Big Science vs. Little Science: How Scientific Impact Scales with Funding.
is it more effective to give large grants to a few elite researchers, or small grants to many researchers? Large grants would be more effective only if scientific impact increases as an accelerating function of grant size. Here, we examine the scientific impact of individual university-based researchers in three disciplines funded by the Natural Sciences and Engineering Research Council of Canada (NSERC). We considered four indices of scientific impact: numbers of articles published, numbers of citations to those articles, the most cited article, and the number of highly cited articles, each measured over a four-year period. We related these to the amount of NSERC funding received. Impact is positively, but only weakly, related to funding. Researchers who received additional funds from a second federal granting council, the Canadian Institutes for Health Research, were not more productive than those who received only NSERC funding. Impact was generally a decelerating function of funding. Impact per dollar was therefore lower for large grant-holders. This is inconsistent with the hypothesis that larger grants lead to larger discoveries. Further, the impact of researchers who received increases in funding did not predictably increase. We conclude that scientific impact (as reflected by publications) is only weakly limited by funding. We suggest that funding strategies that target diversity, rather than "excellence", are likely to prove to be more productive.


Health care utilization among migrant Latino farmworkers: the case of skin disease.
Skin diseases are common occupational illnesses for migrant farmworkers. Farmworkers face many barriers in accessing health care resources. Framed by the Health Behavior Model, the purpose of this study was to assess health care utilization for skin disease by migrant Latino farmworkers. Three hundred and four migrant and seasonal Latino farmworkers in North Carolina were enrolled in a longitudinal study of skin disease and health care utilization over a single agricultural season. Self-reported and dermatologist-diagnosed skin condition data were collected at baseline and at up to 4 follow-up assessments. Medical visit rates were compared to national norms. Self-reported skin problems and diagnosed skin disease were common among farmworkers. However, only 34 health care visits were reported across the entire agricultural season, and none of the visits were for skin diseases. Nevertheless, self-treatment for skin conditions was common, including use of non-prescription preparations (63%), prescription products (9%), and home remedies (6%). General medical office visits were reported in 3.2% of the assessments, corresponding to 1.6 office visits per person year. The migrant farmworker population consists largely of young men who make little use of clinic services. Skin conditions are very common among these workers, but use of medical services for these conditions is not common. Instead, farmworkers rely primarily on self-treatment. Clinic-based studies of farmworker skin conditions will not account for most injury or disease in this population and have the potential for biased estimates.


Heavy metals in zooplankton and decapod crustaceans from the Barents Sea.
Trace metals (Cd, Cu, Pb and Zn) were analysed in zooplankton samples and decapod crustaceans collected on cruises of "RV Walther Herwig III" to the Barents Sea (Summer 1991, 1994 and 2000). We found a substantial spatial heterogeneity in the decapod crustacean Pandalus borealis, with increasing Cd concentrations from the south (North Cape Bank; 0.7 mg kg(-1) DW) to the north (north of Svalbard; 4.7 mg kg(-1)), supporting the hypothesis that the frequently reported Cd-anomaly in polar crustaceans might be extended to the Barents Sea. Regarding various crustaceans and zooplankton collectives (2000) a distinct interspecific heterogeneity of metals was obvious, with lowest Cd concentrations in euphausiids and chaetognaths and highest ones in decapods and hyperiid amphipods; lowest Cu concentrations in chaetognaths and copepods and highest ones in euphausiids and decapods; and lowest Zn concentrations in euphausiids and decapods and highest ones in some copepods. For Pb many values were below or close to the limit of detection, suggesting that Pb concentrations about 0.4 mg kg(-1) might serve as a regional background value. Results for Cd, Cu and Zn in copepods of this study are largely within the reported range, but high Cd concentrations in copepods from summer in contrast to reported lower ones during winter/spring may be related either to changing accumulation strategies of the copepod species involved or to seasonally changing Cd absorption in copepods from food.


CD154 blockade alters innate immune cell recruitment and programs alloreactive CD8+ T cells into KLRG-1(high) short-lived effector T cells.
CD154/CD40 blockade combined with donor specific transfusion remains one of the most effective therapies in prolonging allograft survival. Despite this, the mechanisms by which these pathways synergize to prevent rejection are not completely understood. Utilizing a BALB/c (H2-K(d)) to B6 (H2-K(b)) fully allogeneic skin transplant model system, we performed a detailed longitudinal analysis of the kinetics and magnitude of CD8(+) T cell expansion and differentiation in the presence of CD154/CD40 pathway blockade. Results demonstrated that treatment with anti-CD154 vs. DST had distinct and opposing effects on activated CD44(high) CD62L(low) CD8(+) T cells in skin graft recipients. Specifically, CD154 blockade delayed alloreactive CD8(+) T cell responses, while DST accelerated them. DST inhibited the differentiation of alloreactive CD8(+) T cells into multi-cytokine producing effectors, while CD40/CD154 blockade led to the diminution of the KLRG-1(low) long-lived memory precursor population compared with either untreated or DST treated animals. Moreover, only CD154 blockade effectively inhibited CXCL1 expression and neutrophil recruitment into the graft. When combined, anti-CD154 and DST acted synergistically to profoundly diminish the absolute number of IFN-γ producing alloreactive CD8(+) T cells, and intra-graft expression of inflammatory chemokines. These findings demonstrate that the previously described ability of anti-CD154 and DST to result in alloreactive T cell deletion involves both delayed kinetics of T cell expansion and differentiation and inhibited development of KLRG-1(low) memory precursor cells.


Enabling outsourcing XDS for imaging on the public cloud.
Picture Archiving and Communication System (PACS) has been the main paradigm in supporting medical imaging workflows during the last decades. Despite its consolidation, the appearance of Cross-Enterprise Document Sharing for imaging (XDS-I), within IHE initiative, constitutes a great opportunity to readapt PACS workflow for inter-institutional data exchange. XDS-I provides a centralized discovery of medical imaging and associated reports. However, the centralized XDS-I actors (document registry and repository) must be deployed in a trustworthy node in order to safeguard patient privacy, data confidentiality and integrity. This paper presents XDS for Protected Imaging (XDS-p), a new approach to XDS-I that is capable of being outsourced (e.g. Cloud Computing) while maintaining privacy, confidentiality, integrity and legal concerns about patients' medical information.


Biomarker testing for breast, lung, and gastroesophageal cancers at NCI designated cancer centers.
Molecular biomarkers, a cornerstone of precision oncology, are critical in breast, gastroesophageal, and non-small cell lung cancer management (BC, GEC, NSCLC). Testing practices are intensely debated, impacting diagnostic quality and affecting pathologists, oncologists and patients. However, little is known about testing approaches used in practice. Our study described biomarker practices in BC, GEC, and NSCLC at the leading US cancer centers. We conducted a survey of the National Cancer Institute (NCI) designated centers on BC, GEC, and NSCLC biomarker testing. We used simple frequencies to describe practices, two-sided Fisher's exact test and two-sided McNemar's test for cross-cancer comparison. All statistical tests were two-sided. For BC human epidermal growth factor receptor 2 (HER2), 39% of centers combine guidelines by using in situ hybridization (ISH) and immunohistochemistry (IHC) concurrently, and 21% reflex-test beyond guideline-recommended IHC2+. For GEC HER2, 44% use ISH and IHC concurrently, and 28% reflex-test beyond IHC2+. In NSCLC, the use of IHC is limited to 4% for epidermal growth factor receptor (EGFR) and 7% for anaplastic lymphoma kinase (ALK). 43.5% test NSCLC biomarkers on oncologist order; 34.5% run all biomarkers upfront, and 22% use a sequential protocol. NSCLC external testing is statistically significantly higher than BC (P < .0001) and GEC (P < .0001). NSCLC internally developed tests are statistically significantly more common than BC (P < .0001) and GEC (P < .0001). At the NCI cancer centers, biomarker testing practices vary, but exceeding guidelines is a common practice for established biomarkers and emerging practice for newer biomarkers. Use of internally developed tests declines as biomarkers mature. Implementation of multibiomarker protocols is lagging. Our study represents a step toward developing a biomarker testing practice landscape.


Crystal structure of the GpIbalpha-thrombin complex essential for platelet aggregation.
Direct interaction between platelet receptor glycoprotein Ibalpha (GpIbalpha) and thrombin is required for platelet aggregation and activation at sites of vascular injury. Abnormal GpIbalpha-thrombin binding is associated with many pathological conditions,including occlusive arterial thrombosis and bleeding disorders. The crystal structure of the GpIbalpha-thrombin complex at 2.6 angstrom resolution reveals simultaneous interactions of GpIbalpha with exosite I of one thrombin molecule,and with exosite II of a second thrombin molecule. In the crystal lattice,the periodic arrangement of GpIbalpha-thrombin complexes mirrors a scaffold that could serve as a driving force for tight platelet adhesion. The details of these interactions reconcile GpIbalpha-thrombin binding modes that are presently controversial,highlighting two distinct interfaces that are potential targets for development of novel antithrombotic drugs.


Chromatographic profiles and identification of new phenolic components of Ginkgo biloba leaves and selected products.
Ginkgo biloba leaves and their extracts are one of the most widely used herbal products and/or dietary supplements in the world. A systematic study of the phenolic compounds is necessary to establish quality parameters. A modified LC-DAD-ESI/MS method was used to obtain chromatographic profiles for the flavonoids and terpene lactones of Ginkgo biloba leaves. The method was used to identify 45 glycosylated flavonols and flavones, 3 flavonol aglycones, catechin, 10 biflavones, a dihydroxybenzoic acid, and 4 terpene lactones in an aqueous methanol extract of the leaves. The extracted G. biloba leaf products contained the same flavonoids as the raw leaves except for the lack of biflavones. The detected glycosylated flavonol contents were equal to or more than 0.0008% of the dry plant material. This is the first report of the presence of more than 20 of these flavonoids in G. biloba.


