited lecithin-cholesterol transferase activity. Additionally, higher proprotein convertase subtilisin/kexin type 9 (Pcsk9) serum levels in Abcc6-/- mice and PXE patients and elevated ApoB level in knockout mice were observed, suggesting a potentially altered very low-density lipoprotein synthesis. Our results underline the role of Abcc6 in cholesterol homeostasis and indicate impaired cholesterol metabolism as an important pathomechanism involved in PXE manifestation.


Impact of Historical Changes in Coarse Cereals Consumption in India on Micronutrient Intake and Anemia Prevalence.
Production of rice and wheat increased dramatically in India over the past decades, with reduced proportion of coarse cereals in the food supply. We assess impacts of changes in cereal consumption in India on intake of iron and other micronutrients and whether increased consumption of coarse cereals could help alleviate anemia prevalence. With consumption data from over 800 000 households, we calculate intake of iron and other micronutrients from 84 food items from 1983 to 2011. We use mixed-effect models to relate state-level anemia prevalence in women and children to micronutrient consumption and household characteristics. Coarse cereals reduced from 23% to 6% of calories from cereals in rural households (10% to 3% in urban households) between 1983 and 2011, with wide variations across states. Loss of iron from coarse cereals was only partially compensated by increased iron from other cereals and food groups, with a 21% (rural) and 11% (urban) net loss of total iron intake. Models indicate negative association between iron from cereals and anemia prevalence in women. The benefit from increased iron from coarse cereals is partially offset by the adverse effects from antinutrients. For children, anemia was negatively associated with heme-iron consumption but not with iron from cereals. Loss of coarse cereals in the Indian diet has substantially reduced iron intake without compensation from other food groups, particularly in states where rice rather than wheat replaced coarse cereals. Increased consumption of coarse cereals could reduce anemia prevalence in Indian women along with other interventions.


Parameterization models for pesticide exposure via crop consumption.
An approach for estimating human exposure to pesticides via consumption of six important food crops is presented that can be used to extend multimedia models applied in health risk and life cycle impact assessment. We first assessed the variation of model output (pesticide residues per kg applied) as a function of model input variables (substance, crop, and environmental properties) including their possible correlations using matrix algebra. We identified five key parameters responsible for between 80% and 93% of the variation in pesticide residues, namely time between substance application and crop harvest, degradation half-lives in crops and on crop surfaces, overall residence times in soil, and substance molecular weight. Partition coefficients also play an important role for fruit trees and tomato (Kow), potato (Koc), and lettuce (Kaw, Kow). Focusing on these parameters, we develop crop-specific models by parametrizing a complex fate and exposure assessment framework. The parametric models thereby reflect the framework's physical and chemical mechanisms and predict pesticide residues in harvest using linear combinations of crop, crop surface, and soil compartments. Parametric model results correspond well with results from the complex framework for 1540 substance-crop combinations with total deviations between a factor 4 (potato) and a factor 66 (lettuce). Predicted residues also correspond well with experimental data previously used to evaluate the complex framework. Pesticide mass in harvest can finally be combined with reduction factors accounting for food processing to estimate human exposure from crop consumption. All parametric models can be easily implemented into existing assessment frameworks.


Dengue-3 virus genomic differences that correlate with in vitro phenotype on a human cell line but not with disease severity.
We compared the full genome sequence of nine clinical isolates of dengue virus obtained during an epidemic of dengue-3 in French Polynesia in 1989, from patients with various presentations of disease. The isolates, all belonging to Genotype I, had 25 amino acid substitutions. There was no association with disease severity. When cultured in the K562 human erythroleukemia cell line, the isolates induced a range of cell growth inhibitions that was not associated with the degree of disease severity. By contrast, some substitutions--charge changes in NS1 and NS5, side-chain differences in NS1, loss of the E-153 potential glycosylation site, and 11 nucleotide insertions in the 3'UTR--that have been suggested to result in an increase or attenuation of dengue infection, appeared to be associated with the level of inhibition. These data represent the first documented study of an association between differences in the full dengue-3 genome of clinical isolates and the in vitro phenotype of these isolates on a human cell line.


