Photoexcited Carrier Dynamics of Cu2S Thin Films.
Copper sulfide is a simple binary material with promising attributes for low-cost thin film photovoltaics. However, stable Cu2S-based device efficiencies approaching 10% free from cadmium have yet to be realized. In this Letter, transient absorption spectroscopy is used to investigate the dynamics of the photoexcited state of isolated Cu2S thin films prepared by atomic layer deposition or vapor-based cation exchange of ZnS. While a number of variables including film thickness, carrier concentration, surface oxidation, and grain boundary passivation were examined, grain structure alone was found to correlate with longer lifetimes. A map of excited state dynamics is deduced from the spectral evolution from 300 fs to 300 μs. Revealing the effects of grain morphology on the photophysical properties of Cu2S is a crucial step toward reaching high efficiencies in operationally stable Cu2S thin film photovoltaics.


Differences in peptide presentation between B27 subtypes: the importance of the P1 side chain in maintaining high affinity peptide binding to B*2703.
Susceptibility to spondyloarthropathies is strongly associated with the MHC class I molecule HLA-B27, and is hypothesized to result from the presentation of arthritogenic peptides. Subtypes of B27 that differ structurally but are disease-associated ought to be capable of presenting such peptides, while nondisease-associated subtypes would not. We demonstrate that B*2703, the predominant West African B27 subtype that may not predispose to disease, is not recognized by most B*2705-alloreactive CTL, and does not efficiently present a known B*2705-restricted influenza A nucleoprotein (NP) peptide. We show inefficient presentation is due to a reduced binding affinity of B*2703 for the NP peptide. Furthermore, substituting Arg for the naturally occurring Ser at P1 of the NP peptide, restores high affinity binding and efficient presentation by B*2703. Our results suggest that B*2703 will bind and present efficiently only a subset of the peptides that bind to B*2705, in particular those with Arg or Lys at P1. The apparent lack of disease in individuals with B*2703 may be due to an inability to bind and present putative arthritogenic peptides.


Role of tyrosine kinase enzymes in TNF-alpha and IL-1 induced expression of ICAM-1 and VCAM-1 on human umbilical vein endothelial cells.
The aim of this study was to analyse the potential roles of protein kinase enzymes in tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) induced expression of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on human umbilical vein endothelial cells (HUVEC). The authors observed a marked increase in ICAM-1 and VCAM-1 expression on HUVEC stimulated for 24 h by TNF-alpha (10 ng/ml) or IL-1 (20 ng/ml). Pre-treatment of HUVEC for 30 min with protein tyrosine kinase (PTK) inhibitors genistein and herbimycin A (10 micrograms/ml and 0.5 microgram/ml, respectively) before stimulation with IL-1 did not affect the expression of these molecules. Similar results were observed with respect to VCAM-1 expression on HUVEC stimulated by TNF-alpha. In contrast, pre-incubation of HUVEC with PTK inhibitors prior to the addition of TNF-alpha significantly enhanced subsequent expression of ICAM-1, although spontaneous expression of ICAM-1 on unstimulated HUVEC was unaffected. Western blot analysis demonstrated a significant increase in phosphorylated tyrosine protein levels in HUVEC stimulated by TNF-alpha, and significantly lower levels of these proteins in TNF-alpha stimulated HUVEC pre-treated with PTK inhibitors. These results demonstrate that IL-1 induced ICAM-1 and VCAM-1 expression does not result from activation of PTK-dependent pathways. In the case of TNF-alpha induced responses, the selective co-stimulatory effect of this cytokine in combination with PTK inhibitors on ICAM-1 expression suggests a complicated intracellular pathway of TNF-alpha induced ICAM-1 expression, possibly involving down-modulation of increases in ICAM-1 by PTK enzymes.


Can early initiation of continuous renal replacement therapy improve patient survival with septic acute kidney injury when enrolled in early goal-directed therapy?
The purpose of our study was to investigate the timing of continuous renal replacement therapy (CRRT) application, based on the interval between the start of early goal-directed therapy (EGDT) and CRRT initiation, to ascertain whether the timing was an independent predictor of mortality in patients with septic acute kidney injury (AKI). An observational retrospective cohort study was conducted of 60 patients (>18 years old) who had been admitted to the emergency department and received resuscitation according to the standard EGDT algorithm for severe sepsis and septic shock, and who were treated with CRRT due to septic AKI, between June 2008 and February 2013 at a tertiary hospital in Seoul, Korea. The patients were divided into 2 groups based on the median interval between the start of EGDT and the commencement of CRRT. The main outcome was 28-day all-cause mortality, and a multivariate Cox analysis for mortality was used to evaluate the independent impact of the early CRRT treatment. The mean patient age was 66.3 years, and 52 (86.7%) were male. The most common comorbid disease was diabetes mellitus (35.0%) followed by malignancy (26.7%). The median interval between the start of EGDT and commencement of CRRT was 26.4 hours. During the study period, 28-day mortality was 43.3% (26 of 60 patients). The 28-day all-cause mortality rate was significantly higher in the late CRRT group than in the early CRRT group (56.7 vs 30.0%, P= .037). Furthermore, the higher mortality risk in the late group remained significant even after adjusting for diabetes mellitus, liver failure, and Acute Physiology and Chronic Health Evaluation II scores (hazard ratio, 2.461; 95% confidence interval, 1.044-5.800; P= .026). Early initiation of CRRT may be of benefit. Given the complex nature of this intervention and the ongoing controversy regarding early vs late initiation of therapy in acute and chronic situations, it is vital to develop accurate clinical trials to find definitive answers.


The generation of kidney organoids by differentiation of human pluripotent cells to ureteric bud progenitor-like cells.
This protocol presents recently developed methodologies for the differentiation of human pluripotent stem cells (hPSCs) into ureteric bud (UB) progenitor-like cells. Differentiation of human PSCs to UB progenitor-like cells allows for the generation of chimeric kidney cultures in which the human cells can self-assemble into chimeric 3D structures in combination with embryonic mouse kidney cells over a period of 18 d. UB progenitor-like cells are generated by a two-step process that combines in vitro commitment of human PSCs, whether embryonic stem cells (ESCs) or induced PSCs (iPSCs), under chemically defined culture conditions, with ex vivo cultures for the induction of 3D organogenesis. The models described here provide new opportunities for investigating human kidney development, modeling disease, evaluating regenerative medicine strategies, as well as for toxicology studies.


Identification of copy number variants in whole-genome data using Reference Coverage Profiles.
The identification of DNA copy numbers from short-read sequencing data remains a challenge for both technical and algorithmic reasons. The raw data for these analyses are measured in tens to hundreds of gigabytes per genome; transmitting, storing, and analyzing such large files is cumbersome, particularly for methods that analyze several samples simultaneously. We developed a very efficient representation of depth of coverage (150-1000× compression) that enables such analyses. Current methods for analyzing variants in whole-genome sequencing (WGS) data frequently miss copy number variants (CNVs), particularly hemizygous deletions in the 1-100 kb range. To fill this gap, we developed a method to identify CNVs in individual genomes, based on comparison to joint profiles pre-computed from a large set of genomes. We analyzed depth of coverage in over 6000 high quality (>40×) genomes. The depth of coverage has strong sequence-specific fluctuations only partially explained by global parameters like %GC. To account for these fluctuations, we constructed multi-genome profiles representing the observed or inferred diploid depth of coverage at each position along the genome. These Reference Coverage Profiles (RCPs) take into account the diverse technologies and pipeline versions used. Normalization of the scaled coverage to the RCP followed by hidden Markov model (HMM) segmentation enables efficient detection of CNVs and large deletions in individual genomes. Use of pre-computed multi-genome coverage profiles improves our ability to analyze each individual genome. We make available RCPs and tools for performing these analyses on personal genomes. We expect the increased sensitivity and specificity for individual genome analysis to be critical for achieving clinical-grade genome interpretation.


Structural basis of cargo membrane protein discrimination by the human COPII coat machinery.
Genomic analysis shows that the increased complexity of trafficking pathways in mammalian cells involves an expansion of the number of SNARE, Rab and COP proteins. Thus, the human genome encodes four forms of Sec24, the cargo selection subunit of the COPII vesicular coat, and this is proposed to increase the range of cargo accommodated by human COPII-coated vesicles. In this study, we combined X-ray crystallographic and biochemical analysis with functional assays of cargo packaging into COPII vesicles to establish molecular mechanisms for cargo discrimination by human Sec24 subunits. A conserved IxM packaging signal binds in a surface groove of Sec24c and Sec24d, but the groove is occluded in the Sec24a and Sec24b subunits. Conversely, LxxLE class transport signals and the DxE signal of VSV glycoprotein are selectively bound by Sec24a and Sec24b subunits. A comparative analysis of crystal structures of the four human Sec24 isoforms establishes the structural determinants for discrimination among these transport signals, and provides a framework to understand how an expansion of coat subunits extends the range of cargo proteins packaged into COPII-coated vesicles.


Longitudinal assessment of the nevus phenotype in a melanoma kindred.
Phenotypic characteristics of members of a melanoma prone kindred with a V126D CDKN2A gene mutation were monitored over approximately 15 y. Thirty-eight previously studied subjects were recruited. Participants underwent a complete skin examination by the same dermatologist who examined them initially. The size and location of all nevi were recorded on a body map diagram. Total nevus number (TNN) and total nevus density (TND) were determined. CDKN2A sequencing verified 13 mutation carriers and 16 non-carriers. Nine participants were spouse controls without a history of melanoma and did not carry a CDKN2A mutation. Mutation carriers demonstrated a greater mean TNN and TND at initial and follow-up examinations compared with non-carriers and continued to develop nevi rather than show nevus regression seen in non-carriers and spouse controls. Non-carriers showed an intermediate nevus phenotype between mutation carriers and spouse controls. Four of the 13 mutation carriers and one non-carrier have developed invasive melanoma. Over a 15-y interval, TNN and TND were increased in mutation carriers compared with non-carriers and spouse controls. Continued accumulation of nevi in mutation carriers supports a nevogenic role for this CDKN2A mutation. An intermediate nevus phenotype in non-carrier family members suggests the presence of additional modifier genes.