Susceptibility locus for epidermodysplasia verruciformis not linked to cervical cancer in situ.
Cervical cancer is strongly associated with infection by oncogenic forms of human papillomavirus (HPV), mainly HPV 16 and HPV 18. The aim of this study was to test if a locus previously mapped to a region on chromosome 17 qter in patients with epidermodysplasia verucciformis (EV) and psoriasis and considered to be responsible for an increased susceptibility to HPV 5, also is linked to increased HPV susceptibility in cervical cancer in situ. We also wanted to test whether HPV 16 positivity cluster in families with cervical cancer. DNA was extracted from formalin fixed biopsies of 224 affected from 77 families diagnosed with cervical cancer in situ. Two microsatellite markers (D17S939 and D17S802) containing the locus were genotyped and linkage analysis was performed. No linkage was found to any of the two markers, neither when considering all cancer cases as affected nor when only considering HPV 16 infected cancer cases as affected in the analysis. We conclude that the susceptibility locus for HPV 5 infections associated with EV and psoriasis does not seem to affect susceptibility to HPV 16, frequently detected in cervical cancer. Also, positivity for HPV 16 did not show a significant clustering in families.


A Quantitative PCR Protocol for Detection of Oxyspirura petrowi in Northern Bobwhites (Colinus virginianus).
Oxyspirura petrowi is a parasitic nematode that infects wild birds. This parasite has a broad host range, but has recently been reported in high prevalences from native Galliformes species in the United States. In order to better understand the impact O. petrowi has on wild bird populations, we developed a quantitative PCR protocol to detect infections in wild northern bobwhites (Colinus virginianus). We used paired fecal and cloacal swab samples from wild caught and experimentally infected northern bobwhites and matching fecal float data from experimentally infected birds to validate our assay. Overall we detected more positive birds from fecal samples than the paired cloacal swabs and there was strong agreement between the qPCR results from fecal samples and from fecal flotation (84%; κ = 0.69 [0.53-0.84 95% CI]). We also detected O. petrowi DNA in ten replicates of samples spiked with one O. petrowi egg. This qPCR assay is an effective assay to detect O. petrowi infections in wild birds. Our results suggest that fecal samples are the most appropriate sample for detecting infections; although, cloacal swabs can be useful for determining if O. petrowi is circulating in a population.


Inducement and Evaluation of a Murine Model of Experimental Myopia.
Murine model of myopia can be a powerful tool for myopia research because of the comparatively easy genetic manipulation. One way to induce myopia in animals is to put clear minus lenses in front of eyes for weeks (lens-induced myopia, LIM). However, extant protocols for inducement and evaluation vary from laboratory to laboratory. Here, we described a highly practical and reproducible method to induce LIM in mice using newly designed eyeglasses. The method fixes the lens stably in front of the mouse eye while allows the lens to be taken off for cleaning or topical drug administration. The phenotype is robust and efficient, and the variance is small. The method described here can be applied to mice right after weaning which extends the possible duration for experiments. We also gave technical advises for achieving reproducible results in refraction and axial length measurements. We hope the step-by-step protocol described here and the detailed article can help researchers perform myopia experiments with myopia more smoothly and make the data comparable across laboratories.


Out-of-hours GPs and palliative care-a qualitative study exploring information exchange and communication issues.
Out-of-hours general practitioners (GPs) cover the community over a significant proportion of a given week, and palliative care patients are seen as a priority. Little is known about how well these GPs feel supported in their line of work and whether communication exchanges work well for the proportion of their patients who have palliative care needs. For this study, GPs who provide out-of-hours care were interviewed in order to explore factors that they identified as detrimental or beneficial for good communication between themselves, patients, relatives and other professionals, specifically to palliative care encounters. Nine GPs were interviewed using face-to-face semi-structured interviews. All nine GPs worked regular out-of-hours sessions. Data from transcripts was analysed using Interpretative Phenomenological Analysis. A predominant theme expressed by GPs related to constraints within the system provided by the local private company owned out-of-hours provider. A strong feeling of 'being alone out there' emerged, with some GPs more willing to call for help than others, and others expressing their concern at access to pharmacies and medication being very inconsistent.Out-of-hours GPs felt left alone on occasion, unable to access daytime services and not knowing who to call for advice. Information hand-over systems from in-hours to out-of-hours with regard to palliative care were felt to be inadequate. Out-of-hours doctors interviewed felt left out of the care loop; handover sheets from specialist palliative care providers were a rarity. Out-of-hours services need to be mindful of the needs of the GPs they employ, in particular relating to the palliative care they provide in this setting. Other healthcare professionals should aim to keep their local out-of-hours service informed about palliative care patients they may be called to see.


Active form of ketamine in squid giant axons.
The active form of ketamine has been studied with internally perfused squid qiant axons. The drug was applied internally, and decreases in peak transient and steady-state conductances as measured by voltage clamp technique were taken as an index of activity. When the total internal ketamine concentration was maintained constant, the suppression peak transient and steady-state conductances decreased with an increase in internal pH from 7.0 TO 8.4. When the concentration of the internally present charged form of ketamine was kept constant, the suppression of the peak transient conductance remained almost constant at internal pH values of 7.0, 7.3 and 7.7, but increased at pH 8.4. However, the suppression of the stead-state conductance became more prominent as the pH was raised from 7.0 to 8.4. With a constant internal concentration of the uncharged form, the suppression of both conductances decreased as the pH was raised from 7.0 to 8.4. Computation of dissociation constants to suppretamine is more potent than the charged form at all internal pH values examined. These data also show that the potency to suppress the peak transient conductance by the charged and uncharged forms of ketamine decreased as the intertance of the charged form increased, and that of the uncharged form decreased considerably with increase in the internal pH.


Homogeneous silver colloidal substrates optimal for metal-enhanced fluorescence.
Homogeneous silver colloidal films (SCFs), composed of silver nanoparticles 67-193 nm in diameter, were synthesized by a seeded-growth method as the substrates for metal-enhanced fluorescence (MEF). The homogeneity and uniform particle distribution of the SCFs showed many advantages for the exploration of the MEF mechanism. The fluorescence enhancement of 4-(dicyanomethylene)-2-methyl-6-(4-dimethylaminostyryl)-4H-pyran (DCM) and rhodamine 700 (Rh700) dyes dispersed in a thin layer of polystyrene (PS) with the SCFs was observed by time-resolved fluorescence spectroscopy. The fluorescence enhancements of DCM and Rh700 become larger when the surface plasmon resonance bands of SCFs overlap the emission bands of dyes. The particle-size-dependent changes of the radiative and non-radiative rate constants of both dyes with the SCFs are estimated by an improved analysis combining the fluorescence intensity and lifetime measurements and the finite-difference time-domain method simulations.


Discovery of novel triple helical DNA intercalators by an integrated virtual and actual screening platform.
Virtual Screening is an increasingly attractive way to discover new small molecules with potential medicinal value. We introduce a novel strategy that integrates use of the molecular docking software Surflex with experimental validation by the method of competition dialysis. This integrated approach was used to identify ligands that selectively bind to the triplex DNA poly(dA)-[poly(dT)](2). A library containing approximately 2 million ligands was virtually screened to identify compounds with chemical and structural similarity to a known triplex intercalator, the napthylquinoline MHQ-12. Further molecular docking studies using compounds with high structural similarity resulted in two compounds that were then demonstrated by competition dialysis to have a superior affinity and selectivity for the triplex nucleic acid than MHQ-12. One of the compounds has a different chemical backbone than MHQ-12, which demonstrates the ability of this strategy to 'scaffold hop' and to identify small molecules with novel binding properties. Biophysical characterization of these compounds by circular dichroism and thermal denaturation studies confirmed their binding mode and selectivity. These studies provide a proof-of-principle for our integrated screening strategy, and suggest that this platform may be extended to discover new compounds that target therapeutically relevant nucleic acid morphologies.


Intermediate uveitis associated with MS: Diagnosis, clinical features, pathogenic mechanisms, and recommendations for management.
Uveitis is a major cause of visual impairment and blindness among working-age adults, accounting for 10% of legal blindness in the United States. Among people with MS, the prevalence of uveitis is 10 times higher than among the general population, and because MS and uveitis share similar genetic risk factors and immunologic effector pathways, it is not clear whether uveitis is one of the manifestations of MS or a coincident disorder. This uncertainty raises several diagnostic and management issues for clinicians who look after these patients, particularly with regard to recognizing visual symptoms resulting from demyelination, intraocular inflammation, or the visual complications of disease modifying drugs for MS, e.g., fingolimod. Likewise, management decisions regarding patients with uveitis are influenced by the risk of precipitating or exacerbating episodes of demyelination, e.g., following anti-tumor necrosis factor biologic therapy, and other neurologic complications of immunosuppressive treatments for uveitis. In this review, we explore the similarities in the pathophysiology, clinical features, and treatment of patients with uveitis and MS. Based on the latest evidence, we make a set of recommendations to help guide neurologists and ophthalmologists to best manage patients affected by both conditions.


Birds learn to use distastefulness as a signal of toxicity.
Aposematic prey advertise their toxicity using conspicuous visual signals that predators quickly learn to avoid. However, it is advantageous for predators not to simply avoid toxic prey, but to learn about the amount of toxin that prey contain, and include them in their diets when the nutritional gains are high relative to the costs of ingesting the toxin. Therefore, when foraging on a defended prey population where individuals vary in their toxin concentration, predators should learn to use cues which distinguish prey with different levels of toxicity in order to include less defended individuals in their diets. In this experiment, we found that European starlings (Sturnus vulgaris) could learn to use a bitter taste to predict the amount of toxin that individual prey contained, and use that information to preferentially ingest less toxic prey to maximize their nutrient intake relative to the amount of toxin ingested. Our results suggest that bitter tastes could evolve as reliable signals of toxicity, and can help to explain why many toxins taste bitter. They also highlight the need to develop new mathematical simulations of the evolution of prey defences which incorporate the adaptive decision-making processes underlying nutrient and toxin management.


Effects of an Exercise and Mental Activity Program for People With Dementia and Their Care Partners.
Exercise and mental stimulation may improve cognition, physical function, and well-being of people with dementia (PWD) and older adults more generally. This study evaluated changes in physical function, physical activity, exercise self-efficacy, and mental well-being with participation in Minds in Motion®, a weekly exercise and mental stimulation program for PWD (n = 343) and care partners (n = 318). Most physical function measures improved among PWD and care partners (endurance, upper and lower body strength, upper body flexibility; ps ≤ .009). Participants also reported a significant increase in weekly frequency, duration, and intensity of physical activity (ps < .001) and in mental well-being (p < .001). Exercise self-efficacy did not change (p = .16). These results suggest that Minds in Motion® yields improvements in physical function, which may translate into better functional abilities for PWD and improved ability for their partners to care for people living with dementia.