Additional postcranial elements of Teilhardina belgica: the oldest European primate.
Teilhardina belgica is one of the earliest fossil primates ever recovered and the oldest fossil primate from Europe. As such, this taxon has often been hypothesized as a basal tarsiiform on the basis of its primitive dental formula with four premolars and a simplified molar cusp pattern. Until recently [see Rose et al.: Am J Phys Anthropol 146 (2011) 281-305; Gebo et al.: J Hum Evol 63 (2012) 205-218], little was known concerning its postcranial anatomy with the exception of its well-known tarsals. In this article, we describe additional postcranial elements for T. belgica and compare these with other tarsiiforms and with primitive adapiforms. The forelimb of T. belgica indicates an arboreal primate with prominent forearm musculature, good elbow rotational mobility, and a horizontal, rather than a vertical body posture. The lateral hand positions imply grasps adaptive for relatively large diameter supports given its small body size. The hand is long with very long fingers, especially the middle phalanges. The hindlimb indicates foot inversion capabilities, frequent leaping, arboreal quadrupedalism, climbing, and grasping. The long and well-muscled hallux can be coupled with long lateral phalanges to reconstruct a foot with long grasping digits. Our phyletic analysis indicates that we can identify several postcranial characteristics shared in common for stem primates as well as note several derived postcranial characters for Tarsiiformes.


Developing brief fatigue short forms calibrated to a common mathematical metric: is content-balancing important?
There are clinical and research settings in which concerns about respondent burden make the use of longer self-report measures impractical. Though computer adaptive testing provides an efficient strategy for measuring patient reported outcomes, the requirement of a computer interface makes it impractical for some settings. This study evaluated how well brief short forms, constructed from a longer measure of patient reported fatigue, reproduced scores on the full measure. When the items of an item bank are calibrated using an item response theory model, it is assumed that the items are fungible units. Theoretically, there should be no advantage to balancing the content coverage of the items. We compared short forms developed using a random item selection process to short forms developed with consideration of the items relation to subdomains of fatigue (ie, physical and cognitive fatigue). Scores on short forms developed using content balancing more successfully predicted full item bank scores than did scores on short forms developed by random selection of items.


Is being in paid work beyond state pension age beneficial for health? Evidence from England using a life-course approach.
Given the current policy emphasis in many Western societies on extending working lives, we investigated the health effects of being in paid work beyond state pension age (SPA). Until now, work has largely focused on the health of those who exit the labour force early. Our data come from waves 2-4 of the English Longitudinal Study of Ageing, including the life history interview at wave 3. Using logistic and linear regression models, we assessed the longitudinal associations between being in paid work beyond SPA and 3 measures of health (depression, a latent measure of somatic health and sleep disturbance) among men aged 65-74 and women aged 60-69. Our analyses controlled for baseline health and socioeconomic characteristics, as well as for work histories and health in adulthood and childhood. Approximately a quarter of women and 15% of men were in paid work beyond SPA. Descriptive bivariate analyses suggested that men and women in paid work were more likely to report better health at follow-up. However, once baseline socioeconomic characteristics as well as adulthood and baseline health and labour market histories were accounted for, the health benefits of working beyond SPA were no longer significant. Potential health benefits of working beyond SPA need to be considered in the light of the fact that those who report good health and are more socioeconomically advantaged are more likely to be working beyond SPA to begin with.


Inhibitory effects of curcumin on dengue virus type 2-infected cells in vitro.
Curcumin, a traditional Chinese and Indian treatment for many diseases, has recently been found to alter the in vitro infection processes of various viruses, including hepatitis C virus, human immunodeficiency virus, coxsackievirus, and Japanese encephalitis virus. The present study evaluated the cellular effects of curcumin in an in vitro (cellular) infection model of dengue virus. Within a dose range of 10 to 30 μM and a treatment period of 24 hours, the cytotoxicity of curcumin was low, as determined by MTT assays. Cells infected with dengue virus type 2 at a multiplicity of infection of 5 were treated with various concentrations of curcumin or the proteasome inhibitor MG132. Plaque assays, immunofluorescence analysis, western blots, and in-cell western assays were then performed. Treatment with 10, 15, and 20 μM curcumin decreased the number of plaques produced, caused an intracellular accumulation of viral proteins, and increased the level of Lys48 ubiquitin-conjugated proteins. At 20 μM curcumin, changes in cell and nuclear morphology and alterations in the actin cytoskeleton were also observed. Treatment with MG132 also reduced plaque production. These results show that curcumin can interfere with the infection processes of dengue virus and that this interference may not occur through direct effects on viral particle production but may result from curcumin's effects on various cellular systems such as the cytoskeleton, the ubiquitin-proteasome system, or the apoptosis process.