Association of Drug and Alcohol Use With Adolescent Firearm Homicide at Individual, Family, and Neighborhood Levels.
Homicide is the third leading cause of death for adolescents in the United States and the leading cause of death for adolescents who are African American. Large cities have disproportionate homicide rates. To determine the relationships between exposures to drugs and alcohol at the individual, family, and neighborhood levels and adolescent firearm homicide and to inform new approaches to preventing firearm violence. Population-based case-control study from January 2010 to December 2012 of all 13- to 20-year-olds who were homicide victims in Philadelphia during the study period matched to randomly selected 13- to 20-year-old controls from the general population. Individual drug and alcohol use at the time of injury, history of drug and alcohol use, caregiver drug and alcohol use, and neighborhood availability of alcohol and illegal drugs. We also controlled for age, race, school suspensions, arrests, and neighborhood ethnicity. Adolescent firearm homicide identified from police and medical examiner's reports. We enrolled 161 adolescent homicide cases, including 157 (97.5%) firearm homicide cases and 172 matched controls, including 166 (96.5%) firearm homicide controls. Adolescents with a history of alcohol use (adjusted odds ratio [AOR], 4.1; 95% CI, 1.2-14.0) or drug use (AOR, 4.4; 95% CI, 1.7-11.6) had increased odds of firearm homicide. Adolescents whose caregiver had a history of drug use had increased odds of firearm homicide (AOR, 11.7; 95% CI, 2.8-48.0). Adolescents in neighborhoods with high densities of alcohol outlets (AOR, 3.2; 95% CI, 1.1-9.1) and moderate or high drug availability had increased odds of firearm homicide (AOR, 3.4; 95% CI, 1.1-10.3 vs AOR, 7.5; 95% CI, 2.2-25.8). Almost all adolescent homicides in Philadelphia between 2010 and 2012 were committed with a firearm. Substance use at the individual, family, and neighborhood levels was associated with increased odds of adolescent firearm homicide; drug use was associated at all 3 levels and alcohol at the individual and neighborhood levels. Expanding violence prevention efforts to target drug and alcohol use at multiple levels may help to reduce the firearm violence that disproportionately affects adolescents in minority populations in large US cities.


Between desire and rape - narratives about being intimate partners and becoming pregnant in a violent relationship.
Women subjected to intimate partner violence (IPV) experience different forms of abuse. Sexual violence is often under-reported because physically abused women, in particular, might see forced sex as an obligatory part of the sexual interplay. Accordingly, abused women have less sexual autonomy and experience unplanned pregnancies more often than other women. To describe and analyse nine Swedish women's retrospective stories about IPV with a focus on power and coping strategies as intimate partners, particularly regarding experiences of sex, contraception, and becoming pregnant. Design : Nine qualitative interviews were carried out with women who had been subjected to very severe violence in their intimate relationships and during at least one pregnancy. The stories were analysed using 'Narrative method' with the emphasis on the women's lived experiences. Despite the violence and many contradictory and ambivalent feelings, two of the women described having sex as desirable, reciprocal and as a respite from the rest of the relationship. The other seven women gave a negative and totally different picture, and they viewed sex either as obligatory or as a necessity to prevent or soothe aggression or referred to it as rape and as something that was physically forced upon them. The women's descriptions of their pregnancies ranged from being carefully planned and mostly wanted to completely unwelcome and including flawed contraceptive efforts with subsequent abortions. Women subjected to IPV have diverse and complex experiences that have effects on all parts of the relationship. Intimacy might for some turn into force and rape, but for others sex does not necessarily exclude pleasure and desire and can be a haven of rest from an otherwise violent relationship. Accordingly, women may tell stories that differ from the ones expected as 'the typical abuse story', and this complexity needs to be recognized and dealt with when women seek healthcare, especially concerning contraceptives, abortions, and pregnancies.


Phenotypic selection on a heritable size trait revisited.
One of evolutionary biology's most persistent puzzles is the fact that apparent directional selection on a heritable trait in a natural population often does not produce a selection response. We tested three possible explanations for this problem using data on body size of more than 23,000 individuals, measured over 18 yr, in a collared flycatcher (Ficedula albicollis) population. Using a restricted maximum likelihood "animal model," we found a narrow-sense heritability for fledgling tarsus length of [Formula: see text] SE and substantial common environment effects ([Formula: see text] SE). For survival to adulthood, the selection differential on tarsus length was [Formula: see text] SE. There was, however, no response to this selection over the study period. One explanation for the lack of response might have been that selection was associated with only the environmental (nonheritable) component of phenotype, but we found significant selection on breeding values (the heritable component). There was also no evidence of fluctuating selection pressures or of antagonistic selection between the sexes in selection pressures. Thus, in contrast to earlier investigations in this same population, none of the potential explanations for the absence of a selection response was supported; we discuss alternative hypotheses yet to be investigated.


Subtalar arthrodesis for complications of intra-articular calcaneal fractures.
Eighty six subtalar arthrodeses performed between 1985 and 1996 for complications associated with intra-articular calcaneal fractures were retrospectively evaluated. Patients were divided into three Groups: (I) 59 patients with calcaneal malunions (II) 13 patients with failed open reduction and internal fixation, and (III) eight patients undergoing open reductions and primary fusion for highly comminuted fractures. In each scenario, internal fixation was achieved with cancellous lag screws. Bone graft material consisted of either autogenous iliac crest graft, local graft obtained from the lateral wall exostectomy of the malunion, or freeze-dried cancellous allograft. Fusions in Groups II and III were performed in situ. Fusions in Group I were performed either in situ or utilizing a variety of reconstructive procedures depending upon the type of malunion encountered. Eighty three of the 86 fusion attempts were successful following the initial operations for a union rate of 96%. Fusion rates were similar regardless of the graft material used. Complications included four varus malunions, four cases of osteomyelitis, and two cases of reflex sympathetic dystrophy. A statistically significant shorter hospital stay was found for patients not undergoing iliac crest bone graft procedures. Eighty patients with at least two year follow up achieved a mean American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot score of 75.0. Scores were similar for all three groups and for the various types of reconstructive procedures used. No correlation was found between postoperative talar declination angle and the AOFAS ankle-hindfoot score. Worker's compensation patients tended to have a poorer clinical outcome.


Prescription dose and fractionation predict improved survival after stereotactic radiotherapy for brainstem metastases.
Brainstem metastases represent an uncommon clinical presentation that is associated with a poor prognosis. Treatment options are limited given the unacceptable risks associated with surgical resection in this location. However, without local control, symptoms including progressive cranial nerve dysfunction are frequently observed. The objective of this study was to determine the outcomes associated with linear accelerator-based stereotactic radiotherapy or radiosurgery (SRT/SRS) of brainstem metastases. We retrospectively reviewed 38 tumors in 36 patients treated with SRT/SRS between February 2003 and December 2011. Treatment was delivered with the Cyberknife™ or Trilogy™ radiosurgical systems. The median age of patients was 62 (range: 28-89). Primary pathologies included 14 lung, 7 breast, 4 colon and 11 others. Sixteen patients (44%) had received whole brain radiation therapy (WBRT) prior to SRT/SRS; ten had received prior SRT/SRS at a different site (28%). The median tumor volume was 0.94 cm3 (range: 0.01-4.2) with a median prescription dose of 17 Gy (range: 12-24) delivered in 1-5 fractions. Median follow-up for the cohort was 3.2 months (range: 0.4-20.6). Nineteen patients (52%) had an MRI follow-up available for review. Of these, one patient experienced local failure corresponding to an actuarial 6-month local control of 93%. Fifteen of the patients with available follow-up imaging (79%) experienced intracranial failure outside of the treatment volume. The median time to distant intracranial failure was 2.1 months. Six of the 15 patients with distant intracranial failure (40%) had received previous WBRT. The actuarial overall survival rates at 6- and 12-months were 27% and 8%, respectively. Predictors of survival included Graded Prognostic Assessment (GPA) score, greater number of treatment fractions, and higher prescription dose. Three patients experienced acute treatment-related toxicity consisting of nausea (n = 1) and headaches (n = 2) that resolved with a short-course of dexamethasone. SRT/SRS for brainstem metastases is safe and achieves a high rate of local control. We found higher GPA as well as greater number of treatment fractions and higher prescription dose to be correlated with improved overall survival. Despite this approach, prognosis remains poor and distant intracranial control remains an issue, even in patients previously treated with WBRT.


Road-crossing safety in virtual reality: a comparison of adolescents with and without ADHD.
This study investigated the potential accident-proneness of adolescents with attention deficit hyperactivity disorder (ADHD) in a hazardous road-crossing environment. An immersive virtual reality traffic gap-choice task was used to determine whether ADHD adolescents show more unsafe road-crossing behavior than controls. Participants (ages 13 to 17) were identified with (n = 24) or without (n = 24) ADHD according to a standardized protocol (Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version and Conners' Scales), with equal number of boys (n = 12) and girls (n = 12) in each group. ADHD adolescents did not take stimulant medication on the day of testing. Participants with ADHD had a lower margin of safety, walked slower, underutilized the available gap in incoming traffic, showed greater variability in road-crossing behavior, and evidenced twice as many collisions as compared to controls. No sex differences were found. Virtual reality may help identify and educate those at higher risk of being involved in dangerous traffic situations.


Temporal omics analysis in Syrian hamsters unravel cellular effector responses to moderate COVID-19.
In COVID-19, immune responses are key in determining disease severity. However, cellular mechanisms at the onset of inflammatory lung injury in SARS-CoV-2 infection, particularly involving endothelial cells, remain ill-defined. Using Syrian hamsters as a model for moderate COVID-19, we conduct a detailed longitudinal analysis of systemic and pulmonary cellular responses, and corroborate it with datasets from COVID-19 patients. Monocyte-derived macrophages in lungs exert the earliest and strongest transcriptional response to infection, including induction of pro-inflammatory genes, while epithelial cells show weak alterations. Without evidence for productive infection, endothelial cells react, depending on cell subtypes, by strong and early expression of anti-viral, pro-inflammatory, and T cell recruiting genes. Recruitment of cytotoxic T cells as well as emergence of IgM antibodies precede viral clearance at day 5 post infection. Investigating SARS-CoV-2 infected Syrian hamsters thus identifies cell type-specific effector functions, providing detailed insights into pathomechanisms of COVID-19 and informing therapeutic strategies.