Evaluation of dynamic sentinel lymph node biopsy in patients with squamous cell carcinoma of the penis and palpable inguinal nodes.
To evaluate dynamic sentinel lymph node biopsy (DSLNB) in patients with squamous cell carcinoma (SCC) of the penis and palpable inguinal lymph nodes, using inguinal lymph node dissection (ILND) as the reference standard to assess the reliability of DSLNB, as using radioscintigraphy and colloidal blue-dye injection to locate the SLN was reported to be a useful technique to avoid ILND in men with SCC of the penis and clinically impalpable nodes. The study included 23 consecutive men with SCC of the penis and clinically palpable inguinal nodes treated between August 1999 and July 2006. On the day before surgery the patient had the SLN located by subcutaneous injection of 60 MBq (99m)Tc-nanocolloid 2 cm proximal to the penile tumour. The following day the patient was taken to the operating room for DSLNB, resection of the penile tumour and simultaneous ILND, if considered indicated (G2-3 and/or T3-4 primary tumour). During surgery 2 mL of colloidal blue dye was injected in the same area as the previous (99m)Tc-nanocolloid injection. The SLNs were located during surgery using a gamma-probe and visualization of blue dye in the node(s), which were then surgically removed. After partial or total penectomy, selected patients had ILND through a 10-cm subinguinal incision. The primary tumour, SLNs and ILND specimens were assessed histopathologically, using haematoxylin and eosin staining only. Biopsy of the primary tumour showed SCC grade 1 in six, grade 2 in 13 and grade 3 in two patients. The clinical T stage was T1 in two, T2 in seven, T3 in 13 and T4 in one. There were clinically palpable inguinal lymph nodes bilaterally in 19 and unilaterally in four men. Scintigraphy before surgery showed inguinal nodes bilaterally in 12 and unilaterally in eight patients, while there were no nodes in three. Surgery comprised partial penectomy in 14, radical penectomy in eight and circumcision alone in one patient. Simultaneous bilateral ILND was done in 15 patients. Inguinal node metastases were present in four of the 23 (17%) patients; the SLN was falsely negative in three (13%), one of whom had a small focus of cancer in the SLN that was missed on initial histopathological examination, and in two the dynamically located SLN contained no cancer, but node metastases were found in the ILND specimen. The relatively high false-negative rate of DSLNB indicates that it is not sufficiently reliable to replace complete ILND in men with a high suspicion of nodal metastases, i.e. a high-grade or high-stage primary lesion with clinically palpable inguinal nodes.


Metabolic phenotyping guidelines: assessing glucose homeostasis in rodent models.
The pathophysiology of diabetes as a disease is characterised by an inability to maintain normal glucose homeostasis. In type 1 diabetes, this is due to autoimmune destruction of the pancreatic β-cells and subsequent lack of insulin production, and in type 2 diabetes it is due to a combination of both insulin resistance and an inability of the β-cells to compensate adequately with increased insulin release. Animal models, in particular genetically modified mice, are increasingly being used to elucidate the mechanisms underlying both type 1 and type 2 diabetes, and as such the ability to study glucose homeostasis in vivo has become an essential tool. Several techniques exist for measuring different aspects of glucose tolerance and each of these methods has distinct advantages and disadvantages. Thus the appropriate methodology may vary from study to study depending on the desired end-points, the animal model, and other practical considerations. This review outlines the most commonly used techniques for assessing glucose tolerance in rodents and details the factors that should be taken into account in their use. Representative scenarios illustrating some of the practical considerations of designing in vivo experiments for the measurement of glucose homeostasis are also discussed.


Comparison of serum insulin-like growth factor-1 and growth hormone levels in osteoporotic and non-osteoporotic postmenopausal women.
The purpose of this study was to compare the insulin-like growth factor-1 (IGF-1) levels and the growth hormone (GH) levels in osteoporotic and non-osteoporotic postmenopausal women. Eleven non-osteoporotic postmenopausal women and 9 women with untreated postmenopausal osteoporosis were included in the study. Bone mineral density (BMD) was assessed by dual energy X-ray absorbtiometry. Serum was assayed for calcium, phosphorus, alkaline phosphatase, bone-specific alkaline phosphatase, parathyroid hormone, IGF-1 and GH levels. IGF-1 levels were 98.8 +/- 43.5 ng/ml for osteoporotic women and 169.8 +/- 50.3 ng/ml for the women with normal BMD (p < 0.05). GH levels were 1.3 +/- 1.1 ng/ml and 1.3 +/- 1.0 ng/ml, respectively. When compared with normal postmenopausal women, IGF-1 levels were found to be lower in women with osteoporosis. IGF-1 seems to play an important role in the development of low bone mass and the present results suggest that IGF-1 is a useful predictor of the presence of osteoporosis.


Cutting Edge: Notch Signaling Promotes the Plasticity of Group-2 Innate Lymphoid Cells.
The mechanisms underlying lymphocyte lineage stability and plasticity remain elusive. Recent work indicates that innate lymphoid cells (ILC) possess substantial plasticity. Whereas natural ILC2 (nILC2) produce type-2 cytokines, plastic inflammatory ILC2 (iILC2) can coproduce both type-2 cytokines and the ILC3-characteristic cytokine, IL-17. Mechanisms that elicit this lineage plasticity, and the importance in health and disease, remain unclear. In this study we show that iILC2 are potent inducers of airway inflammation in response to acute house dust mite challenge. We find that Notch signaling induces lineage plasticity of mature ILC2 and drives the conversion of nILC2 into iILC2. Acute blockade of Notch signaling abolished functional iILC2, but not nILC2, in vivo. Exposure of isolated nILC2 to Notch ligands induced Rorc expression and elicited dual IL-13/IL-17 production, converting nILC2 into iILC2. Together these results reveal a novel role for Notch signaling in eliciting ILC2 plasticity and driving the emergence of highly proinflammatory innate lymphocytes.


Experimental Determination of Dynamical Lee-Yang Zeros.
Statistical physics provides the concepts and methods to explain the phase behavior of interacting many-body systems. Investigations of Lee-Yang zeros-complex singularities of the free energy in systems of finite size-have led to a unified understanding of equilibrium phase transitions. The ideas of Lee and Yang, however, are not restricted to equilibrium phenomena. Recently, Lee-Yang zeros have been used to characterize nonequilibrium processes such as dynamical phase transitions in quantum systems after a quench or dynamic order-disorder transitions in glasses. Here, we experimentally realize a scheme for determining Lee-Yang zeros in such nonequilibrium settings. We extract the dynamical Lee-Yang zeros of a stochastic process involving Andreev tunneling between a normal-state island and two superconducting leads from measurements of the dynamical activity along a trajectory. From the short-time behavior of the Lee-Yang zeros, we predict the large-deviation statistics of the activity which is typically difficult to measure. Our method paves the way for further experiments on the statistical mechanics of many-body systems out of equilibrium.


Gene expression of behaviorally relevant genes in the cerebral hemisphere changes after selection for tameness in Red Junglefowl.
The process of domestication in animals has led to alterations in behavior, physiology and phenotypic traits, changes that may be driven by correlations with reduced fear of humans. We used Red Junglefowl, ancestors of all domesticated chickens selected for either high or low fear of humans for five generations to study the effects of selection on gene transcription in the cerebral hemisphere, which is heavily involved in behaviour control. A total of 24 individuals from the parental generation as well as from the fifth selected generation were used. Twenty-two genes were significantly differentially expressed at p < 0.05 after false discovery rate (FDR) correction. Those genes that were upregulated in the low fearful animals were found to be involved in neural functions. Gene ontology and pathway analysis revealed enrichment for terms associated with behavioural processes. We conclude that five generations of divergent selection for high or low tameness has significantly changed gene expression patterns in the cerebral hemisphere in the Red Junglefowl population used here, which could underlie a range of changes in the domestic phenotype.


The fully synthetic MAG-Tn3 therapeutic vaccine containing the tetanus toxoid-derived TT830-844 universal epitope provides anti-tumor immunity.
Malignant transformations are often associated with aberrant glycosylation processes that lead to the expression of new carbohydrate antigens at the surface of tumor cells. Of these carbohydrate antigens, the Tn antigen is particularly highly expressed in many carcinomas, especially in breast carcinoma. We designed MAG-Tn3, a fully synthetic vaccine based on three consecutive Tn moieties that are O-linked to a CD4+ T cell epitope, to induce anti-Tn antibody responses that could be helpful for therapeutic vaccination against cancer. To ensure broad coverage within the human population, the tetanus toxoid-derived peptide TT830-844 was selected as a T-helper epitope because it can bind to various HLA-DRB molecules. We showed that the MAG-Tn3 vaccine, which was formulated with the GSK proprietary immunostimulant AS15 and designed for human cancer therapy, is able to induce an anti-Tn antibody response in mice of various H-2 haplotypes, and this response correlates with the ability to induce a specific T cell response against the TT830-844 peptide. The universality of the TT830-844 peptide was extended to new H-2 and HLA-DRB molecules that were capable of binding this T cell epitope. Finally, the MAG-Tn3 vaccine was able to induce anti-Tn antibody responses in cynomolgus monkeys, which targeted Tn-expressing tumor cells and mediated tumor cell death both in vitro and in vivo. Thus, MAG-Tn3 is a highly promising anticancer vaccine that is currently under evaluation in a phase I clinical trial.


End-of-Life Decision Support in the ICU: Where Are We Now?
Determining effective decision support strategies that enhance quality of end-of-life decision making in the intensive care unit is a research priority. This systematic review identified interventional studies describing the effectiveness of decision support interventions administered to critically ill patients or their surrogate decision makers. We conducted a systematic literature search using PubMed, CINAHL, and Cochrane. Our search returned 121 articles, 22 of which met the inclusion criteria. The search generated studies with significant heterogeneity in the types of interventions evaluated and varied patient and surrogate decision-maker outcomes, which limited the comparability of the studies. Few studies demonstrated significant improvements in the primary outcomes. In conclusion, there is limited evidence on the effectiveness of end-of-life decision support for critically ill patients and their surrogate decision makers. Additional research is needed to develop and evaluate innovative decision support interventions for end-of-life decision making in the intensive care unit.