Higher BMI is associated with reduced brain volume in heart failure.
Heart failure (HF) patients are at risk for structural brain changes due to cerebral hypoperfusion. Past work shows obesity is linked with reduced cerebral blood flow and associated with brain atrophy in healthy individuals, although its effects on the brain in HF are unclear. This study examined the association among body mass index (BMI), cerebral perfusion, and brain volume in HF patients. Eighty HF patients underwent transcranial Doppler sonography to quantify cerebral blood flow velocity of the middle cerebral artery (CBF-V of the MCA) and brain magnetic resonance imaging (MRI) to quantify total brain, total and subcortical gray matter, white matter volume, and white matter hyperintensities. Body mass index (BMI) operationalized weight status. Nearly 45% of HF patients exhibited a BMI consistent with obesity. Regression analyses adjusting for medical variables, demographic characteristics, and CBF-V of the MCA, showed increased BMI was associated with reduced white matter volume (p <.05). BMI also interacted with cerebral perfusion to impact total gray matter volume, but this pattern did not emerge for any other MRI indices (p < 0.05). Our findings suggest increased BMI negatively affects brain volume in HF, and higher BMI interacts with cerebral perfusion to impact gray matter volume. The mechanisms for these findings remain unclear and likely involve multiple physiological processes. Prospective studies are needed to elucidate the exact pattern and rates of brain changes in obese HF persons.


AKT regulates NPM dependent ARF localization and p53mut stability in tumors.
Nucleophosmin (NPM) is known to regulate ARF subcellular localization and MDM2 activity in response to oncogenic stress, though the precise mechanism has remained elusive. Here we describe how NPM and ARF associate in the nucleoplasm to form a MDM2 inhibitory complex. We find that oligomerization of NPM drives nucleolar accumulation of ARF. Moreover, the formation of NPM and ARF oligomers antagonizes MDM2 association with the inhibitory complex, leading to activation of MDM2 E3-ligase activity and targeting of p53. We find that AKT phosphorylation of NPM-Ser48 prevents oligomerization that results in nucleoplasmic localization of ARF, constitutive MDM2 inhibition and stabilization of p53. We also show that ARF promotes p53 mutant stability in tumors and suppresses p73 mediated p21 expression and senescence. We demonstrate that AKT and PI3K inhibitors may be effective in treatment of therapeutically resistant tumors with elevated AKT and carrying gain of function mutations in p53. Our results show that the clinical candidate AKT inhibitor MK-2206 promotes ARF nucleolar localization, reduced p53(mut) stability and increased sensitivity to ionizing radiation in a xenograft model of pancreatic cancer. Analysis of human tumors indicates that phospho-S48-NPM may be a useful biomarker for monitoring AKT activity and in vivo efficacy of AKT inhibitor treatment. Critically, we propose that combination therapy involving PI3K-AKT inhibitors would benefit from a patient stratification rationale based on ARF and p53(mut) status.