Model of phytoplankton absorption based on three size classes.
Using the phytoplankton size-class model of Brewin et al. [Ecol. Model.221, 1472 (2010)], the two-population absorption model of Sathyendranath et al. [Int. J. Remote. Sens.22, 249 (2001)] and Devred et al. [J. Geophys. Res.111, C03011 (2006)] is extended to three populations of phytoplankton, namely, picophytoplankton, nanophytoplankton, and microphytoplankton. The new model infers total and size-dependent phytoplankton absorption as a function of the total chlorophyll-a concentration. A main characteristic of the model is that all the parameters that describe it have biological or optical interpretation. The three-population model performs better than the two-population model at retrieving total phytoplankton absorption. Accounting for the contributions of picophytoplankton and nanophytoplankton, rather than the combination of both as in the two-population model, improved significantly the retrieval of phytoplankton absorption at low chlorophyll-a concentrations. Class-dependent specific absorption of phytoplankton derived using the model compares well with previously published models. However, the model presented in this paper provides the specific absorption of three size classes and is applicable to a continuum of chlorophyll-a concentrations. Absorption obtained from remotely sensed chlorophyll-a using our model compares well with in situ absorption measurements.


Neural Prediction Errors Distinguish Perception and Misperception of Speech.
Humans use prior expectations to improve perception, especially of sensory signals that are degraded or ambiguous. However, if sensory input deviates from prior expectations, then correct perception depends on adjusting or rejecting prior expectations. Failure to adjust or reject the prior leads to perceptual illusions, especially if there is partial overlap (and thus partial mismatch) between expectations and input. With speech, "slips of the ear" occur when expectations lead to misperception. For instance, an entomologist might be more susceptible to hear "The ants are my friends" for "The answer, my friend" (in the Bob Dylan song Blowing in the Wind). Here, we contrast two mechanisms by which prior expectations may lead to misperception of degraded speech. First, clear representations of the common sounds in the prior and input (i.e., expected sounds) may lead to incorrect confirmation of the prior. Second, insufficient representations of sounds that deviate between prior and input (i.e., prediction errors) could lead to deception. We used crossmodal predictions from written words that partially match degraded speech to compare neural responses when male and female human listeners were deceived into accepting the prior or correctly reject it. Combined behavioral and multivariate representational similarity analysis of fMRI data show that veridical perception of degraded speech is signaled by representations of prediction error in the left superior temporal sulcus. Instead of using top-down processes to support perception of expected sensory input, our findings suggest that the strength of neural prediction error representations distinguishes correct perception and misperception.SIGNIFICANCE STATEMENT Misperceiving spoken words is an everyday experience, with outcomes that range from shared amusement to serious miscommunication. For hearing-impaired individuals, frequent misperception can lead to social withdrawal and isolation, with severe consequences for wellbeing. In this work, we specify the neural mechanisms by which prior expectations, which are so often helpful for perception, can lead to misperception of degraded sensory signals. Most descriptive theories of illusory perception explain misperception as arising from a clear sensory representation of features or sounds that are in common between prior expectations and sensory input. Our work instead provides support for a complementary proposal: that misperception occurs when there is an insufficient sensory representations of the deviation between expectations and sensory signals.


Effect of Tissue Material Properties in Blast Loading: Coupled Experimentation and Finite Element Simulation.
Computational models of blast-induced traumatic brain injury (bTBI) require a robust definition of the material models of the brain. The mechanical constitutive models of these tissues are difficult to characterize, leading to a wide range of values reported in literature. Therefore, the sensitivity of the intracranial pressure (ICP) and maximum principal strain to variations in the material model of the brain was investigated through a combined computational and experimental approach. A finite element model of a rat was created to simulate a shock wave exposure, guided by the experimental measurements of rats subjected to shock loading conditions corresponding to that of mild traumatic brain injury in a field-validated shock tube. In the numerical model, the properties of the brain were parametrically varied. A comparison of the ICP measured at two locations revealed that experimental and simulated ICP were higher in the cerebellum (p < 0.0001), highlighting the significance of pressure sensor locations within the cranium. The ICP and strain were correlated with the long-term bulk (p < 0.0001) and shear moduli (p < 0.0001), with an 80 MPa effective bulk modulus value matching best with experimental measurements. In bTBI, the solution is sensitive to the brain material model, necessitating robust validation methods.


Protein Folding and Structure Prediction from the Ground Up: The Atomistic Associative Memory, Water Mediated, Structure and Energy Model.
The associative memory, water mediated, structure and energy model (AWSEM) is a coarse-grained force field with transferable tertiary interactions that incorporates local in sequence energetic biases using bioinformatically derived structural information about peptide fragments with locally similar sequences that we call memories. The memory information from the protein data bank (PDB) database guides proper protein folding. The structural information about available sequences in the database varies in quality and can sometimes lead to frustrated free energy landscapes locally. One way out of this difficulty is to construct the input fragment memory information from all-atom simulations of portions of the complete polypeptide chain. In this paper, we investigate this approach first put forward by Kwac and Wolynes in a more complete way by studying the structure prediction capabilities of this approach for six α-helical proteins. This scheme which we call the atomistic associative memory, water mediated, structure and energy model (AAWSEM) amounts to an ab initio protein structure prediction method that starts from the ground up without using bioinformatic input. The free energy profiles from AAWSEM show that atomistic fragment memories are sufficient to guide the correct folding when tertiary forces are included. AAWSEM combines the efficiency of coarse-grained simulations on the full protein level with the local structural accuracy achievable from all-atom simulations of only parts of a large protein. The results suggest that a hybrid use of atomistic fragment memory and database memory in structural predictions may well be optimal for many practical applications.


Artificial nighttime lighting impacts visual ecology links between flowers, pollinators and predators.
The nighttime environment is being altered rapidly over large areas worldwide through introduction of artificial lighting, from streetlights and other sources. This is predicted to impact the visual ecology of many organisms, affecting both their intra- and interspecific interactions. Here, we show the effects of different artificial light sources on multiple aspects of hawkmoth visual ecology, including their perception of floral signals for pollination, the potential for intraspecific sexual signalling, and the effectiveness of their visual defences against avian predators. Light sources fall into three broad categories: some that prevent use of chromatic signals for these behaviours, others that more closely mimic natural lighting conditions, and, finally, types whose effects vary with light intensity and signal colour. We find that Phosphor Converted (PC) amber LED lighting - often suggested to be less harmful to nocturnal insects - falls into this third disruptive group, with unpredictable consequences for insect visual ecology depending on distance from the light source and the colour of the objects viewed. The diversity of impacts of artificial lighting on hawkmoth visual ecology alone argues for a nuanced approach to outdoor lighting in environmentally sensitive areas, employing intensities and spectra designed to limit those effects of most significant concern.


Ocean acidification and desalination: climate-driven change in a Baltic Sea summer microplanktonic community.
Helcom scenario modelling suggests that the Baltic Sea, one of the largest brackish-water bodies in the world, could expect increased precipitation (decreased salinity) and increased concentration of atmospheric CO2 over the next 100 years. These changes are expected to affect the microplanktonic food web, and thereby nutrient and carbon cycling, in a complex and possibly synergistic manner. In the Baltic Proper, the extensive summer blooms dominated by the filamentous cyanobacteria Aphanizomenon sp., Dolichospermum spp. and the toxic Nodularia spumigena contribute up to 30% of the yearly new nitrogen and carbon exported to the sediment. In a 12 days outdoor microcosm experiment, we tested the combined effects of decreased salinity (from 6 to 3) and elevated CO2 concentrations (380 and 960 µatm) on a natural summer microplanktonic community, focusing on diazotrophic filamentous cyanobacteria. Elevated pCO2 had no significant effects on the natural microplanktonic community except for higher biovolume of Dolichospermum spp. and lower biomass of heterotrophic bacteria. At the end of the experimental period, heterotrophic bacterial abundance was correlated to the biovolume of N. spumigena. Lower salinity significantly affected cyanobacteria together with biovolumes of dinoflagellates, diatoms, ciliates and heterotrophic bacteria, with higher biovolume of Dolichospermum spp. and lower biovolume of N. spumigena, dinoflagellates, diatoms, ciliates and heterotrophic bacteria in reduced salinity. Although the salinity effects on diatoms were apparent, they could not clearly be separated from the influence of inorganic nutrients. We found a clear diurnal cycle in photosynthetic activity and pH, but without significant treatment effects. The same diurnal pattern was also observed in situ (pCO2, pH). Thus, considering the Baltic Proper, we do not expect any dramatic effects of increased pCO2 in combination with decreased salinity on the microplanktonic food web. However, long-term effects of the experimental treatments need to be further studied, and indirect effects of the lower salinity treatments could not be ruled out. Our study adds one piece to the complicated puzzle to reveal the combined effects of increased pCO2 and reduced salinity levels on the Baltic microplanktonic community.


Enhanced oligonucleotide-nanoparticle conjugate stability using thioctic acid modified oligonucleotides.
Metallic nanoparticles of gold functionalized with oligonucleotides conventionally use a terminal thiol modification and have been used in a wide range of applications. Although readily available, the oligonucleotide-nanoparticle conjugates prepared in this way suffer from a lack of stability when exposed to a variety of small molecules or elevated temperatures. If silver is used in place of gold then this lack of stability is even more pronounced. In this study we report the synthesis of highly stabilized oligonucleotide-nanoparticle conjugates using a simple oligonucleotide modification. A modified solid support was used to generate 3'-thioctic acid modified oligonucleotides by treatment with an N-hydroxysuccimidyl ester of thioctic acid. Unusually, both gold and silver nanoparticles have been investigated in this study and show that these disulphide-modified oligonucleotide probes offer significant improvements in nanoparticle stability when treated with dithiothreitol (DTT) compared with monothiol analogues. This is a significant advance in oligonucleotide-nanoparticle conjugate stability and for the first time allows silver nanoparticles to be prepared that are more stable than standard gold-thiol functionalized nanoparticles. This opens up the possibility of using silver nanoparticles functionalized with oligonucleotides as an alternative to gold.