Fluoride Occurrence and Human Health Risk in Drinking Water Wells from Southern Edge of Chinese Loess Plateau.
Fluoride hydrogeochemistry and associated human health risks implications are investigated in several aquifers along the southern edge of the Chinese Loess Plateau. Locally, 64% shallow groundwater samples in loess aquifer exceed the fluoride limit (1.5 mg/L) with the maximum of 3.8 mg/L. Presently, the shallow groundwater is the main source of private wells for domestic use, and this is clearly a potential risk for human health. Hydrogeochemistry and stable isotopes are used to elucidate the diversity of occurrence mechanisms. Enrichment of fluoride in groundwater is largely controlled by the F-containing minerals dissolution. Furthermore, alkaline condition and calcium-removing processes promote water-rock interactions. Stable isotopes of hydrogen and oxygen (δD and δ18O) in study area waters demonstrate that groundwater in loess aquifer is old, which means groundwater remains in the aquifer for a long time. Long residence time induces sufficient water-rock interactions, which play significant roles in the resolution of fluoride minerals. Samples from the shallow loess aquifer show elevated fluoride levels, which may pose human health risk for both adults (60%) and children (94%) via oral intake. To ensure drinking water safety, management measures such as popularizing fluoride-removing techniques and optimizing water supply strategies need to be implemented.


Lipid mediators in plasma of autism spectrum disorders.
Inflammation is increasingly recognized as being of both physiological and pathological importance in the immature brain. Cerebellar pathology occurs in autism, as a neurodevelopmental disorder with genetic and environmental origins. The genesis of this disorder is still not understood but inflammation in utero or early in childhood is an environmental risk factor. Prostaglandin E2 (PGE2), cysteinyl leukotriene as two important lipid mediators together with 8 isoprostane as marker of oxidative stress were measured using ELISA in plasma of 20 male autistic patients compared to 19 age and gender matching control participants. PGE2, leukotrienes and isoprostanes recorded significantly elevated levels in autistics compared to controls. Role of these measured parameters in inflammation and autoimmunity as two etiological factors in autism were discussed in details. Receiver Operating Characteristic (ROC) curve analysis shows satisfactory values of area under the curve (AUC) which could reflect the high degree of specificity and sensitivity of the altered PGE2, leukotrienes and isoprostanes as predictive biomarkers in autistic patients from Saudi Arabia.


Cardiometabolic risk factors and atrial fibrillation.
Atrial fibrillation (AF) is the most common arrhythmia worldwide; it is a significant risk factor for stroke and embolization, and has an impact on cardiac function. Despite its impact on morbidity and mortality, our understanding of the etiology and pathophysiology of this disease process is still incomplete. Over the past several decades, there has been evidence to suggest that AF has a significant correlation with metabolic syndrome (MetS). Furthermore, AF appears to be more closely related to specific components of MetS compared with others. This article provides an overview of the various components of MetS and their impact on AF.


Prevalence of rotator cuff tears in adults with traumatic brachial plexus injuries.
Restoration of shoulder function is a primary goal when treating patients with traumatic brachial plexus injury. A concomitant rotator cuff tear may alter the treatment approach and prognosis for these individuals. The purpose of this study was to define the prevalence of rotator cuff tears in patients with traumatic brachial plexus injuries. This is a retrospective review of 280 adult patients with traumatic brachial plexus injury treated at a single institution over a twelve-year period. An upper-extremity magnetic resonance imaging (MRI) scan was acquired for all patients as part of the initial evaluation for posttraumatic brachial plexus injury. The radiographic and clinical data on these patients were reviewed to document partial or full-thickness rotator cuff tears, mechanism and location of the brachial plexus injury, and age. Twenty-three patients (8.2%) had a full-thickness rotator cuff tear: one patient had tears involving three tendons, eight patients had tears involving two tendons, twelve patients had a single-tendon tear, one patient had a single-tendon tear in each shoulder, and one patient had a single-tendon tear in one shoulder and a two-tendon tear in the other. Twenty-one tears involved the supraspinatus, eight involved the infraspinatus, and seven involved the subscapularis. Thirteen patients underwent surgical repair of the rotator cuff. The average age of the patients in this cohort was 33.4 years, and older age was associated with an increased risk of full-thickness rotator cuff tears (odds ratio [OR], 1.06 per year). Patients with infraclavicular brachial plexus injury had a significantly higher rate of full-thickness rotator cuff tears. Concomitant rotator cuff tears are present in approximately one in ten patients with traumatic brachial plexus injury. These injuries may contribute to shoulder dysfunction; therefore, evaluation of the rotator cuff with imaging studies is appropriate when formulating treatment strategies. Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.


NCR3 polymorphism, haematological parameters, and severe malaria in Senegalese patients.
Host factors, including host genetic variation, have been shown to influence the outcome of Plasmodium falciparum infection. Genome-wide linkage studies have mapped mild malaria resistance genes on chromosome 6p21, whereas NCR3-412 polymorphism (rs2736191) lying within this region was found to be associated with mild malaria. Blood samples were taken from 188 Plasmodium falciparum malaria patients (76 mild malaria patients, 85 cerebral malaria patients, and 27 severe non-cerebral malaria patients). NCR3-412 (rs2736191) was analysed by sequencing, and haematological parameters were measured. Finally, their association with clinical phenotypes was assessed. We evidenced an association of thrombocytopenia with both cerebral malaria and severe non-cerebral malaria, and of an association of high leukocyte count with cerebral malaria. Additionally, we found no association of NCR3-412 with either cerebral malaria, severe non-cerebral malaria, or severe malaria after grouping cerebral malaria and severe non-cerebral malaria patients. Our results suggest that NCR3 genetic variation has no effect, or only a small effect on the occurrence of severe malaria, although it has been strongly associated with mild malaria. We discuss the biological meaning of these results. Besides, we confirmed the association of thrombocytopenia and high leukocyte count with severe malaria phenotypes.


Systemic Administration of Glibenclamide Fails to Achieve Therapeutic Levels in the Brain and Cerebrospinal Fluid of Rodents.
Activating mutations in the Kir6.2 (KCNJ11) subunit of the ATP-sensitive potassium channel cause neonatal diabetes (ND). Patients with severe mutations also suffer from neurological complications. Glibenclamide blocks the open KATP channels and is the treatment of choice for ND. However, although glibenclamide successfully restores normoglycaemia, it has a far more limited effect on the neurological problems. To assess the extent to which glibenclamide crosses the blood-brain barrier (BBB) in vivo, we quantified glibenclamide concentrations in plasma, cerebrospinal fluid (CSF), and brain tissue of rats, control mice, and mice expressing a human neonatal diabetes mutation (Kir6.2-V59M) selectively in neurones (nV59M mice). As only small sample volumes can be obtained from rodents, we developed a highly sensitive method of analysis, using liquid chromatography tandem mass spectrometry acquisition with pseudo-selected reaction monitoring, achieving a quantification limit of 10ng/ml (20nM) glibenclamide in a 30μl sample. Glibenclamide was not detectable in the CSF or brain of rats after implantation with subcutaneous glibenclamide pellets, despite high plasma concentrations. Further, one hour after a suprapharmacological glibenclamide dose was administered directly into the lateral ventricle of the brain, the plasma concentration was twice that of the CSF. This suggests the drug is rapidly exported from the CSF. Elacridar, an inhibitor of P-glycoprotein and breast cancer resistance protein (major multidrug resistance transporters at the BBB), did not affect glibenclamide levels in CSF and brain tissue. We also identified a reduced sensitivity to volatile anaesthetics in nV59M mice and showed this was not reversed by systemic delivery of glibenclamide. Our results therefore suggest that little glibenclamide reaches the central nervous system when given systemically, that glibenclamide is rapidly removed across the BBB when given intracranioventricularly, and that any glibenclamide that does enter (and is below our detection limit) is insufficient to influence neuronal function as assessed by anaesthesia sensitivity.


Copper ions induce dityrosine-linked dimers in human but not in murine islet amyloid polypeptide (IAPP/amylin).
Dysregulation and aggregation of the peptide hormone IAPP (islet amyloid polypeptide, a.k.a. amylin) into soluble oligomers that appear to be cell-toxic is a known aspect of diabetes mellitus (DM) Type 2 pathology. IAPP aggregation is influenced by several factors including interactions with metal ions such as Cu(II). Because Cu(II) ions are redox-active they may contribute to metal-catalyzed formation of oxidative tyrosyl radicals, which can generate dityrosine cross-links. Here, we show that such a process, which involves Cu(II) ions bound to the IAPP peptide together with H2O2, can induce formation of large amounts of IAPP dimers connected by covalent dityrosine cross-links. This cross-linking is less pronounced at low pH and for murine IAPP, likely due to less efficient Cu(II) binding. Whether IAPP can carry out its hormonal function as a cross-linked dimer is unknown. As dityrosine concentrations are higher in blood plasma of DM Type 2 patients - arguably due to disease-related oxidative stress - and as dimer formation is the first step in protein aggregation, generation of dityrosine-linked dimers may be an important factor in IAPP aggregation and thus relevant for DM Type 2 progression.


Mechanism of action of antidepressant medications.
The psychopharmacology of depression is a field that has evolved rapidly in just under 5 decades. Early antidepressant medications--tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs)--were discovered through astute clinical observations. These first-generation medications were effective because they enhanced serotonergic or noradrenergic mechanisms or both. Unfortunately, the TCAs also blocked histaminic, cholinergic, and alpha1-adrenergic receptor sites, and this action brought about unwanted side effects such as weight gain, dry mouth, constipation, drowsiness, and dizziness. MAOIs can interact with tyramine to cause potentially lethal hypertension and present potentially dangerous interactions with a number of medications and over-the-counter drugs. The newest generation of antidepressants, including the single-receptor selective serotonin reuptake inhibitors (SSRIs) and multiple-receptor antidepressants venlafaxine, mirtazapine, bupropion, trazodone, and nefazodone, target one or more specific brain receptor sites without, in most cases, activating unwanted sites such as histamine and acetylcholine. This paper discusses the new antidepressants, particularly with regard to mechanism of action, and looks at future developments in the treatment of depression.