Cardiovascular responses to the stimulation of alpha-1 and alpha-2 adrenoceptors in the conscious dog.
Hemodynamic responses to the selective stimulation of alpha-1 and alpha-2 adrenoceptors were examined in chronically instrumented, conscious dogs. Norepinephrine (0.02-0.1 micrograms/kg/min), a mixed alpha-1/alpha-2 adrenoceptor agonist, phenylephrine (0.2-1.0 micrograms/kg/min), a selective alpha-adrenoceptor agonist and B-HT 920 (0.5-2.0 micrograms/kg/min), a selective alpha-2 adrenoceptor agonist, were infused i.v. after ganglionic (hexamethonium, 30 mg/kg i.v.), beta adrenoceptor (propranolol, 1, mg/kg i.v.) and muscarinic receptor (atropine methylbromide, 0.1 mg/kg i.v.) antagonism. Each of the alpha adrenoceptor agonists increased mean arterial pressure and total peripheral resistance but had no significant effect on cardiac output, stroke volume or heart rate. Equipressor doses of the alpha adrenoceptor agonists caused similar increases in left ventricular systolic and end-diastolic pressure, but there were no significant changes in left ventricular dP/dt or heart rate with any of the alpha adrenoceptor agonists. Selective antagonism of alpha-1 adrenoceptors with prazosin (1 mg/kg i.v.) abolished the pressor and vasoconstrictor responses to phenylephrine but had a lesser effect on the response to B-HT 920. Antagonism of alpha-2 adrenoceptors with rauwolscine (0.1 mg/kg i.v.) caused a significantly greater attenuation of the pressor and vasoconstrictor responses to B-HT 920 than to phenylephrine. The responses to norepinephrine were significantly attenuated by antagonism of either alpha-1 or alpha-2 adrenoceptors. Thus, in the conscious dog with reflex pathways blocked, selective stimulation of either postsynaptic alpha-1 or alpha-2 adrenoceptors increases arterial pressure and total peripheral resistance but does not significantly change heart rate, left ventricular dP/dt, stroke volume or cardiac output.


Flexible navigation response in common cuckoos Cuculus canorus displaced experimentally during migration.
Migrating birds follow innate species-specific migration programs capable of guiding them along complex spatio-temporal routes, which may include several separate staging areas. Indeed, migration routes of common cuckoos Cuculus canorus show little variation between individuals; yet, satellite tracks of 11 experimentally displaced adults revealed an unexpected flexibility in individual navigation responses. The birds compensated for the translocation to unfamiliar areas by travelling toward population-specific staging areas, demonstrating true navigation capabilities. Individual responses varied from travelling toward the first stopover in northern Europe to flying toward the Central-African winter grounds, the latter including several stopovers in unfamiliar areas. Apparently, the cuckoos possess spatial knowledge far beyond their population-specific flyway scale, and make individual decisions likely based on an assessment of perceived gain and cost of alternative route options.


Treatment of pulmonary embolism.
The treatment of pulmonary embolism is going to be deeply modified by the development of Direct Oral Anticoagulants (DOACs). There are currently three anti-Xa factors (rivaroxaban, apixaban, edoxaban) and one anti-IIa factor (dabigatran) labeled by the FDA and the EMA. All these drugs are direct anticoagulant, orally effective, without the need for adaptation to hemostasis test. As kidney excretion is involved for all of them, they are contra-indicated in patients with severe renal failure (creatinine clearance < 30 mL/min according to Cockcroft & Gault formula). All the anti-Xa factor drugs are metabolized by liver cytochromes and then contra-indicated in case of liver insufficiency. Of note, the four DOACS have been evaluated in non-inferiority trials, including one open-label trial (the EINSTEIN program with the rivaroxaban). Moreover, two of them (rivaroxaban and apixaban) were evaluated in a single drug approach (provided initial increased doses: 15 mg bid during 21 days for rivaroxaban and 10 mg bid during 7 days for apixaban) whereas the two others (edoxaban and dabigatran) were evaluated after at least 5 days of parenteral heparin. They were found to be non-inferior to the conventional treatment, but also seem to be associated with a decreased risk of major bleeding, in a quite young and without significant comorbidities population. The risk/benefit ratio of DOACs in specific subgroups deserves prospective validations.