Factors and determinants of disease emergence.
Emerging infectious diseases can be defined as infections that have newly appeared in a population or are rapidly increasing in incidence or geographic range. Many of these diseases are zoonoses, including such recent examples as avian influenza, severe acute respiratory syndrome, haemolytic uraemic syndrome (a food-borne infection caused by certain strains of Escherichia coli) and probably human immunodeficiency virus/acquired immune deficiency syndrome. Specific factors precipitating the emergence of a disease can often be identified. These include ecological, environmental or demographic factors that place people in increased contact with the natural host for a previously unfamiliar zoonotic agent or that promote the spread of the pathogen. These factors are becoming increasingly prevalent, suggesting that infections will continue to emerge and probably increase. Strategies for dealing with the problem include focusing special attention on situations that promote disease emergence, especially those in which animals and humans come into contact, and implementing effective disease surveillance and control.


Gate-controlled mid-infrared light bending with aperiodic graphene nanoribbons array.
Graphene plasmonic nanostructures enable subwavelength confinement of electromagnetic energy from the mid-infrared down to the terahertz frequencies. By exploiting the spectrally varying light scattering phase at the vicinity of the resonant frequency of the plasmonic nanostructure, it is possible to control the angle of reflection of an incoming light beam. We demonstrate, through full-wave electromagnetic simulations based on Maxwell equations, the electrical control of the angle of reflection of a mid-infrared light beam by using an aperiodic array of graphene nanoribbons, whose widths are engineered to produce a spatially varying reflection phase profile that allows for the construction of a far-field collimated beam towards a predefined direction.


The effect of acute exercise on environmentally induced symptoms of dry eye.
The purpose of this study was to investigate the effects of acute exercise on environmentally induced symptoms of dry eye. Twelve participants without dry eye disease volunteered to complete three experimental visits in a randomized order; (1) control condition seated for 1 h at a relative humidity (RH) of 40% (CONT), (2) dry condition seated for 1 h at a RH of 20% (DRY), and (3) exercise condition seated for 40 min followed by 20 min of cycling exercise at a RH of 20% (EXER). Tear volume, tear matrix metalloproteinase 9 (MMP-9), perception of dry eye symptoms (frequency and severity), core temperature, and ocular surface temperature (OST) were measured at the end of each exposure. The perception of dry eye frequency and MMP-9 concentration were significantly higher in DRY compared to CONT (P < 0.012), with no differences in EXER compared to CONT. The results suggest that an acute bout of exercise may attenuate symptoms of environmentally induced dry eye, and warrant further research.


Regional analgesia in the emergency department for hip fractures: survey of current UK practice and its impact on services in a teaching hospital.
While the benefits of regional analgesia (RA) for preoperative pain relief in hip fracture (HF) in elderly patients are well recognised, this service is yet to be established in many UK emergency departments (EDs). We set out to discover how widely RA is adopted in the UK EDs. In April-July 2010, we conducted a postal survey of 218 UK EDs, followed up with fax reminders for non-respondents. A total of 147/218 (67%) EDs completed the survey. Sixty five (44%) respondents reported use of RA blocks for HF. The commonest stated reasons for not using RA were lack of trained staff (36%) or appropriate equipment (22%). RA users practiced femoral nerve block most widely (60% of EDs) followed by fascia iliaca compartment block (FICB) (22%). It is more a lack of trained staff and suitable equipment that prevents RA blocks being widely adopted in the UK. We advocate FICB in HF patients, which is an easy landmark-based block that can be safely performed by ED doctors. Our survey initiated multidisciplinary consultation and development of a protocol for preoperative FICB in HFs in our teaching hospital ED. RA for HFs is not widely used in UK EDs, proving that there is room for improvement .The finding that RA blocks are performed by the ED medical staff in 84% of the responding EDs practising RA was reassuring for developing the service in our hospital. FICB should be considered as an alternative to parenteral analgesia in adult patients with HF.


Energy Absorption Capacity in Natural Fiber Reinforcement Composites Structures.
The study of natural fiber reinforcement composite structures has focused the attention of the automobile industry due to the new regulation in relation to the recyclability and the reusability of the materials preserving and/or improving the mechanical characteristics. The influence of different parameters on the material behavior of natural fiber reinforced plastic structures has been investigated, showing the potential for transport application in energy absorbing structures. Two different woven fabrics (twill and hopsack) made of flax fibers as well as a non-woven mat made of a mixture of hemp and kenaf fibers were employed as reinforcing materials. These reinforcing textiles were impregnated with both HD-PE (high-density polyethylen) and PLA (polylactic acid) matrix, using a continuous compression molding press. The impregnated semi-finished laminates (so-called organic sheets) were thermoformed in a second step to half-tubes that were assembled through vibration-welding process to cylindric crash absorbers. The specimens were loaded by compression to determine the specific energy absorption capacity. Quasi-static test results were compared to dynamic test data obtained on a catapult arrangement. The differences on the specific energies absorption (SEA) as a function of different parameters, such as the wall thickness, the weave material type, the reinforced textiles, and the matrix used, depending on the velocity rate application were quantified. In the case of quasi-static analysis it is observed a 20% increment in the SEA value when wove Hopsack fabric reinforcement is employed. No velocity rate influence from the material was observed on the SEA evaluation at higher speeds used to perform the experiments. The influence of the weave configuration (Hopsack) seems to be more stable against buckling effects at low loading rates with 10% higher SEA values. An increase of SEA level of up to 72% for PLA matrix was observed when compared with HD-PE matrix.


Vinorelbine and continuous low-dose cyclophosphamide as maintenance chemotherapy in patients with high-risk rhabdomyosarcoma (RMS 2005): a multicentre, open-label, randomised, phase 3 trial.
For more than three decades, standard treatment for rhabdomyosarcoma in Europe has included 6 months of chemotherapy. The European paediatric Soft tissue sarcoma Study Group (EpSSG) aimed to investigate whether prolonging treatment with maintenance chemotherapy would improve survival in patients with high-risk rhabdomyosarcoma. RMS 2005 was a multicentre, open-label, randomised, controlled, phase 3 trial done at 102 hospitals in 14 countries. We included patients aged 6 months to 21 years with rhabdomyosarcoma who were considered to be at high risk of relapse: those with non-metastatic incompletely resected embryonal rhabdomyosarcoma occurring at unfavourable sites with unfavourable age (≥10 years) or tumour size (>5 cm), or both; those with any non-metastatic rhabdomyosarcoma with nodal involvement; and those with non-metastatic alveolar rhabdomyosarcoma but without nodal involvement. Patients in remission after standard treatment (nine cycles of ifosfamide, vincristine, dactinomycin with or without doxorubicin, and surgery or radiotherapy, or both) were randomly assigned (1:1) to stop treatment or continue maintenance chemotherapy (six cycles of intravenous vinorelbine 25 mg/m2 on days 1, 8, and 15, and daily oral cyclophosphamide 25 mg/m2, on days 1-28). Randomisation was done by use of a web-based system and was stratified (block size of four) by enrolling country and risk subgroup. Neither investigators nor patients were masked to treatment allocation. The primary outcome was disease-free survival in the intention-to-treat population. Secondary outcomes were overall survival and toxicity. This trial is registered with EudraCT, number 2005-000217-35, and ClinicalTrials.gov, number NCT00339118, and follow-up is ongoing. Between April 20, 2006, and Dec 21, 2016, 371 patients were enrolled and randomly assigned to the two groups: 186 to stop treatment and 185 to receive maintenance chemotherapy. Median follow-up was 60·3 months (IQR 32·4-89·4). In the intention-to-treat population, 5-year disease-free survival was 77·6% (95% CI 70·6-83·2) with maintenance chemotherapy versus 69·8% (62·2-76·2) without maintenance chemotherapy (hazard ratio [HR] 0·68 [95% CI 0·45-1·02]; p=0·061), and 5-year overall survival was 86·5% (95% CI 80·2-90·9) with maintenance chemotherapy versus 73·7% (65·8-80·1) without (HR 0·52 [95% CI 0·32-0·86]; p=0·0097). Toxicity was manageable in patients who received maintenance chemotherapy: 136 (75%) of 181 patients had grade 3-4 leucopenia, 148 (82%) had grade 3-4 neutropenia, 19 (10%) had anaemia, two (1%) had thrombocytopenia, and 56 (31%) had an infection. One (1%) patient had a grade 4 non-haematological toxicity (neurotoxicity). Two treatment-related serious adverse events occurred: one case of inappropriate antidiuretic hormone secretion and one of a severe steppage gait with limb pain, both of which resolved. Adding maintenance chemotherapy seems to improve survival for patients with high-risk rhabdomyosarcoma. This approach will be the new standard of care for patients with high-risk rhabdomyosarcoma in future EpSSG trials. Fondazione Città della Speranza, Association Léon Berard Enfant Cancéreux, Clinical Research Hospital Program (French Ministry of Health), and Cancer Research UK.


The influence of wing morphology upon the dispersal, geographical distributions and diversification of the Corvides (Aves; Passeriformes).
New species are sometimes known to arise as a consequence of the dispersal and establishment of populations in new areas. It has nevertheless been difficult to demonstrate an empirical link between rates of dispersal and diversification, partly because dispersal abilities are challenging to quantify. Here, using wing morphology as a proxy for dispersal ability, we assess this relationship among the global radiation of corvoid birds. We found that species distributions are associated with wing shape. Widespread species (occurring on both islands and continents), and those that are migratory, exhibit wing morphologies better adapted to long-distance flight compared with sedentary continental or insular forms. Habitat preferences also strongly predict wing form, with species that occur in canopies and/or areas of sparse vegetation possessing dispersive morphologies. By contrast, we found no significant differences in diversification rates among either the migratory or habitat classifications, but species distributed in island settings diversify at higher rates than those found on continents. This latter finding may reflect the elevated dispersal capabilities of widespread taxa, facilitating the radiation of these lineages across insular areas. However, as the correlations between wing morphology and diversification rates were consistently weak throughout our dataset, this suggests that historical patterns of diversification are not particularly well reflected by present-day wing morphology.