Vocal classification of vocalizations of a pair of Asian small-clawed otters to determine stress.
Asian Small-Clawed Otters (Aonyx cinerea) are a small, protected but threatened species living in freshwater. They are gregarious and live in monogamous pairs for their lifetimes, communicating via scent and acoustic vocalizations. This study utilized a hidden Markov model (HMM) to classify stress versus non-stress calls from a sibling pair under professional care. Vocalizations were expertly annotated by keepers into seven contextual categories. Four of these-aggression, separation anxiety, pain, and prefeeding-were identified as stressful contexts, and three of them-feeding, training, and play-were identified as non-stressful contexts. The vocalizations were segmented, manually categorized into broad vocal type call types, and analyzed to determine signal to noise ratios. From this information, vocalizations from the most common contextual categories were used to implement HMM-based automatic classification experiments, which included individual identification, stress vs non-stress, and individual context classification. Results indicate that both individual identity and stress vs non-stress were distinguishable, with accuracies above 90%, but that individual contexts within the stress category were not easily separable.


Strategies to attract prospective students to the nursing profession.
The stagnation in the supply of nurses necessitates the adoption of contextually-relevant strategies to attract recruits to the profession. The objective of this study was to understand how prospective candidates could be influenced to enter the profession, by determining what motivated current South African nurses to choose nursing as a profession. Support on entering the profession and employment security were rated as most important, while the influence of others and extrinsic rewards associated with nursing were perceived to be less important. Although private sector nurses and nurses who intended to change their employment sector were significantly more likely to rate employment security and extrinsic rewards highly, and public sector nurses and nurses from the more rural areas thought that the immediacy of support on entering the profession and intrinsic factors where more important, a homogenous approach to recruitment is possible.


Role of extracellular matrix in adaptation of tendon and skeletal muscle to mechanical loading.
The extracellular matrix (ECM), and especially the connective tissue with its collagen, links tissues of the body together and plays an important role in the force transmission and tissue structure maintenance especially in tendons, ligaments, bone, and muscle. The ECM turnover is influenced by physical activity, and both collagen synthesis and degrading metalloprotease enzymes increase with mechanical loading. Both transcription and posttranslational modifications, as well as local and systemic release of growth factors, are enhanced following exercise. For tendons, metabolic activity, circulatory responses, and collagen turnover are demonstrated to be more pronounced in humans than hitherto thought. Conversely, inactivity markedly decreases collagen turnover in both tendon and muscle. Chronic loading in the form of physical training leads both to increased collagen turnover as well as, dependent on the type of collagen in question, some degree of net collagen synthesis. These changes will modify the mechanical properties and the viscoelastic characteristics of the tissue, decrease its stress, and likely make it more load resistant. Cross-linking in connective tissue involves an intimate, enzymatical interplay between collagen synthesis and ECM proteoglycan components during growth and maturation and influences the collagen-derived functional properties of the tissue. With aging, glycation contributes to additional cross-linking which modifies tissue stiffness. Physiological signaling pathways from mechanical loading to changes in ECM most likely involve feedback signaling that results in rapid alterations in the mechanical properties of the ECM. In developing skeletal muscle, an important interplay between muscle cells and the ECM is present, and some evidence from adult human muscle suggests common signaling pathways to stimulate contractile and ECM components. Unaccostumed overloading responses suggest an important role of ECM in the adaptation of myofibrillar structures in adult muscle. Development of overuse injury in tendons involve morphological and biochemical changes including altered collagen typing and fibril size, hypervascularization zones, accumulation of nociceptive substances, and impaired collagen degradation activity. Counteracting these phenomena requires adjusted loading rather than absence of loading in the form of immobilization. Full understanding of these physiological processes will provide the physiological basis for understanding of tissue overloading and injury seen in both tendons and muscle with repetitive work and leisure time physical activity.


Pseudomonas aeruginosa Quorum-Sensing and Type VI Secretion System Can Direct Interspecific Coexistence During Evolution.
It is reported that a wide range of bacterial infections are polymicrobial, and the members in a local microcommunity can influence the growth of neighbors through physical and chemical interactions. Pseudomonas aeruginosa is an important opportunistic pathogen that normally causes a variety of acute and chronic infections, and clinical evidences suggest that P. aeruginosa can be frequently coisolated with other pathogens from the patients with chronic infections. However, the interspecific interaction and the coexisting mechanism of P. aeruginosa with coinfecting bacterial species during evolution still remain largely unclear. In this study, the relationships of P. aeruginosa with other Gram-positive (Staphylococcus aureus) and Gram-negative (Klebsiella pneumoniae) are investigated by using a series of on-plate proximity assay, in vitro coevolution assay, and RNA-sequencing. We find that although the development of a quorum-sensing system contributes P. aeruginosa a significant growth advantage to compete with S. aureus and K. pneumoniae, the quorum-sensing regulation of P. aeruginosa will be decreased during evolution and thus provides a basis for the formation of interspecific coexistence. The results of comparative transcriptomic analyses suggest that the persistent survival of S. aureus in the microcommunity has no significant effect on the intracellular transcriptional pattern of P. aeruginosa, while a more detailed competition happens between P. aeruginosa and K. pneumoniae. Specifically, the population of P. aeruginosa with decreased quorum-sensing regulation can still restrict the proportion increase of K. pneumoniae by enhancing the type VI secretion system-elicited cell aggressivity during further coevolution. These findings provide a general explanation for the formation of a dynamic stable microcommunity consisting of more than two bacterial species, and may contribute to the development of population biology and clinical therapy.


A possible neuroprotective action of a vinylic telluride against Mn-induced neurotoxicity.
Manganese (Mn) is a metal required by biological systems. However, environmental or occupational exposure to high levels of Mn can produce a neurological disorder called manganism, which has similarities to Parkinson's disease. Diethyl-2-phenyl-2-tellurophenyl vinylphosphonate (DPTVP) is an organotellurium compound with a high antioxidant activity, especially in the brain. The present study was designed to investigate the effects of long-term low-dose exposure to Mn in drinking water on behavioral and biochemical parameters in rats and to determine the effectiveness of vinylic telluride in attenuating the effects of Mn. After 4 months of treatment with MnCl(2) (13.7 mg/kg), rats exhibited clear signs of neurobehavioral toxicity, including a decrease in the number of rearings in the open field and altered motor performance in rotarod. The administration of DPTVP (0.150 micromol/kg, ip, 2 weeks) improved the motor performance of Mn-treated rats, indicating that the compound could be reverting Mn neurotoxicity. Ex vivo, we observed that Mn concentrations in the Mn-treated group were highest in the striatum, consistent with a statistically significant decrease in mitochondrial viability and [(3)H]glutamate uptake, and increased lipid peroxidation. Mn levels in the hippocampus and cortex were indistinguishable from controls, and no significant differences were noted in the ex vivo assays in these areas. Treatment with DPTVP fully reversed the biochemical parameters altered by Mn. Furthermore, DPTVP treatment was also associated with a reduction in striatal Mn levels. Our results demonstrate that DPTVP has neuroprotective activity against Mn-induced neurotoxicity, which may be attributed to its antioxidant activity and/or its effect on striatal Mn transport.


Diagnostic doses and times for Phlebotomus papatasi and Lutzomyia longipalpis sand flies (Diptera: Psychodidae: Phlebotominae) using the CDC bottle bioassay to assess insecticide resistance.
Insecticide resistance to synthetic chemical insecticides is a worldwide concern in phlebotomine sand flies (Diptera: Psychodidae), the vectors of Leishmania spp. parasites. The CDC bottle bioassay assesses resistance by testing populations against verified diagnostic doses and diagnostic times for an insecticide, but the assay has been used limitedly with sand flies. The objective of this study was to determine diagnostic doses and diagnostic times for laboratory Lutzomyia longipalpis (Lutz & Nieva) and Phlebotomus papatasi (Scopoli) to ten insecticides, including pyrethroids, organophosphates, carbamates, and DDT, that are used worldwide to control vectors. Bioassays were conducted in 1,000-ml glass bottles each containing 10-25 sand flies from laboratory colonies of L. longipalpis or P. papatasi. Four pyrethroids, three organophosphates, two carbamates and one organochlorine, were evaluated. A series of concentrations were tested for each insecticide, and four replicates were conducted for each concentration. Diagnostic doses were determined only during the exposure bioassay for the organophosphates and carbamates. For the pyrethroids and DDT, diagnostic doses were determined for both the exposure bioassay and after a 24-hour recovery period. Both species are highly susceptible to the carbamates as their diagnostic doses are under 7.0 μg/ml. Both species are also highly susceptible to DDT during the exposure assay as their diagnostic doses are 7.5 μg/ml, yet their diagnostic doses for the 24-h recovery period are 650.0 μg/ml for Lu. longipalpis and 470.0 μg/ml for P. papatasi. Diagnostic doses and diagnostic times can now be incorporated into vector management programs that use the CDC bottle bioassay to assess insecticide resistance in field populations of Lu. longipalpis and P. papatasi. These findings provide initial starting points for determining diagnostic doses and diagnostic times for other sand fly vector species and wild populations using the CDC bottle bioassay.


A model of the Parkinsonian visual system: support for the dark adaptation hypothesis.
Considerable evidence suggests that some visual abnormalities in Parkinson's disease are mediated by disruption of dopaminergic processes in the retina. Since dopamine is thought to be involved in the process of dark adaptation, and some of these abnormalities are similar to the changes which accompany dark adaptation in normal subjects, it has been proposed that the parkinsonian retina behaves as though inappropriately dark-adapted. In Parkinson's disease, the apparent contrast of peripherally viewed medium and high spatial frequency gratings is reduced. In our first experiment, normal subjects were dark-adapted, and were required to match the apparent contrast of a peripherally viewed grating to that of a foveally viewed grating. The results showed an interaction between spatial frequency and dark adaptation, reflecting a greater reduction in the apparent contrast of peripheral high spatial frequency gratings. In a second experiment, no effect of dark adaptation was found on the apparent spatial frequency of a peripherally viewed grating required to match that of a foveally viewed grating. The first experiment supports the dark adaptation hypothesis of parkinsonian vision, and the second suggests that the changes in apparent contrast are mediated by different amounts of change in contrast gain in central and peripheral vision, rather than by differential changes in receptive field size.