The influence of genetic and environmental factors among MDMA users in cognitive performance.
This study is aimed to clarify the association between MDMA cumulative use and cognitive dysfunction, and the potential role of candidate genetic polymorphisms in explaining individual differences in the cognitive effects of MDMA. Gene polymorphisms related to reduced serotonin function, poor competency of executive control and memory consolidation systems, and high enzymatic activity linked to bioactivation of MDMA to neurotoxic metabolites may contribute to explain variations in the cognitive impact of MDMA across regular users of this drug. Sixty ecstasy polydrug users, 110 cannabis users and 93 non-drug users were assessed using cognitive measures of Verbal Memory (California Verbal Learning Test, CVLT), Visual Memory (Rey-Osterrieth Complex Figure Test, ROCFT), Semantic Fluency, and Perceptual Attention (Symbol Digit Modalities Test, SDMT). Participants were also genotyped for polymorphisms within the 5HTT, 5HTR2A, COMT, CYP2D6, BDNF, and GRIN2B genes using polymerase chain reaction and TaqMan polymerase assays. Lifetime cumulative MDMA use was significantly associated with poorer performance on visuospatial memory and perceptual attention. Heavy MDMA users (>100 tablets lifetime use) interacted with candidate gene polymorphisms in explaining individual differences in cognitive performance between MDMA users and controls. MDMA users carrying COMT val/val and SERT s/s had poorer performance than paired controls on visuospatial attention and memory, and MDMA users with CYP2D6 ultra-rapid metabolizers performed worse than controls on semantic fluency. Both MDMA lifetime use and gene-related individual differences influence cognitive dysfunction in ecstasy users.


Fabrication of a pencil-shaped fiber probe with a nanometric protrusion from a metal film for near-field optical microscopy.
We propose a method to fabricate a probe with a nanometric protrusion for near-field optical microscopy. The method involves tapering process based on selective etching of an GeO2 doped fiber in buffered hydrogen fluoride solution and metallizing process by vacuum evaporation and chemical polishing. We obtained the tapered probe having a protrusion emerged from a metal film. The protrusion has an apex diameter less than 10nm and a foot diameter less than 20nm. Employing the probe, we succeeded in obtaining a highly spatially resolved image of 20nm sized gold particles.


Psychiatric disorders after childhood stroke.
To determine the rate, types, and correlates of psychiatric disorder (PD) following stroke and orthopedic disorders in children and adolescents. Children aged 5 to 19 were assessed. The study used a cross-sectional design that compared 29 stroke subjects with 29 congenital clubfoot or scoliosis subjects. Assessments of psychiatric status; cognitive, adaptive, academic, and family functioning; family psychiatric history; neuroimaging; and neurological status were conducted. The main outcome measure was a current PD not present before the stroke or orthopedic disorder. Poststroke PD occurred significantly more often than postorthopedic diagnosis PD (17/29 [59%] versus 4/29 [14%], p < or =.001). Subjects with ongoing poststroke PD had significantly more impaired intellectual and adaptive functioning, higher intensity family psychiatric history scores, and tended toward higher neurological severity index scores, but they were not different regarding lesion volume or family functioning compared with stroke subjects without PD. Regression analyses showed that neurological severity and family psychiatric history independently contributed significantly to predicting PD. The data suggest that there are significant biopsychosocial correlates of PD in children with focal neurological lesions. These include a relatively abnormal neurological exam, lower IQ, and increased family psychopathology.


Management of Diverticular Bleeding: Evaluation, Stabilization, Intervention, and Recurrence of Bleeding and Indications for Resection after Control of Bleeding.
Diverticular bleeding is the most common cause of lower gastrointestinal bleeding with nearly 200,000 admissions in the United States annually. Less than 5% of patients with diverticulosis present with diverticular bleeding and present usually as painless, intermittent, and large volume of lower gastrointestinal bleeding. Management algorithm for patients presenting with diverticular bleeding includes resuscitation followed by diagnostic evaluation. Colonoscopy is the recommended first-line investigation and helps in identifying the stigmata of recent hemorrhage and endoscopic management of the bleeding. Radionuclide scanning is the most sensitive but least accurate test due to low spatial resolution. Angiography is helpful when patients are actively bleeding and therapeutic interventions are performed with angioembolization. Surgery for diverticular bleeding is necessary when associated with hemodynamic instability and after failed endoscopic or angiographic interventions. When the bleeding site is localized preoperatively, partial colectomy is sufficient, but subtotal colectomy is necessary when localization is not possible preoperatively.