Implantation of esterified hyaluronic acid in microdissected Reinke's space after vocal fold microsurgery: short- and long-term results.
In this study are reported the laryngeal and vocal results obtained after a microflap excision of benign vocal fold (VF) lesions and immediate implantation of esterified hyaluronic acid (EHA) in the surgical wound. In a previous pilot study on 11 cases, we have shown an excellent tolerance of this bioimplant. The objectives are to confirm the innocuity of the technique, to demonstrate the laryngeal and vocal evolution at short and long term, and to evaluate the eventual positive impact of EHA implantation on the pliability of the superficial layer of the lamina propria (SLLP) and on voice. This is a prospective and comparative study on 83 patients suffering from various benign VF lesions. Thirty-three patients were implanted with EHA, whereas 50 patients did not undergo implantation at the end of the microsurgical procedure. All patients undergo rigid laryngoscopy and microflap excision procedure under general anesthesia. After freeing up of the Reinke's space and creation of a mucosal microflap, a few fibers of EHA are inserted in the surgical wound, before closure of the incision with fibrin glue. Serial laryngeal and vocal assessments are performed in all patients using videostroboscopy (Wolff and Xion), perceptual and objective voice evaluation (MDVP software, Kay Elemetrics), and phonatory function measurements (Aerophone II). Pre- and early postoperative means are compared by analysis of variance. Delayed and long-term evolution of laryngeal and vocal data are compared by means of nonparametric statistical methods. The longest follow-up in the implanted group is 4 years. Early postoperative results are similar in both groups: a significant improvement of a majority of laryngeal and vocal data is observed after microsurgery. In the long term, the two groups exhibit a different behavior: further improvement of voice, as an ongoing process, is only observed in the EHA implanted group, together with improvement of some videostroboscopic characteristics. The nonimplanted group remains stable, with no further improvement of the voice quality obtained after microsurgery. Excellent short- and long-term tolerance of EHA implantation is confirmed by this larger series. The use of EHA implant in microdissected SLLP is safe and leads to good laryngeal and vocal outcomes in the treated patients. More interestingly, treated cases exhibit a continuous improvement over a long period of time.


Shared polygenic risk for ADHD, executive dysfunction and other psychiatric disorders.
Many psychiatric disorders are associated with impaired executive functioning (EF). The associated EF component varies by psychiatric disorders, and this variation might be due to genetic liability. We explored the genetic association between five psychiatric disorders and EF in clinically-recruited attention deficit hyperactivity disorder (ADHD) children using polygenic risk score (PRS) methodology. Genome-wide association study (GWAS) summary data for ADHD, major depressive disorder (MDD), schizophrenia (SZ), bipolar disorder (BIP) and autism were used to calculate the PRSs. EF was evaluated by the Stroop test for inhibitory control, the trail-making test for cognitive flexibility, and the digital span test for working memory in a Chinese ADHD cohort (n = 1147). Exploratory factor analysis of the three measures identified one principal component for EF (EF-PC). Linear regression models were used to analyze the association between each PRS and the EF measures. The role of EF measures in mediating the effects of the PRSs on ADHD symptoms was also analyzed. The result showed the PRSs for MDD, ADHD and BIP were all significantly associated with the EF-PC. For each EF component, the association results were different for the PRSs of the five psychiatric disorders: the PRSs for ADHD and MDD were associated with inhibitory control (adjusted P = 0.0183 and 0.0313, respectively), the PRS for BIP was associated with working memory (adjusted P = 0.0416), and the PRS for SZ was associated with cognitive flexibility (adjusted P = 0.0335). All three EF measures were significantly correlated with ADHD symptoms. In mediation analyses, the ADHD and MDD PRSs, which were associated with inhibitory control, had significant indirect effects on ADHD symptoms through the mediation of inhibitory control. These findings indicate that the polygenic risks for several psychiatric disorders influence specific executive dysfunction in children with ADHD. The results helped to clarify the relationship between risk genes of each mental disorder and the intermediate cognitive domain, which may further help elucidate the risk genes and motivate efforts to develop EF measures as a diagnostic marker and future treatment target.


Akt-mediated phosphorylation of Bmi1 modulates its oncogenic potential, E3 ligase activity, and DNA damage repair activity in mouse prostate cancer.
Prostate cancer (PCa) is a major lethal malignancy in men, but the molecular events and their interplay underlying prostate carcinogenesis remain poorly understood. Epigenetic events and the upregulation of polycomb group silencing proteins including Bmi1 have been described to occur during PCa progression. Here, we found that conditional overexpression of Bmi1 in mice induced prostatic intraepithelial neoplasia, and elicited invasive adenocarcinoma when combined with PTEN haploinsufficiency. In addition, Bmi1 and the PI3K/Akt pathway were coactivated in a substantial fraction of human high-grade tumors. We found that Akt mediated Bmi1 phosphorylation, enhancing its oncogenic potential in an Ink4a/Arf-independent manner. This process also modulated the DNA damage response and affected genomic stability. Together, our findings demonstrate the etiological role of Bmi1 in PCa, unravel an oncogenic collaboration between Bmi1 and the PI3K/Akt pathway, and provide mechanistic insights into the modulation of Bmi1 function by phosphorylation during prostate carcinogenesis.


In vitro and in vivo activity of ATP-based kinase inhibitors AP23464 and AP23848 against activation-loop mutants of Kit.
Oncogenic mutations of the Kit receptor tyrosine kinase occur in several types of malignancy. Juxtamembrane domain mutations are common in gastrointestinal stromal tumors, whereas mutations in the kinase activation loop, most commonly D816V, are seen in systemic mastocytosis and acute myelogenous leukemia. Kit activation-loop mutants are insensitive to imatinib mesylate and have been largely resistant to targeted inhibition. We determined the sensitivities of both Kit mutant classes to the adenosine triphosphate (ATP)-based inhibitors AP23464 and AP23848. In cell lines expressing activation-loop mutants, low-nM concentrations of AP23464 inhibited phosphorylation of Kit and its downstream targets Akt and signal transducer and activator of transcription 3 (STAT3). This was associated with cell-cycle arrest and apoptosis. Wild-type Kit-and juxtamembrane-mutant-expressing cell lines required considerably higher concentrations for equivalent inhibition, suggesting a therapeutic window in which cells harboring D816V Kit could be eliminated without interfering with normal cellular function. Additionally, AP23464 did not disrupt normal hematopoietic progenitor-cell growth at concentrations that inhibited activation-loop mutants of Kit. In a murine model, AP23848 inhibited activation-loop mutant Kit phosphorylation and tumor growth. Thus, AP23464 and AP23848 potently and selectively target activation-loop mutants of Kit in vitro and in vivo and could have therapeutic potential against D816V-expressing malignancies.


Ecological approaches and the development of "truly integrated" pest management.
Recent predictions of growth in human populations and food supply suggest that there will be a need to substantially increase food production in the near future. One possible approach to meeting this demand, at least in part, is the control of pests and diseases, which currently cause a 30-40% loss in available crop production. In recent years, strategies for controlling pests and diseases have tended to focus on short-term, single-technology interventions, particularly chemical pesticides. This model frequently applies even where so-called integrated pest management strategies are used because in reality, these often are dominated by single technologies (e.g., biocontrol, host plant resistance, or biopesticides) that are used as replacements for chemicals. Very little attention is given to the interaction or compatibility of the different technologies used. Unfortunately, evidence suggests that such approaches rarely yield satisfactory results and are unlikely to provide sustainable pest control solutions for the future. Drawing on two case histories, this paper demonstrates that by increasing our basic understanding of how individual pest control technologies act and interact, new opportunities for improving pest control can be revealed. This approach stresses the need to break away from the existing single-technology, pesticide-dominated paradigm and to adopt a more ecological approach built around a fundamental understanding of population biology at the local farm level and the true integration of renewable technologies such as host plant resistance and natural biological control, which are available to even the most resource-poor farmers.


The influence of shoe aging on children running biomechanics.
Athletic children are prone to overuse injuries, especially at the heel and knee. Since footwear is an extrinsic factor of lower limb injury risk, the aim of this study was to assess the influence of shoe aging on children running biomechanics. Fourteen children active in sports participated in a laboratory biomechanical evaluation. A new pair of shoes was provided to each participant at an inclusion visit. Four months later, the participants performed a running task and their kinematics and kinetics were assessed both with their used shoes and with a new pair of shoes identical to the first. Furthermore, mechanical cushioning properties of shoes were evaluated before and after in-vivo aging. After 4months of use, the sole stiffness increased by 16% and the energy loss capacity decreased by 18% (p<0.001). No ankle or knee kinematic adjustment was found at foot strike in used shoes but changes were observed later during stance. Running with used shoes produced a higher loading rate of the vertical ground reaction force (+23%, p=0.016), suggesting higher compressive forces under the heel and placing children at risk to experience impact-related injuries. Nevertheless, the decreased peak ankle and knee power absorption in used shoes (-11%, p=0.010 and -12%, p=0.029, respectively) suggests a lower ankle and knee joints loading during the absorption phase that may be beneficial regarding stretch-related injuries.


Technical note: A noninvasive urine collection device for female cattle: modification of the urine cup collection method.
Total urine collection from female cattle requires the use of indwelling urinary catheters or an external device requiring secure attachment with adhesive to the animal; neither method is ideal for the welfare of the cattle. A urine collection device was developed to enable total urine collection in female dairy cattle without the use of adhesive to attach the device to the vulva of the animal; the device was a modification of one described previously for female cattle. The urine collection device was made from polypropylene with maximum dimensions (height x width x depth) of 17.5 x 11.0 x 6.0 cm and an opening of approximately 42 cm(2) to cover the vulva. The device was secured using a commercially available udder support harness that provided snap-fasteners and support for the device to be positioned at the level of the vulva. At the point of attachment, a metal brace surrounded the device and was connected to the udder support by metal rings, which kept the urine cup in proper position as the animal arched to urinate. A metal O-clamp and pieces of rubber, serving as leak-proof washers, connected the bottom of the device to Gooch tubing. Another metal clamp was attached to a polyvinyl chloride adapter that was connected to a rubber hose, and urine was collected into carboys located on the floor approximately 1.5 m behind the animals. This modification of a urine cup allows several noninvasive total feces and urine collection studies of unrestricted length to be undertaken without the use of adhesive to attach the device. The floor-level collection system is a practical, portable, and handy system that will permit researchers to perform nutrient balance and metabolic studies on female cattle.