Tea polyphenols epigallocatechin gallete and theaflavin restrict mouse liver carcinogenesis through modulation of self-renewal Wnt and hedgehog pathways.
The aim of this study is to evaluate chemopreventive and therapeutic efficacy of tea polyphenols epigallocatechin gallete (EGCG) and theaflavin (TF) on self-renewal Wnt and Hedgehog (Hh) pathways during CCl4/N-nitosodiethylamine-induced mouse liver carcinogenesis. For this purpose, the effect of EGCG/TF was investigated in liver lesions of different groups at pre-, continuous and post initiation stages of carcinogenesis. Comparatively increased body weights were evident due to EGCG/TF treatment than carcinogen control mice. Both EGCG and TF could restrict the development of hepatocellular carcinoma at 30th week of carcinogen application showing potential chemoprevention in continuous treated group (mild dysplasia) followed by pretreated (moderate dysplasia) and therapeutic efficacy in posttreated group (mild dysplasia). This restriction was associated with significantly reduced proliferation, increased apoptosis, decreased prevalence of hepatocyte progenitor cell (AFP) and stem cell population (CD44) irrespective of EGCG/TF treatments. The EGCG/TF could modulate the Wnt pathway by reducing β-catenin and phospho-β-catenin-Y-654 expressions along with up-regulation of sFRP1 (secreted frizzled-related protein 1) and adenomatosis polyposis coli during the restriction. In case of the Hh pathway, EGCG/TF could also reduce expressions of glioma-associated oncogene homolog 1 (Gli1) and SMO (smoothened homolog) along with up-regulation of PTCH1 (patched homolog 1). As a result, in Wnt/Hh regulatory pathways decreased expressions of β-catenin/Gli1 target genes like CyclinD1, cMyc and EGFR/phospho-EGFR-Y-1173 and up-regulation of E-cadherin were seen during the restriction. Thus, the restriction of liver carcinogenesis by EGCG/TF was due to reduction in hepatocyte progenitor cell/stem cell population along with modulation of Wnt/Hh and other regulatory pathways.


Effectiveness of community forestry in Prey Long forest, Cambodia.
Cambodia has 57% forest cover, the second highest in the Greater Mekong region, and a high deforestation rate (1.2%/year, 2005-2010). Community forestry (CF) has been proposed as a way to reduce deforestation and support livelihoods through local management of forests. CF is expanding rapidly in Cambodia. The National Forests Program aims to designate one million hectares of forest to CF by 2030. However, the effectiveness of CF in conservation is not clear due to a global lack of controlled comparisons, multiple meanings of CF, and the context-specific nature of CF implementation. We assessed the effectiveness of CF by comparing 9 CF sites with paired controls in state production forest in the area of Prey Long forest, Cambodia. We assessed forest condition in 18-20 randomly placed variable-radius plots and fixed-area regeneration plots. We surveyed 10% of households in each of the 9 CF villages to determine the proportion that used forest products, as a measure of household dependence on the forest. CF sites had fewer signs of anthropogenic damage (cut stems, stumps, and burned trees), higher aboveground biomass, more regenerating stems, and reduced canopy openness than control areas. Abundance of economically valuable species, however, was higher in control sites. We used survey results and geographic parameters to model factors affecting CF outcomes. Interaction between management type, CF or control, and forest dependence indicated that CF was more effective in cases where the community relied on forest products for subsistence use and income.


Microbial Community Structure of Subglacial Lake Whillans, West Antarctica.
Subglacial Lake Whillans (SLW) is located beneath ∼800 m of ice on the Whillans Ice Stream in West Antarctica and was sampled in January of 2013, providing the first opportunity to directly examine water and sediments from an Antarctic subglacial lake. To minimize the introduction of surface contaminants to SLW during its exploration, an access borehole was created using a microbiologically clean hot water drill designed to reduce the number and viability of microorganisms in the drilling water. Analysis of 16S rRNA genes (rDNA) amplified from samples of the drilling and borehole water allowed an evaluation of the efficacy of this approach and enabled a confident assessment of the SLW ecosystem inhabitants. Based on an analysis of 16S rDNA and rRNA (i.e., reverse-transcribed rRNA molecules) data, the SLW community was found to be bacterially dominated and compositionally distinct from the assemblages identified in the drill system. The abundance of bacteria (e.g., Candidatus Nitrotoga, Sideroxydans, Thiobacillus, and Albidiferax) and archaea (Candidatus Nitrosoarchaeum) related to chemolithoautotrophs was consistent with the oxidation of reduced iron, sulfur, and nitrogen compounds having important roles as pathways for primary production in this permanently dark ecosystem. Further, the prevalence of Methylobacter in surficial lake sediments combined with the detection of methanogenic taxa in the deepest sediment horizons analyzed (34-36 cm) supported the hypothesis that methane cycling occurs beneath the West Antarctic Ice Sheet. Large ratios of rRNA to rDNA were observed for several operational taxonomic units abundant in the water column and sediments (e.g., Albidiferax, Methylobacter, Candidatus Nitrotoga, Sideroxydans, and Smithella), suggesting a potentially active role for these taxa in the SLW ecosystem. Our findings are consistent with chemosynthetic microorganisms serving as the ecological foundation in this dark subsurface environment, providing new organic matter that sustains a microbial ecosystem beneath the West Antarctic Ice Sheet.


Early referral strategies for management of people with markers of renal disease: a systematic review of the evidence of clinical effectiveness, cost-effectiveness and economic analysis.
Chronic kidney disease (CKD) is a long-term condition and has been described as the gradual loss of kidney function over time. Early in the disease process, people with CKD often experience no symptoms. For a long time, CKD has been an underdiagnosed condition. Even in the absence of symptoms, CKD appears to add significantly to the burden of cardiovascular disease and death and, for an important minority, can progress to kidney failure. To systematically review the evidence of the clinical effectiveness and cost-effectiveness of early referral strategies for management of people with markers of renal disease. Electronic searches of 12 major databases (such as MEDLINE, EMBASE, CINAHL, etc.) were conducted for the time period of 1990 to April 2008 to identify studies comparing early referral to other care options for people with CKD. Additional searching was performed in the NHS Economic Evaluation Database to support the cost-effectiveness literature review. Two authors reviewed all titles, abstracts and full papers to select relevant literature. A Markov model was constructed to represent the natural history of CKD. The model allowed cohorts to be tracked according to estimated glomerular filtration rate (eGFR) status and the presence of other complications known to influence CKD progression and the incidence of cardiovascular events. From 36 relevant natural history studies, CKD was found to be, despite marked heterogeneity between studies, a marker of increased risk of mortality, renal progression and end-stage renal disease. Mortality was generally high and increased with stage of CKD. After adjustment for comorbidities, the relative risk of mortality among those with CKD identified from the general population increased with stage. For clinical populations, the relative risk was higher. All three outcomes increased as eGFR fell. Only seven studies, and no randomised controlled trials, were identified as relevant to assessing the clinical effectiveness of early referral strategies for CKD. In the five retrospective studies constructed from cohorts starting on renal replacement therapy (RRT), mortality was reduced in the early referral group (more than 12 months prior to RRT) even as late as 5 years after initiation of RRT. Only two studies included predialysis participants. One study, in people screened for diabetic nephropathy, reported a reduction in the decline in renal function associated with early referral to nephrology specialists (eGFR decline 3.4 ml/min/1.73 m(2)) when compared with a similar group that had no access to nephrology services until dialysis was required (eGFR decline 12.0 ml/min/1.73 m(2)). The second study, among a group of veterans with two creatinine levels of at least 140 mg/dl, reported that a composite end point of death or progression was lower in the group receiving nephrology follow-up than in those receiving only primary care follow-up. The greatest effect was observed in those with stage 3 or worse disease after adjustment for comorbidities, age, race, smoking and proteinuria {stage 3: hazard ratio (HR) 0.8 [95% confidence interval (CI) 0.61 to 0.9)]; stage 4: HR 0.75 (95% CI 0.45 to 0.89)}. In the base-case analysis, all early referral strategies produced more quality-adjusted life-years (QALYs) than referral upon transit to stage 5 CKD (eGFR 15 ml/min/1.73 m(2)). Referral for everyone with an eGFR below 60 ml/min/1.73 m(2) (stage 3a CKD) generated the most QALYs and, compared with referral for stage 4 CKD (eGFR < 30 ml/min/1.73 m(2)), had an incremental cost-effectiveness ratio of approximately 3806 pounds per QALY. Because of a lack of data on the natural history of CKD in individuals without diabetes, and a lack of evidence on the costs and effects of early referral, the Markov model relied on many assumptions. The findings were particularly sensitive to changes in eGFR decline rates and the relative effect of early referral on CKD progression and cardiovascular events; the latter parameter being derived from a single non-randomised study. Despite substantial focus on the early identification and proactive management of CKD in the last few years, we have identified significant evidence gaps about how best to manage people with CKD. There was some evidence to suggest that the care of people with CKD could be improved and, because these people are at risk from both renal and cardiovascular outcomes, strategies to improve the management of people with CKD have the potential to offer an efficient use of health service resources. Given the number of people now being recognised as having markers of kidney impairment, there is an urgent need for further research to support service change.


Predicting the impact of border control on malaria transmission: a simulated focal screen and treat campaign.
South Africa is one of many countries committed to malaria elimination with a target of 2018 and all malaria-endemic provinces, including Mpumalanga, are increasing efforts towards this ambitious goal. The reduction of imported infections is a vital element of an elimination strategy, particularly if a country is already experiencing high levels of imported infections. Border control of malaria is one tool that may be considered. A metapopulation, non-linear stochastic ordinary differential equation model is used to simulate malaria transmission in Mpumalanga and Maputo province, Mozambique (the source of the majority of imported infections) to predict the impact of a focal screen and treat campaign at the Mpumalanga-Maputo border. This campaign is simulated by nesting an individual-based model for the focal screen and treat campaign within the metapopulation transmission model. The model predicts that such a campaign, simulated for different levels of resources, coverage and take-up rates with a variety of screening tools, will not eliminate malaria on its own, but will reduce transmission substantially. Making the campaign mandatory decreases transmission further though sub-patent infections are likely to remain undetected if the diagnostic tool is not adequately sensitive. Replacing screening and treating with mass drug administration results in substantially larger decreases as all (including sub-patent) infections are treated before movement into Mpumalanga. The reduction of imported cases will be vital to any future malaria control or elimination strategy. This simulation predicts that FSAT at the Mpumalanga-Maputo border will be unable to eliminate local malaria on its own, but may still play a key role in detecting and treating imported infections before they enter the country. Thus FSAT may form part of an integrated elimination strategy where a variety of interventions are employed together to achieve malaria elimination.