Subjective cues to deception/honesty in a high stakes situation: an exploratory approach.
The low ecological validity of much of the research on deception detection is a limitation recognized by researchers in the field. Consequently, the present studies investigated subjective cues to deception using the real life, high stakes situation of people making public appeals for help with missing or murdered relatives. It was expected that cues related to affect would be particularly salient in this context. Study 1 was a qualitative investigation identifying cues to deception reportedly used by people accurate at detecting deception. Studies 2 and 3 were then empirical investigations that mainly employed the cues reported in Study 1. A number of subjective cues were found to discriminate between honest and deceptive appeals, including some previously unidentified cues, and cues likely to be context-specific. Most could be categorized under the themes of authenticity of emotion, and negative and positive affective reactions to the appealer. It is concluded that some cues to deception may emerge only in real life, high stakes situations; however, it is argued that some of these may be influenced by observers' perceptions of the characteristics of offenders, rather than acts of deception per se.


Erosive Vulvovaginitis Associated With Borrelia burgdorferi Infection.
We describe a case of acute erosive vulvovaginitis accompanying Borrelia burgdorferi infection. The patient is a 57-year-old woman previously diagnosed with Lyme disease who presented with a painful erosive genital lesion. At the time of the outbreak, she was being treated with oral antibiotics, and she tested serologically positive for B burgdorferi and serologically negative for syphilis. Histological examination of biopsy tissue from the lesion was not characteristic of dermatopathological patterns typical of erosive vulvar conditions. Dieterle-stained biopsy sections revealed visible spirochetes throughout the stratum spinosum and stratum basale, and anti- B burgdorferi immunostaining was positive. Motile spirochetes were observed by darkfield microscopy and cultured in Barbour-Stoner-Kelly-complete medium inoculated with skin scrapings from the lesion. Cultured spirochetes were identified genetically as B burgdorferi sensu stricto by polymerase chain reaction, while polymerase chain reaction amplification of treponemal gene targets was negative. The condition resolved after treatment with additional systemic antibiotic therapy and topical antibiotics. In cases of genital ulceration that have no identifiable etiology, the possibility of B burgdorferi spirochetal infection should be considered.


Responsiveness to Change of Self-Report and Device-Based Physical Activity Measures in the Living Well With Diabetes Trial.
This study evaluated the responsiveness to change in physical activity of 2 self-report measures and an accelerometer in the context of a weight loss intervention trial. 302 participants (aged 20 to 75 years) with type 2 diabetes were randomized into telephone counseling (n = 151) or usual care (n = 151) groups. Physical activity (minutes/week) was assessed at baseline and 6-months using the Active Australia Survey (AAS), the United States National Health Interview Survey (USNHIS) walking for exercise items, and accelerometer (Actigraph GT1M; ≥1952 counts/minute). Responsiveness to change was calculated as responsiveness index (RI), Cohen's d (postscores) and Cohen's d (change-scores). All instruments showed significant improvement in the intervention group (P < .001) and no significant change for usual care (P > .05). Accelerometer consistently ranked as the most responsive instrument while the least responsive was the USHNIS (responsiveness index) or AAS (Cohen's d). RIs for AAS, USNHIS and accelerometer did not differ significantly and were, respectively: 0.45 (95% CI: 0.26-0.65); 0.38 (95% CI: 0.20-0.56); and, 0.49 (95% CI: 0.23-0.74). Accelerometer tended to have the highest responsiveness but differences were small and not statistically significant. Consideration of factors, such as validity, feasibility and cost, in addition to responsiveness, is important for instrument selection in future trials.