Fungal degradation of calcium-, lead- and silicon-bearing minerals.
The aim of this study was to examine nutritional influence on the ability of selected filamentous fungi to mediate biogenic weathering of the minerals, apatite, galena and obsidian in order to provide further understanding of the roles of fungi as biogeochemical agents, particularly in relation to the cycling of metals and associated elements found in minerals. The impact of three organic acid producing fungi (Aspergillus niger, Serpula himantioides and Trametes versicolor) on apatite, galena and obsidian was examined in the absence and presence of a carbon and energy source (glucose). Manifestation of fungal weathering included corrosion of mineral surfaces, modification of the mineral substrate through transformation into secondary minerals (i.e. crystal formation) and hyphal penetration of the mineral substrate. Physicochemical interactions of fungal metabolites, e.g. H+ and organic acids, with the minerals are thought to be the primary driving forces responsible. All experimental fungi were capable of mineral surface colonization in the absence and presence of glucose but corrosion of the mineral surface and secondary mineral formation were affected by glucose availability. Only S. himantioides and T. versicolor were able to corrode apatite in the absence of glucose but none of the fungi were capable of doing so with the other minerals. In addition, crystal formation with galena was entirely dependent on the availability of glucose. Penetration of the mineral substrates by fungal hyphae occurred but this did not follow any particular pattern. Although the presence of glucose in the media appeared to influence positively the mineral penetrating abilities of the fungi, the results obtained also showed that some geochemical change(s) might occur under nutrient-limited conditions. It was, however, unclear whether the hyphae actively penetrated the minerals or were growing into pre-existing pores or cracks.


Juvenile songbirds compensate for displacement to oceanic islands during autumn migration.
To what degree juvenile migrant birds are able to correct for orientation errors or wind drift is still largely unknown. We studied the orientation of passerines on the Faroe Islands far off the normal migration routes of European migrants. The ability to compensate for displacement was tested in naturally occurring vagrants presumably displaced by wind and in birds experimentally displaced 1100 km from Denmark to the Faroes. The orientation was studied in orientation cages as well as in the free-flying birds after release by tracking departures using small radio transmitters. Both the naturally displaced and the experimentally displaced birds oriented in more easterly directions on the Faroes than was observed in Denmark prior to displacement. This pattern was even more pronounced in departure directions, perhaps because of wind influence. The clear directional compensation found even in experimentally displaced birds indicates that first-year birds can also possess the ability to correct for displacement in some circumstances, possibly involving either some primitive form of true navigation, or 'sign posts', but the cues used for this are highly speculative. We also found some indications of differences between species in the reaction to displacement. Such differences might be involved in the diversity of results reported in displacement studies so far.


Non-inferiority of short-term urethral catheterization following fistula repair surgery: study protocol for a randomized controlled trial.
A vaginal fistula is a devastating condition, affecting an estimated 2 million girls and women across Africa and Asia. There are numerous challenges associated with providing fistula repair services in developing countries, including limited availability of operating rooms, equipment, surgeons with specialized skills, and funding from local or international donors to support surgeries and subsequent post-operative care. Finding ways of providing services in a more efficient and cost-effective manner, without compromising surgical outcomes and the overall health of the patient, is paramount. Shortening the duration of urethral catheterization following fistula repair surgery would increase treatment capacity, lower costs of services, and potentially lower risk of healthcare-associated infections among fistula patients. There is a lack of empirical evidence supporting any particular length of time for urethral catheterization following fistula repair surgery. This study will examine whether short-term (7 day) urethral catheterization is not worse by more than a minimal relevant difference to longer-term (14 day) urethral catheterization in terms of incidence of fistula repair breakdown among women with simple fistula presenting at study sites for fistula repair service. This study is a facility-based, multicenter, non-inferiority randomized controlled trial (RCT) comparing the new proposed short-term (7 day) urethral catheterization to longer-term (14 day) urethral catheterization in terms of predicting fistula repair breakdown. The primary outcome is fistula repair breakdown up to three months following fistula repair surgery as assessed by a urinary dye test. Secondary outcomes will include repair breakdown one week following catheter removal, intermittent catheterization due to urinary retention and the occurrence of septic or febrile episodes, prolonged hospitalization for medical reasons, catheter blockage, and self-reported residual incontinence. This trial will be conducted among 512 women with simple fistula presenting at 8 study sites for fistula repair surgery over the course of 24 months at each site. If no major safety issues are identified, the data from this trial may facilitate adoption of short-term urethral catheterization following repair of simple fistula in sub-Saharan Africa and Asia. ClinicalTrials.gov Identifier NCT01428830.


Candida virulence properties and adverse clinical outcomes in neonatal candidiasis.
To determine whether premature infants with invasive Candida infection caused by strains with increased virulence properties have worse clinical outcomes than those infected with less virulent strains. Clinical isolates were studied from 2 populations of premature infants, those colonized with Candida spp (commensal; n = 27) and those with invasive candidiasis (n = 81). Individual isolates of C albicans and C parapsilosis were tested for virulence in 3 assays: phenotypic switching, adhesion, and cytotoxicity. Invasive isolates were considered to have enhanced virulence if detected at a level >1 SD above the mean for the commensal isolates in at least one assay. Outcomes of patients with invasive isolates with enhanced virulence were compared with those with invasive isolates lacking enhanced virulence characteristics. Enhanced virulence was detected in 61% of invasive isolates of C albicans and 42% of invasive isolates of C parapsilosis. All C albicans cerebrospinal fluid isolates (n = 6) and 90% of urine isolates (n = 10) had enhanced virulence, compared with 48% of blood isolates (n = 40). Infants with more virulent isolates were younger at the time of positive culture and had higher serum creatinine levels. Individual isolates of Candida species vary in their virulence properties. Strains with higher virulence are associated with certain clinical outcomes.


Epigenetic regulation of gene expression in cervical cancer cells by the tumor microenvironment.
Evidence is accumulating that the adverse tumor microenvironment both modifies the malignant progression of tumor cells and contributes to chemotherapy and radiation resistance. We hypothesized that some of the effects on malignant progression are mediated through the transcriptional regulation of genes responsive to the stresses of the microenvironment, such as low oxygen or low glucose conditions. To determine epigenetic changes in gene expression that were consistent with that hypothesis, we used an in vitro subtractive hybridization method, representational difference analysis, to identify hypoxia-induced cDNAs from cultured human cervical epithelial cells. We identified 12 induced genes: two novel genes (HIG1 and HIG2), three genes known to be hypoxia-inducible (tissue factor, GAPDH, thioredoxin), and seven genes not previously identified as hypoxia-inducible [HNRNP(a1), ribosomal L7, annexin V, lipocortin 2, Ku(70), PRPP synthase, and acetoacetyl-CoA thiolase]. In cultured cells, HIG1 and HIG2 expression is induced by hypoxia and by glucose deprivation, but their expression is not induced by serum deprivation, UV, or ionizing radiation. The putative HIG1 and HIG2 open reading frames are expressed in cells, as confirmed by epitope tagging. In addition, tumor xenografts derived from human cervical cancer cells display increased expression of HIG1 and HIG2 when they are deprived of oxygen. Taken together, these data suggest a coordinated transcriptional response of eukaryotic cells to microenvironmental stresses found in the solid tumor.


Synthesis of the rosette-inducing factor RIF-1 and analogs.
Studies on the origin of animal multicellularity have increasingly focused on one of the closest living relatives of animals, the choanoflagellate Salpingoeca rosetta. Single cells of S. rosetta can develop into multicellular rosette-shaped colonies through a process of incomplete cytokinesis. Unexpectedly, the initiation of rosette development requires bacterially produced small molecules. Previously, our laboratories reported the planar structure and femtomolar rosette-inducing activity of one rosette-inducing small molecule, dubbed rosette-inducing factor 1 (RIF-1), produced by the Gram-negative Bacteroidetes bacterium Algoriphagus machipongonensis. RIF-1 belongs to the small and poorly explored class of sulfonolipids. Here, we report a modular total synthesis of RIF-1 stereoisomers and structural analogs. Rosette-induction assays using synthetic RIF-1 stereoisomers and naturally occurring analogs defined the absolute stereochemistry of RIF-1 and revealed a remarkably restrictive set of structural requirements for inducing rosette development.


Characterization of the hrpF pathogenicity peninsula of Xanthomonas oryzae pv. oryzae.
The hrp gene cluster of Xanthomonas spp. contains genes for the assembly and function of a type III secretion system (TTSS). The hrpF genes reside in a region between hpaB and the right end of the hrp cluster. The region of the hrpF gene of Xanthomonas oryzae pv. oryzae is bounded by two IS elements and also contains a homolog of hpaF of X. campestris pv. vesicatoria and two newly identified genes, hpa3 and hpa4. A comparison of the hrp gene clusters of different species of Xanthomonas revealed that the hrpF region is a constant yet more variable peninsula of the hrp pathogenicity island. Mutations in hpaF, hpa3, and hpa4 had no effect on virulence, whereas hrpF mutants were severely reduced in virulence on susceptible rice cultivars. The hrpF genes from X. campestris pv. vesicatoria, X. campestris pv. campestris, and X. axonopodis pv. citri each were capable of restoring virulence to the hrpF mutant of X. oryzae pv. oryzae. Correspondingly, none of the Xanthomonas pathovars with hrpF from X. oryzae pv. oryzae elicited a hypersensitive reaction in their respective hosts. Therefore, no evidence was found for hrpF as a host-specialization factor. In contrast to the loss of Bs3-dependent reactions by hrpF mutants of X. campestris pv. vesicatoria, hrpF mutants of X. oryzae pv. oryzae with either avrXa10 or avrXa7 elicited hypersensitive reactions in rice cultivars with the corresponding R genes. A double hrpFxoo-hpa1 mutant also elicited an Xa10-dependent resistance reaction. Thus, loss of hrpF, hpal, or both may reduce delivery or effectiveness of type III effectors. However, the mutations did not completely prevent the delivery of effectors from X. oryzae pv. oryzae into the host cells.