Alcohol use and cigarette smoking as risk factors for post-endoscopic retrograde cholangiopancreatography pancreatitis.
Alcohol use and cigarette smoking are associated with various pancreatic diseases, but it is not known whether they associate with post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). We performed a retrospective case-control study to determine if these activities increase the risk of PEP. We identified 7638 patients who had undergone ERCP in the University of Michigan Health System and applied exclusion criteria to identify 123 with PEP. We randomly selected 308 age- and sex-stratified controls (2.5-fold case sample); after applying exclusion criteria 248 remained. In a masked fashion, we collected data for alcohol use, cigarette smoking, and 5 internal control variables: suspected sphincter of Oddi dysfunction (SOD), pancreatic sphincterotomy, moderate/difficult cannulation, 2 or more pancreatic injections, and pancreatic stent placement. The univariate model showed an increased frequency of PEP in current drinkers (P < .001), former drinkers (P < .001), and former smokers (P < .001), as well as patients who were suspected of having SOD (P < .001), had undergone pancreatic sphincterotomy (P < .001), had a moderate/difficult cannulation (P = .001), and/or had 2 or more pancreatic injections (P = .007). The frequency of PEP was reduced in current smokers (P < .001). The multivariate model showed that the only independent significant predictors of PEP were current drinking (odds ratio [OR], 4.70; 95% confidence interval [CI], 2.60-8.50; P < .0001), former cigarette smoking (OR, 3.29; 95% CI, 1.28-8.44; P < .013), suspected SOD (OR, 3.69; 95% CI, 1.94-7.02; P < .001), and pancreatic sphincterotomy (OR, 5.91; 95% CI, 2.04-17.14; P = .001). Current alcohol use and potentially former cigarette smoking are new risk factors for PEP. It is important to consider these variables in designing PEP prevention trials.


Plasma mammalian leptin analogue predicts reproductive phenology, but not reproductive output in a capital-income breeding seaduck.
To invest in energetically demanding life history stages, individuals require a substantial amount of resources. Physiological traits, particularly those related to energetics, can be useful for examining variation in life history decisions and trade-offs because they result from individual responses to environmental variation. Leptin is a protein hormone found in mammals that is proportional to the amount of endogenous fat stores within an individual. Recently, researchers have confirmed that a mammalian leptin analogue (MLA), based on the mammalian sequence of leptin, is present with associated receptors and proteins in avian species, with an inhibitory effect on foraging and body mass gain at high circulating levels. While MLA has been both quantified and manipulated in avian species, little is currently known regarding whether plasma MLA in wild-living species and individuals is associated with key reproductive decisions. We quantified plasma MLA in wild, Arctic-nesting female common eiders (Somateria mollissima) at arrival on the breeding grounds and followed them to determine subsequent breeding propensity, and reproductive phenology, investment, and success. Common eiders are capital-income breeding birds that require the accumulation of substantial fat stores to initiate laying and successfully complete incubation. We found that females with lower plasma MLA initiated breeding earlier and in a shorter period of time. However, we found no links between plasma MLA levels and breeding propensity, clutch size, or reproductive success. Although little is still known about plasma MLA, based on these results and its role in influencing foraging behaviors and condition gain, plasma MLA appears to be closely linked to reproductive timing and is therefore likely to underlie trade-offs surrounding life history decisions.


Best-Practice Aspects of Quantum-Computer Calculations: A Case Study of the Hydrogen Molecule.
Quantum computers are reaching one crucial milestone after another. Motivated by their progress in quantum chemistry, we performed an extensive series of simulations of quantum-computer runs that were aimed at inspecting the best-practice aspects of these calculations. In order to compare the performance of different setups, the ground-state energy of the hydrogen molecule was chosen as a benchmark for which the exact solution exists in the literature. Applying the variational quantum eigensolver (VQE) to a qubit Hamiltonian obtained by the Bravyi-Kitaev transformation, we analyzed the impact of various computational technicalities. These included (i) the choice of the optimization methods, (ii) the architecture of the quantum circuits, as well as (iii) the different types of noise when simulating real quantum processors. On these, we eventually performed a series of experimental runs as a complement to our simulations. The simultaneous perturbation stochastic approximation (SPSA) and constrained optimization by linear approximation (COBYLA) optimization methods clearly outperformed the Nelder-Mead and Powell methods. The results obtained when using the Ry variational form were better than those obtained when the RyRz form was used. The choice of an optimum entangling layer was sensitively interlinked with the choice of the optimization method. The circular entangling layer was found to worsen the performance of the COBYLA method, while the full-entangling layer improved it. All four optimization methods sometimes led to an energy that corresponded to an excited state rather than the ground state. We also show that a similarity analysis of measured probabilities can provide a useful insight.


Health Aspects of Climate Change in Cities with Mediterranean Climate, and Local Adaptation Plans.
Cities with a Mediterranean-type climate (Med-cities) are particularly susceptible to health risks from climate change since they are located in biogeographical hot-spots that experience some of the strongest effects of the changing climate. The study aims to highlight health impacts of climate change in Med-cities, analyze local climate adaptation plans and make adaptation policy recommendations for the Med-city level. We identified five Med-cities with a climate change adaptation plan: Adelaide, Barcelona, Cape Town, Los Angeles and Santiago. Beyond their similar Med-climate features (although Santiago's are slightly different), the cities have different socio-economic characteristics in various aspects. We analyzed each plan according to how it addresses climate change-related drivers of health impacts among city dwellers. For each driver, we identified the types of policy adaptation tools that address it in the urban climate adaptation plans. The surveyed cities address most of the fundamental climate change-related drivers of risks to human health, including rising temperatures, flooding and drought, but the policy measures to reduce negative impacts vary across cities. We suggest recommendations for Med-cities in various aspects, depending on their local needs and vulnerability challenges: assessment of health risks, extreme events management and long-term adaptation, among others.


Endotoxemia in rats is associated with induction of the P4504A subfamily and suppression of several other forms of cytochrome P450.
Bacterial lipopolysaccharide (LPS) has been previously shown to down-regulate the mRNA and protein expression of the hepatic cytochrome P450 (P450) isozymes 2C11 and 2C12. In this study, we examined the effects of LPS on the constitutive expression of P4503A2, P4502E1, and the P4504A subfamily in the rat. Fischer 344 and Sprague-Dawley rats were each administered 1 mg/kg LPS intraperitoneally and killed for hepatic RNA and microsome isolation at different times. LPS treatment was found to suppress P4502C11, P4503A2, and P4502E1 protein and mRNA expression in both strains of rat. Total microsomal P450 levels decreased by 30%, which was smaller than the effects on the levels of individual isozymes. The magnitude of suppression exhibited in the Sprague-Dawley rats, however, seemed to be more variable than that in the F344 strain. The mRNAs of all three of the P4504A subfamily members were induced 2- to 6-fold in the F344 rat livers after LPS administration. P4504A3 protein expression increased 2-fold, whereas P4504A1/2 protein levels decreased by 30%. Lauric acid omega-hydroxylase activity increased 1.6-fold in LPS-treated Fischer 344 rats and omega-1-hydroxylase activity decreased by 38%. In the Sprague-Dawley strain, however, decreases were seen in both omega- and omega-1-hydroxylase activities after LPS treatment. Our data demonstrate that LPS administration induces P4504A subfamily mRNA and P4504A3 protein expression. Furthermore, our findings also suggest strain differences in both suppression and induction of P450s between the Sprague-Dawley and F344 rats.


Transcriptional Signatures of Sleep Duration Discordance in Monozygotic Twins.
Habitual short sleep duration is associated with adverse metabolic, cardiovascular, and inflammatory effects. Co-twin study methodologies account for familial (eg, genetics and shared environmental) confounding, allowing assessment of subtle environmental effects, such as the effect of habitual short sleep duration on gene expression. Therefore, we investigated gene expression in monozygotic twins discordant for actigraphically phenotyped habitual sleep duration. Eleven healthy monozygotic twin pairs (82% female; mean age 42.7 years; SD = 18.1), selected based on subjective sleep duration discordance, were objectively phenotyped for habitual sleep duration with 2 weeks of wrist actigraphy. Peripheral blood leukocyte (PBL) RNA from fasting blood samples was obtained on the final day of actigraphic measurement and hybridized to Illumina humanHT-12 microarrays. Differential gene expression was determined between paired samples and mapped to functional categories using Gene Ontology. Finally, a more comprehensive gene set enrichment analysis was performed based on the entire PBL transcriptome. The mean 24-hour sleep duration of the total sample was 439.2 minutes (SD = 46.8 minutes; range 325.4-521.6 minutes). Mean within-pair sleep duration difference per 24 hours was 64.4 minutes (SD = 21.2; range 45.9-114.6 minutes). The twin cohort displayed distinctive pathway enrichment based on sleep duration differences. Habitual short sleep was associated with up-regulation of genes involved in transcription, ribosome, translation, and oxidative phosphorylation. Unexpectedly, genes down-regulated in short sleep twins were highly enriched in immuno-inflammatory pathways such as interleukin signaling and leukocyte activation, as well as developmental programs, coagulation cascade, and cell adhesion. Objectively assessed habitual sleep duration in monozygotic twin pairs appears to be associated with distinct patterns of differential gene expression and pathway enrichment. By accounting for familial confounding and measuring real life sleep duration, our study shows the transcriptomic effects of habitual short sleep on dysregulated immune response and provides a potential link between sleep deprivation and adverse metabolic, cardiovascular, and inflammatory outcomes.