Hepatitis B virus infection and development of chronic kidney disease: a cohort study.
The effect of chronic hepatitis B virus (HBV) infection on the risk of chronic kidney disease (CKD) is controversial. We examined the prospective association between hepatitis B surface antigen (HBsAg) serology status and incident CKD in a large cohort of men and women. Cohort study of 299,913 adults free of CKD at baseline who underwent health screening exams between January 2002 and December 2016 in South Korea. Incident CKD was defined as the development of an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m2 and/or proteinuria. Over 1,673,701 person-years of follow-up, we observed 13,924 incident cases of CKD (3225 cases of eGFR < 60 ml/min/1.73m2 and 11,072 cases of proteinuria). In fully adjusted models comparing positive to negative HBsAg participants, the hazard ratio (HR, 95% confidence interval) for incident CKD was 1.11 (1.03-1.21; P = 0.01). The corresponding HR for incident proteinuria and for eGFR < 60 ml/min/1.73m2 were 1.23 (1.12-1.35; P < 0.001) and 0.89 (0.73-1.07; P = 0.21), respectively. The associations were similar across categories of liver enzyme levels at baseline. In this large cohort, HBsAg positive serology was associated with higher risk of incident CKD, and we provide novel evidence that this association was due to a higher incidence of proteinuria in HBsAg positive participants. Our study adds to the growing body of evidence suggesting that chronic HBV infection may be a contributor to the increasing incidence of CKD.


Landscape planning for agricultural nonpoint source pollution reduction III: assessing phosphorus and sediment reduction potential.
Riparian buffers have the potential to improve stream water quality in agricultural landscapes. This potential may vary in response to landscape characteristics such as soils, topography, land use, and human activities, including legacies of historical land management. We built a predictive model to estimate the sediment and phosphorus load reduction that should be achievable following the implementation of riparian buffers; then we estimated load reduction potential for a set of 1598 watersheds (average 54 km(2)) in Wisconsin. Our results indicate that land cover is generally the most important driver of constituent loads in Wisconsin streams, but its influence varies among pollutants and according to the scale at which it is measured. Physiographic (drainage density) variation also influenced sediment and phosphorus loads. The effect of historical land use on present-day channel erosion and variation in soil texture are the most important sources of phosphorus and sediment that riparian buffers cannot attenuate. However, in most watersheds, a large proportion (approximately 70%) of these pollutants can be eliminated from streams with buffers. Cumulative frequency distributions of load reduction potential indicate that targeting pollution reduction in the highest 10% of Wisconsin watersheds would reduce total phosphorus and sediment loads in the entire state by approximately 20%. These results support our approach of geographically targeting nonpoint source pollution reduction at multiple scales, including the watershed scale.


Structural Insights into Yeast Telomerase Recruitment to Telomeres.
Telomerase maintains chromosome ends from humans to yeasts. Recruitment of yeast telomerase to telomeres occurs through its Ku and Est1 subunits via independent interactions with telomerase RNA (TLC1) and telomeric proteins Sir4 and Cdc13, respectively. However, the structures of the molecules comprising these telomerase-recruiting pathways remain unknown. Here, we report crystal structures of the Ku heterodimer and Est1 complexed with their key binding partners. Two major findings are as follows: (1) Ku specifically binds to telomerase RNA in a distinct, yet related, manner to how it binds DNA; and (2) Est1 employs two separate pockets to bind distinct motifs of Cdc13. The N-terminal Cdc13-binding site of Est1 cooperates with the TLC1-Ku-Sir4 pathway for telomerase recruitment, whereas the C-terminal interface is dispensable for binding Est1 in vitro yet is nevertheless essential for telomere maintenance in vivo. Overall, our results integrate previous models and provide fundamentally valuable structural information regarding telomere biology.


Elevated HbA1c levels in individuals not diagnosed with type 2 diabetes in Qatar: a pilot study.
The prevalence of type 2 diabetes (T2D) in Qatar and the Middle East is one of the highest in the world. It is estimated that about one quarter of the individuals with tbl2D are undiagnosed. Elevated HbA1c levels are an indicator of tbl2D or a pre-diabetic state. In this study we set out to examine which factors, such as anthropometric and socio-demographic risk factors, are associated with elevated HbA1c levels in a population without tbl2D. We examined 191 subjects with no record of tbl2D. Anthropometrics and HbA1c were measured. Socio-demographic (age, gender, ethnicity and educational level) and health information were assessed through questionnaires. Elevated HbA1c levels were defined as >6.0% (>42 mmol/mol). Individual risk factors were examined in relationship to having elevated HbA1c levels using logistic regression. Thirty-eight (20%) study participants had elevated HbA1c levels. Participants from South Asian and Filipino descent were more likely to present with elevated HbA1c levels than Arab participants (adjusted odds ratios (OR): 13.30 (95% confidence interval (CI): 4.24, 41.79), p < 0.001 for South Asian and 4.54 (95% CI: 1.04, 19.83), p = 0.04 for Filipinos). A body mass index of above 30 kg/m(2) was associated with elevated HbA1c levels (adjusted OR: 2.90 (95% CI: 1.29, 6.51), p = 0.01). Neither gender nor educational level was associated with elevated HbA1c levels. Elevated HbA1c levels in individuals not diagnosed with diabetes were most frequently found in the South Asian and Filipino immigrant population. Special attention should therefore be given to the early identification of tbl2D in these subjects.