Antifungal Activity of Gallic Acid In Vitro and In Vivo.
Gallic acid (GA) is a polyphenol natural compound found in many medicinal plant species, including pomegranate rind (Punica granatum L.), and has been shown to have antiinflammatory and antibacterial properties. Pomegranate rind is used to treat bacterial and fungal pathogens in Uyghur and other systems of traditional medicine, but, surprisingly, the effects of GA on antifungal activity have not yet been reported. In this study, we aimed to investigate the inhibitory effects of GA on fungal strains both in vitro and in vivo. The minimal inhibitory concentration (MIC) was determined by the NCCLS (M38-A and M27-A2) standard method in vitro, and GA was found to have a broad spectrum of antifungal activity, with MICs for all the tested dermatophyte strains between 43.75 and 83.33 μg/mL. Gallic acid was also active against three Candida strains, with MICs between 12.5 and 100.0 μg/mL. The most sensitive Candida species was Candida albicans (MIC = 12.5 μg/mL), and the most sensitive filamentous species was Trichophyton rubrum (MIC = 43.75 μg/mL), which was comparable in potency to the control, fluconazole. The mechanism of action was investigated for inhibition of ergosterol biosynthesis using an HPLC-based assay and an enzyme linked immunosorbent assay. Gallic acid reduced the activity of sterol 14α-demethylase P450 (CYP51) and squalene epoxidase in the T. rubrum membrane, respectively. In vivo model demonstrated that intraperitoneal injection administration of GA (80 mg/kg d) significantly enhanced the cure rate in a mice infection model of systemic fungal infection. Overall, our results confirm the antifungal effects of GA and suggest a mechanism of action, suggesting that GA has the potential to be developed further as a natural antifungal agent for clinical use. Copyright © 2017 John Wiley & Sons, Ltd.


Application of an OCT-based 3D reconstruction framework to the hemodynamic assessment of an ulcerated coronary artery plaque.
The rupture of a vulnerable plaque, known as ulceration, is the most common cause of myocardial infarction. It can be recognized by angiographic features, such as prolonged intraluminal filling and delayed clearance of the contrast liquid. The diagnosis of such an event is an open challenge due to the limited angiographic resolution and acquisition frequency. The treatment of ulcerated plaques is an open discussion, due to the high heterogeneity and the lack of evidences that support particular strategies. Therefore, the therapeutic decision should follow a detailed investigation with angiography and intravascular imaging, such as optical coherence tomography (OCT), to locate the lesion, besides its geometric features and the lumen occlusion severity. The aim of this study is the application of a framework for the in-silico analysis of the disrupted hemodynamics due to an ulcerated lesion. The study employed a validated OCT-based reconstruction methodology and computational fluid dynamics (CFD) simulations for the computation of local hemodynamic quantities, such as wall shear stress. The reported findings, such as disrupted pre-operative flow conditions, proved the applicability of the developed framework for CFD analyses on complicated patient-specific anatomies that feature ulcerated plaques. The prediction of lesion expansion and the clinical decision making can benefit from a reliable computation of wall shear stress distributions that result from the peculiar anatomy of the lesion. The application of intravascular OCT imaging, high fidelity 3D reconstructions and CFD simulations might guide the treatment of such pathology.


Parieto-occipital areas involved in efficient filtering in search: a time course analysis of visual marking using behavioural and functional imaging procedures.
Search for a colour-form conjunction target can be facilitated by presenting one set of distractors prior to the second set of distractors and the target: the preview benefit (Watson & Humphreys, 1997). The early presentation of one set of distractors enables them to be efficiently filtered from search. We report two studies investigating the time course of the preview benefit. In Experiment 1 we use a standard reaction time analysis to show that the benefit has a relatively slow time course; old items need to precede the new set by 600 ms or more in order to be fully filtered from search. Furthermore, the reductions in reaction time across time in the preview condition varied nonlinearly with the display size, suggesting that old items were discounted from search in parallel. In Experiment 2 we examined the neural locus of this filtering effect over time, using positron emission tomography (PET). We show that regions of parieto-occipital cortex are selectively activated in a preview search condition relative to a detection baseline. These regions also increase in activation as the preview interval increases (and search then becomes easier), consistent with them modulating the parallel filtering of distractors from targets in spatial search. Interestingly, the same areas as those activated in preview search were also active in conjunction search relative to its own detection baseline. Thus these regions either modulate parallel filtering in conjunction search too, or they modulate different behavioural functions according to task constraints.


Disparities in child access to emergency care for acute oral injury.
We examined the impact of insurance status on dental practices' willingness to schedule an appointment for a child with a symptomatic fractured permanent front tooth. Between February and May 2010, 6 research assistants posed as mothers of a 10-year-old boy seeking an urgent dental appointment. Two calls 4 weeks apart, with the same clinical scenario, were made by the same caller to a stratified random sample of dental practices, one-half of which were enrolled in the state's combined Medicaid and Children's Health Insurance Program (CHIP) dental program. The only difference in the calls was the child's insurance coverage (Medicaid/CHIP versus private Blue Cross dental coverage). We estimated differences in the log-odds probability of scheduling an appointment for a child with public versus private insurance by using exact conditional (fixed-effects) logistic regression, which accounts for paired data. Of 170 paired calls to 85 dental practices (41 participating in the Medicaid program), only 36.5% of Medicaid beneficiaries obtained any appointment compared with 95.4% of Blue Cross-insured children with the same oral injury. Among dental providers enrolled in the Medicaid program, children with Medicaid were still 18.2 times more likely to be denied an appointment than privately insured counterparts (95% confidence interval: 3.1 to ∞; P < .001). Illinois dentists, including those participating in Medicaid, are less likely to see a child for an urgent dental complaint if the child has public versus private dental coverage. These results have implications for developing policies that improve access to oral health care.


Recombinant human growth hormone plus recombinant human insulin-like growth factor-1 coadministration therapy in short children with low insulin-like growth factor-1 and growth hormone sufficiency: results from a randomized, multicenter, open-label, parallel-group, active treatment-controlled trial.
Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) both contribute to growth. To determine if recombinant human (rh)GH + rhIGF-1 therapy is more effective than rhGH alone to treat short stature, we assessed the efficacy and safety of coadministered rhGH + rhIGF-1 in short children with GH sufficiency and low IGF-1. In a 3-year, randomized, multicenter, open-label trial, patients with height SD score ≤-2.0 and IGF-1 SD score ≤-1.0 for age and sex, and with stimulated GH ≥10 ng/ml for age and sex, were randomized to receive (all doses in µg/kg/day): 45 rhGH alone (group A), 45 rhGH + 50 rhIGF-1 (group B), 45 rhGH + 100 rhIGF-1 (group C) or 45 rhGH + 150 rhIGF-1 (group D). Height velocity (HV) and Δ height SD score were measured. The first-year HV (modified intention-to-treat population) was 9.3 ± 1.7 cm/year (group A), 10.1 ± 1.3 cm/year (group B), 9.7 ± 2.5 cm/year (group C) and 11.2 ± 2.1 cm/year (group D) (p = 0.001 for groups A vs. D). This effect was sustained, resulting in a height SD score improvement during the second and third years. Most treatment-emergent adverse events were mild and transient. In children with short stature, GH sufficiency and low IGF-1, coadministration of rhGH/rhIGF-1 (45/150 µg/kg) significantly accelerated linear growth compared with rhGH alone, with a safety profile similar to the individual monotherapies.


Glomerular membranopathy in children with IgA nephropathy and Henoch Schönlein purpura.
We evaluated renal biopsies from 34 children with IgA nephropathy or Henoch Schönlein purpura to further characterize the ultrastructural features of the glomerular membranopathy that occurs in these disorders. Focal glomerular basement membrane damage was identified in 29 children and was severe in 4 of the children. Alterations included focal and segmental attenuation, splitting, duplications, and spike-like subepithelial protrusions of the lamina densa, along with saccular glomerular microaneurysms arising at the paramesangium. Those cases with extensive glomerular basement membrane lesions had either moderate or severe glomerular alterations apparent by light microscopy. Over half of the cases with glomerular membranopathy had immunohistological or ultrastructural evidence of focal peripheral glomerular capillary wall immune deposits and electron-dense deposits occurred at sites of glomerular basement membrane splitting. Despite the focal attenuation of the glomerular basement membrane, we did not identify any biopsy with findings of thin basement membrane disease. The glomerular basement membrane ultrastructural findings we describe are characteristic of IgA nephropathy and Henoch Schönlein purpura, are common in children with these disorders, and are similar to the ultrastructural alterations of the basement membrane that occur in other glomerulonephritides. These basement membrane injuries may be inflammatory cell or immune mediated but their pathogenesis requires further study.


Pancreatic cancer risk in Peutz-Jeghers syndrome patients: a large cohort study and implications for surveillance.
Although Peutz-Jeghers syndrome (PJS) is known to be associated with pancreatic cancer (PC), estimates of this risk differ widely. This hampers counselling of patients and implementation of surveillance strategies. We therefore aimed to determine the PC risk in a large cohort of Dutch PJS patients. PJS was defined by diagnostic criteria recommended by the WHO, a proven LKB1 mutation, or both. All patients with a presumptive diagnosis of pancreatic, ampullary or distal bile duct cancer were identified. Cases were reviewed clinically, radiologically and immunohistochemically. Cumulative PC risks were calculated by Kaplan-Meier analysis and relative risks by Poisson regression analysis. We included 144 PJS patients (49% male) from 61 families (5640 person years follow-up). Seven (5%) patients developed PC at a median age of 54 years. Four patients (3%) were diagnosed with distal bile duct (n=2) or ampullary cancer (n=2) at a median age of 55 years. The cumulative risk for PC was 26% (95% CI 4% to 47%) at age 70 years and relative risk was 76 (95% CI 36 to 160; p<0.001). The cumulative risk for pancreatico-biliary cancer was 32% (95% CI 11% to 52%) at age 70 years, with a relative risk of 96 (95% CI 53 to 174; p<0.001). PJS patients have a highly increased risk for pancreatico-biliary cancer. Therefore, patients are eligible for surveillance within well defined research programmes to establish the benefit of such surveillance.