Learning gaps among statistical competencies for clinical and translational science learners.
Statistical literacy is essential in clinical and translational science (CTS). Statistical competencies have been published to guide coursework design and selection for graduate students in CTS. Here, we describe common elements of graduate curricula for CTS and identify gaps in the statistical competencies. We surveyed statistics educators using e-mail solicitation sent through four professional organizations. Respondents rated the degree to which 24 educational statistical competencies were included in required and elective coursework in doctoral-level and master's-level programs for CTS learners. We report competency results from institutions with Clinical and Translational Science Awards (CTSAs), reflecting institutions that have invested in CTS training. There were 24 CTSA-funded respondents representing 13 doctoral-level programs and 23 master's-level programs. For doctoral-level programs, competencies covered extensively in required coursework for all doctoral-level programs were basic principles of probability and hypothesis testing, understanding the implications of selecting appropriate statistical methods, and computing appropriate descriptive statistics. The only competency extensively covered in required coursework for all master's-level programs was understanding the implications of selecting appropriate statistical methods. The least covered competencies included understanding the purpose of meta-analysis and the uses of early stopping rules in clinical trials. Competencies considered to be less fundamental and more specialized tended to be covered less frequently in graduate courses. While graduate courses in CTS tend to cover many statistical fundamentals, learning gaps exist, particularly for more specialized competencies. Educational material to fill these gaps is necessary for learners pursuing these activities.


A systems perspective of slip and fall accidents on icy and snowy surfaces.
Current research on slips and falls has mainly focused on floors and/or contaminated floors. Although icy and snowy surfaces near melting temperature are more slippery, more important still, slip and falls on icy and snowy surfaces involve not only outdoor workers, but also pedestrians and the general public; and occur in cold regions and in the winter season in many parts of the world. However, in comparison with the size of the problem, research work done so far in this area has been limited. The objective of this paper is to present a systems perspective of slip and fall accidents, with special focus on its occurrence on icy and snowy surfaces. In order to explore the aetiology of slip and fall accidents further, and to provide the basis for prevention, the authors put forward a systems model towards the slips and falls on icy and snowy surfaces based on a review of literature and current knowledge. Various contributing factors are systematically discussed to highlight the multi-factorial nature of the problem, providing the possibility of a multi-faceted approach to reach systematic prevention. Unresolved issues related to slips and falls on ice and snow are also identified, which necessitate further research.


Effect of low-level laser irradiation and epidermal growth factor on adult human adipose-derived stem cells.
The study investigated the effects of low-level laser radiation and epidermal growth factor (EGF) on adult adipose-derived stem cells (ADSCs) isolated from human adipose tissue. Isolated cells were cultured to semi-confluence, and the monolayers of ADSCs were exposed to low-level laser at 5 J/cm(2) using 636 nm diode laser. Cell viability and proliferation were monitored using adenosine triphosphate (ATP) luminescence and optical density at 0 h, 24 h and 48 h after irradiation. Application of low-level laser irradiation at 5 J/cm(2) on human ADSCs cultured with EGF increased the viability and proliferation of these cells. The results indicate that low-level laser irradiation in combination with EGF enhances the proliferation and maintenance of ADSCs in vitro.


TCF21 hypermethylation in genetically quiescent clear cell sarcoma of the kidney.
Clear Cell Sarcoma of the Kidney (CCSK) is a rare childhood tumor whose molecular pathogenesis remains poorly understood. We analyzed a discovery set of 13 CCSKs for changes in chromosome copy number, mutations, rearrangements, global gene expression and global DNA methylation. No recurrent segmental chromosomal copy number changes or somatic variants (single nucleotide or small insertion/deletion) were identified. One tumor with t(10;17)(q22;p13) involving fusion of YHWAE with NUTM2B was identified. Integrated analysis of expression and methylation data identified promoter hypermethylation and low expression of the tumor suppressor gene TCF21 (Pod-1/capsulin/epicardin) in all CCSKs except the case with t(10;17)(q22;p13). TARID, the long noncoding RNA responsible for demethylating TCF21, was virtually undetectable in most CCSKs. TCF21 hypermethylation and decreased TARID expression were validated in an independent set of CCSK tumor samples. The presence of significant hypermethylation of TCF21, a transcription factor known to be active early in renal development, supports the hypothesis that hypermethylation of TCF21 and/or decreased TARID expression lies within the pathogenic pathway of most CCSKs. Future studies are needed to functionally verify a tumorigenic role of TCF21 down-regulation and to tie this to the unique gene expression pattern of CCSK.


Modeling and simulations for molecular scale hydrodynamics of the moving contact line in immiscible two-phase flows.
This paper starts with an introduction to the Onsager principle of minimum energy dissipation which governs the optimal paths of deviation and restoration to equilibrium. Then there is a review of the variational approach to moving contact line hydrodynamics. To demonstrate the validity of our continuum hydrodynamic model, numerical results from model calculations and molecular dynamics simulations are presented for immiscible Couette and Poiseuille flows past homogeneous solid surfaces, with remarkable overall agreement. Our continuum model is also used to study the contact line motion on surfaces patterned with stripes of different contact angles (i.e. surfaces of varying wettability). Continuum calculations predict the stick-slip motion for contact lines moving along these patterned surfaces, in quantitative agreement with molecular dynamics simulation results. This periodic motion is tunable through pattern period (geometry) and contrast in wetting property (chemistry). The consequence of stick-slip contact line motion on energy dissipation is discussed.


Physical activity in urban school-aged children with asthma.
To compare the physical activity levels of children with and without asthma and evaluate predictors of activity level in children with asthma. Parents of 137 children with asthma and 106 controls 6 to 12 years old who attended an urban primary care pediatric clinic were interviewed by telephone. A structured survey evaluated 1 day's total activity and the number of days active in a typical week; asthma characteristics and treatment; physician advice; opportunities for physical activity; and caregiver beliefs about physical activity. The activity levels of children with and without asthma were compared. Predictors of activity level of children with asthma were evaluated. Children with asthma were less active than their peers. The mean amount of daily activity differed by group: 116 (asthma) vs 146 (nonasthma) minutes; 21% (asthma) vs 9% (nonasthma) were active <30 minutes/day; and 23% (asthma) vs 11% (nonasthma) were active <3 days/week. Among children with asthma, disease severity and parental beliefs regarding exercise and asthma predicted activity level. Children with moderate or severe persistent asthma were more likely to be active <30 minutes/day (odds ratio: 3.0; confidence interval: 1.2-7.5), and children whose parents believed exercise could improve asthma were more likely to be highly active > or = 120 minutes/day (odds ratio: 2.5; confidence interval: 1.2-5.4). Disease severity and parental health beliefs contribute to the lower activity level of children with asthma. Pediatricians should evaluate exercise level as an indicator of disease control and address exercise and its benefits with patients and caregivers to help achieve the goal of normal physical activity in children with asthma.


The use of meshes and matrices in breast reconstruction.
Breast cancer is the most common cancer diagnosed in the UK ( Cancer Research UK, 2018 ). Breast reconstruction following mastectomy can be performed with prosthetic devices or autologous tissue. In the UK implant-based breast reconstruction following mastectomy is the most common type of breast reconstruction, estimated to account for 70% of the reconstructive caseload in the UK. Since 2001 there has been a considerable increase in the number of prosthetic reconstructions performed with the use of mesh or matrix to augment the reconstructive pocket. This article introduces the main types of mesh and matrix used in implant-based breast reconstruction, reconstructive techniques and reviews the benefits and complications associated with their use.


Coinfecting prion strains compete for a limiting cellular resource.
Prion strain interference can influence the emergence of a dominant strain from a mixture; however, the mechanisms underlying prion strain interference are poorly understood. In our model of strain interference, inoculation of the sciatic nerve with the drowsy (DY) strain of the transmissible mink encephalopathy (TME) agent prior to superinfection with the hyper (HY) strain of TME can completely block HY TME from causing disease. We show here that the deposition of PrP(Sc), in the absence of neuronal loss or spongiform change, in the central nervous system corresponds with the ability of DY TME to block HY TME infection. This suggests that DY TME agent-induced damage is not responsible for strain interference but rather prions compete for a cellular resource. We show that protein misfolding cyclic amplification (PMCA) of DY and HY TME maintains the strain-specific properties of PrP(Sc) and replicates infectious agent and that DY TME can interfere, or completely block, the emergence of HY TME. DY PrP(Sc) does not convert all of the available PrP(C) to PrP(Sc) in PMCA, suggesting the mechanism of prion strain interference is due to the sequestering of PrP(C) and/or other cellular components required for prion conversion. The emergence of HY TME in PMCA was controlled by the initial ratio of the TME agents. A higher ratio of DY to HY TME agent is required for complete blockage of HY TME in PMCA compared to several previous in vivo studies, suggesting that HY TME persists in animals coinfected with the two strains. This was confirmed by PMCA detection of HY PrP(Sc) in animals where DY TME had completely blocked HY TME from causing disease.


Tuning T Cell Signaling Sensitivity Alters the Behavior of CD4+ T Cells during an Immune Response.
Intricate processes in the thymus and periphery help curb the development and activation of autoreactive T cells. The subtle signals that govern these processes are an area of great interest, but tuning TCR sensitivity for the purpose of affecting T cell behavior remains technically challenging. Previously, our laboratory described the derivation of two TCR-transgenic CD4 T cell mouse lines, LLO56 and LLO118, which recognize the same cognate Listeria epitope with the same affinity. Despite the similarity of the two TCRs, LLO56 cells respond poorly in a primary infection whereas LLO118 cells respond robustly. Phenotypic examination of both lines revealed a substantial difference in their surface of expression of CD5, which serves as a dependable readout of the self-reactivity of a cell. We hypothesized that the increased interaction with self by the CD5-high LLO56 was mediated through TCR signaling, and was involved in the characteristic weak primary response of LLO56 to infection. To explore this issue, we generated an inducible knock-in mouse expressing the self-sensitizing voltage-gated sodium channel Scn5a. Overexpression of Scn5a in peripheral T cells via the CD4-Cre promoter resulted in increased TCR-proximal signaling. Further, Scn5a-expressing LLO118 cells, after transfer into BL6 recipient mice, displayed an impaired response during infection relative to wild-type LLO118 cells. In this way, we were able to demonstrate that tuning of TCR sensitivity to self can be used to alter in vivo immune responses. Overall, these studies highlight the critical relationship between TCR-self-pMHC interaction and an immune response to infection.