The tumor suppressor SirT2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of H4K20 methylation.
The establishment of the epigenetic mark H4K20me1 (monomethylation of H4K20) by PR-Set7 during G2/M directly impacts S-phase progression and genome stability. However, the mechanisms involved in the regulation of this event are not well understood. Here we show that SirT2 regulates H4K20me1 deposition through the deacetylation of H4K16Ac (acetylation of H4K16) and determines the levels of H4K20me2/3 throughout the cell cycle. SirT2 binds and deacetylates PR-Set7 at K90, modulating its chromatin localization. Consistently, SirT2 depletion significantly reduces PR-Set7 chromatin levels, alters the size and number of PR-Set7 foci, and decreases the overall mitotic deposition of H4K20me1. Upon stress, the interaction between SirT2 and PR-Set7 increases along with the H4K20me1 levels, suggesting a novel mitotic checkpoint mechanism. SirT2 loss in mice induces significant defects associated with defective H4K20me1-3 levels. Accordingly, SirT2-deficient animals exhibit genomic instability and chromosomal aberrations and are prone to tumorigenesis. Our studies suggest that the dynamic cross-talk between the environment and the genome during mitosis determines the fate of the subsequent cell cycle.


Climate risk, culture and the Covid-19 mortality: A cross-country analysis.
Why have some countries done significantly better than others in fighting the Covid-19 pandemic? Had some countries been better prepared than others? This paper attempts to shed light on these questions by examining the role of climate risk and culture in explaining the cross-country variation in the Covid-19 mortality, while controlling for other potential drivers. In our analysis, we consider climate risk, readiness to climate change and individualism as main indicators reflecting the climate and culture status of individual countries. Using data from 110 countries, we find that the greater the climate risk; the lower the readiness to climate change and the more individualistic the society, the higher the pandemic mortality rate. We also present a series of sensitivity checks and show that our findings are robust to different specifications, alternative definitions of the mortality rate; and different estimation methods. One policy implication arising from our results is that countries that were better prepared for the climate emergency were also better placed to fight the pandemic. Overall, countries in which individuals look after each other and the environment, creating sustainable societies, are better able to cope with climate and public health emergencies.


Quiet eye duration and gun motion in elite shotgun shooting.
No literature exists to document skill-related differences in shotgun shooting and whether these may be a function of eye movements and control of gun motion. We therefore conducted an exploratory investigation of the visual search behaviors and gun barrel kinematics used by elite and subelite shooters across the three shotgun shooting subdisciplines. Point of gaze and gun barrel kinematics were recorded in groups of elite (n = 24) and subelite (n = 24) shooters participating in skeet, trap, and double trap events. Point of gaze was calculated in relation to the scene, while motion of the gun was captured by two stationary external cameras. Quiet eye (final fixation or tracking gaze that is located on a specific location/object in the visual display for a minimum of 100 ms) duration and onset were analyzed as well as gun motion profiles in the horizontal and vertical planes. In skeet, trap, and double trap disciplines, elite shooters demonstrated both an earlier onset and a longer relative duration of quiet eye than their subelite counterparts did. Also, in all three disciplines, quiet eye duration was longer and onset earlier during successful compared with unsuccessful trials for elite and subelite shooters. Kinematic analyses indicated that a slower movement of the gun barrel was used by elite compared with subelite shooters. Overall, stable gun motion and a longer quiet eye duration seem critical to a successful performance in all three shotgun disciplines.