Novel treatment approaches to fibrosis in scleroderma.
The molecular mechanisms leading to tissue fibrosis were only poorly understood in the past, and even today the cause or trigger of systemic sclerosis is still unknown. Remarkable breakthrough findings have been obtained regarding the identification of key molecules, key cellular mechanisms, and key intracellular signaling cascades, which mediate the perpetuation of fibrosis rather than trigger it. These findings have true translational implications, because modifiers of these key mediators and key mechanisms are often in clinical use in other disease indications, such as cancer. This article summarizes the clinical and preclinical evidence of examples of these novel antifibrotic treatment approaches in systemic sclerosis, including stem cell transplantation, modifiers of transforming growth factor-beta1 signaling, intravenous immunoglobulins, tyrosine kinase inhibitors, and histone deacetylase inhibitors.


Differential regulation of genes transcribed by nucleus-encoded plastid RNA polymerase, and DNA amplification, within ribosome-deficient plastids in stable phenocopies of cereal albino mutants.
We isolated stable albino plants of barley and maize by inhibiting plastid protein synthesis with streptomycin and propagating bleached seedlings in the absence of antibiotics in vitro. Albino plants are deficient in plastid translation products and plastid ribosomal RNAs, and are stable phenocopies of the barley albostrians and maize iojap mutants, which contain ribosome-free plastids. Once plastid ribosomes are lost they cannot be re-synthesized because about one-third of plastid ribosomal proteins are themselves plastid encoded. The group II/subgroup IIA intron in plastid rpl2 transcripts was not processed in albinos, providing strong evidence for the absence of plastid translation. Photosynthesis-related plastid mRNAs and plastid tRNAs were down-regulated in albino leaves. A differential influence of plastid ribosome deficiency on mRNA levels allowed us to divide genes transcribed by nucleus-encoded plastid RNA polymerase into two groups. Northern analysis revealed increases in the levels of clpP, rpl2, rpl23, rps15 and rpoB mRNAs in total RNA from albino leaves relative to those in green leaves. In contrast, albinism did not increase the band intensities of rps2 and rps4 messages. Plastid ribosome-associated factor(s) or plastid-encoded product(s) play a role in the initiation, termination, processing or stability of transcripts containing trnG(UCC) and rps4. Excision and 100-fold amplification of a 5.2-kb region of plastid DNA encompassing the trnG(UCC) and trnE(UUC) genes was observed in one of four albino barley plants. Gene amplification was correlated with the accumulation of abundant novel transcripts derived from regions flanking the trnG(UCC) gene.


Association between light exposure at night and manic symptoms in bipolar disorder: cross-sectional analysis of the APPLE cohort.
Previous studies have found that keeping the room dark at night was associated with a decrease in manic symptoms for patients with bipolar disorder (BD). However, the association between light at night of real-life conditions and manic symptoms is unclear. We investigated the association between bedroom light exposure at night and manic symptoms in BD patients. One-hundred and eighty-four outpatients with BD participated in this cross-sectional study. The average light intensity at night during sleep was evaluated using a portable photometer for seven consecutive nights. Manic symptoms were assessed using the Young Mania Rating Scale (YMRS), and scores ≥5 were treated as a "hypomanic state." The median (interquartile range) YMRS score was 2.0 (0-5.0), and 52 (28.2%) participants were in a hypomanic state. The prevalence of a hypomanic state was significantly higher in the participants with an average light intensity at night exposure of ≥3 lux than in those with <3 lux (36.7% versus 21.9%; P = .02). In multivariable logistic regression analysis adjusted for BD type, depressive symptoms, sleep duration, and daytime physical activity, the odds ratio (OR) for a hypomanic state was significantly higher for the participants with an average light intensity at night exposure of ≥3 lux than for those with <3 lux (OR: 2.15, 95% confidence interval: 1.09-4.22, P = .02). This association remained significant at the cutoff value of YMRS score ≥6 (OR: 2.51, 95% confidence interval: 1.15-5.46; P = .02). The findings of this study indicate bedroom light exposure at night is significantly associated with manic symptoms in BD patients. Although the results of this cross-sectional investigation do not necessarily imply causality, they may serve to inform beneficial nonpharmacological intervention and personalized treatment of BD patients.


Amycolatopsis palatopharyngis sp. nov., a potentially pathogenic actinomycete isolated from a human clinical source.
The taxonomic position of an actinomycete, strain 1BDZ(T), isolated from a clinical human source was determined using a polyphasic approach. Phylogenetic analysis based on almost complete 16S rDNA sequences showed that this organism consistently formed a distinct line with the Amycolatopsis methanolica subclade within the genus Amycolatopsis, and shared moderately low 16S rDNA similarity (<96.5 %) with other species. The organism was also found to have chemical and morphological properties typical of members of the genus Amycolatopsis. A range of phenotypic characteristics readily distinguished this strain from representatives of all species of Amycolatopsis with validly published names. On the basis of these data, a novel species, Amycolatopsis palatopharyngis sp. nov., is proposed to accommodate strain 1BDZ(T) (=AS 4.1729(T)=PCM 2600(T)).


Exploring and explaining low participation in physical activity among children and young people with asthma: a review.
Asthma is the most common chronic illness among children and accounts for 1 in 5 of all child GP consultations. This paper reviews and discusses recent literature outlining the growing problem of physical inactivity among young people with asthma and explores the psychosocial dimensions that may explain inactivity levels and potentially relevant interventions and strategies, and the principles that should underpin them. A narrative review based on an extensive and documented search of search of CinAHL, Embase, Medline, PsycINFO and the Cochrane Library. Children and young people with asthma are generally less active than their non-asthmatic peers. Reduced participation may be influenced by organisational policies, family illness beliefs and behaviours, health care advice, and inaccurate symptom perception and attribution. Schools can be reluctant to encourage children to take part in physical education or normal play activity due to misunderstanding and a lack of clear corporate guidance. Families may accept a child's low level of activity if it is perceived that breathlessness or the need to take extra inhalers is harmful. Many young people themselves appear to accept sub-optimal control of symptoms and frequently misinterpret healthy shortness of breath on exercising with the symptoms of an impending asthma attack. A multi-faceted approach is needed to translate the rhetoric of increasing activity levels in young people to the reality of improved fitness. Physical activity leading to improved fitness should become part of a goal orientated management strategy by schools, families, health care professionals and individuals. Exercise induced asthma should be regarded as a marker of poor control and a need to increase fitness rather as an excuse for inactivity. Individuals' perceptual accuracy deserves further research attention.


Management of Brain Metastases in Patients With Melanoma.
Melanoma is the third most common systemic cancer that leads to brain metastases. The annual incidence of melanoma has increased over time, with brain metastases developing in 40% to 50% of patients with advanced melanoma. Traditional management of melanoma-related brain metastases has focused on symptom control as a result of the significant neurologic morbidity associated with the disease. Median overall survival for these patients, if untreated, is approximately 3 months. As with other brain metastases, a multidisciplinary treatment approach that includes surgery and radiation therapy is typically used, with historically little role for systemic, cytotoxic therapy. During the past decade, advancement within the field of genomics has led to the identification of melanoma-specific mutations, namely, v-Raf murine sarcoma viral oncogene homolog B and neuroblastoma RAS viral oncogene homolog, as well as to the development of agents that target these driver mutations. In addition, the advent of immunotherapies, specifically, agents that target cytotoxic T-lymphocyte antigen-4, anti-programmed death-1, and programmed death ligand-1, has increased the potential therapeutic options available to patients with both systemic and brain disease. With these advances, early trials have demonstrated improved overall survival in patients with brain metastases who receive these therapies either as single agents or as part of multimodality treatment regimens.


Mapping standard ophthalmic outcome sets to metrics currently reported in eight eye hospitals.
To determine alignment of proposed international standard outcomes sets for ophthalmic conditions to metrics currently reported by eye hospitals. Mixed methods comparative benchmark study, including eight eye hospitals in Australia, India, Singapore, Sweden, U.K., and U.S. All are major international tertiary care and training centers in ophthalmology. Main outcome measure is consistency of ophthalmic outcomes measures reported. International agreed standard outcomes (ICHOM) sets are available for cataract surgery (10 metrics) and macular degeneration (7 metrics). The eight hospitals reported 22 different metrics for cataract surgery and 2 for macular degeneration, which showed only limited overlap with the proposed ICHOM metrics. None of the hospitals reported patient reported visual functioning or vision-related quality of life outcomes measures (PROMs). Three hospitals (38%) reported rates for uncomplicated cataract surgeries only. There was marked variation in how and at what point postoperatively visual outcomes following cataract, cornea, glaucoma, strabismus and oculoplastics procedures were reported. Seven (87.5%) measured post-operative infections and four (50%) measured 30 day unplanned reoperation rates. Outcomes reporting for ophthalmic conditions currently widely varies across hospitals internationally and does not include patient-reported outcomes. Reaching consensus on measures and consistency in data collection will allow meaningful comparisons and provide an evidence base enabling improved sharing of "best practices" to improve eye care globally. Implementation of international standards is still a major challenge and practice-based knowledge on measures should be one of the inputs of the international standardization process.


Modelling intracellular H(+) ion diffusion.
Intracellular pH, an important modulator of cell function, is regulated by plasmalemmal proteins that transport H(+), or its equivalent, into or out of the cell. The pH(i) is also stabilised by high-capacity, intrinsic buffering on cytoplasmic proteins, oligopeptides and other solutes, and by the extrinsic CO(2)/HCO(3)(-) (carbonic) buffer. As mobility of these buffers is lower than for the H(+) ion, they restrict proton diffusion. In this paper we use computational approaches, based on the finite difference and finite element methods (FDM and FEM, respectively), for analysing the spatio-temporal behaviour of [H(+)] when it is locally perturbed. We analyse experimental data obtained for various cell-types (cardiac myocytes, duodenal enterocytes, molluscan neurons) where pH(i) has been imaged confocally using intracellular pH-sensitive dyes. We design mathematical algorithms to generate solutions for two-dimensional diffusion that fit data in terms of an apparent intracellular H(+) diffusion coefficient, D(H)(app). The models are used to explore how the spatial distribution of [H(+)](i) is affected by membrane H(+)-equivalent transport and by cell geometry. We then develop a mechanistic model, describing spatio-temporal changes of [H(+)](i) in a cardiac ventricular myocyte in terms of H(+)-shuttling on mobile buffers and H(+)-anchoring on fixed buffers. We also discuss how modelling may include the effects of extrinsic carbonic-buffering. Overall, our computational approach provides a framework for future analyses of the physiological consequences of pH(i) non-uniformity.