Characterization of a Halotolerant Fungus from a Marine Sponge.
Marine sponges have established symbiotic interactions with a large number of microorganisms including fungi. Most of the studies so far have focussed on the characterization of sponge-associated bacteria and archaea with only a few reports on sponge-associated fungi. During the isolation and characterization of bacteria from marine sponges of South Australia, we observed multiple types of fungi. One isolate in particular was selected for further investigation due to its unusually large size and being chromogenic. Here, we report on the investigations on the physical, morphological, chemical, and genotypic properties of this yeast-like fungus. Sponge samples were collected from South Australian marine environments, and microbes were isolated using different isolation media under various incubation conditions. Microbial isolates were identified on the basis of morphology, staining characteristics, and their 16S rRNA or ITS/28S rRNA gene sequences. Twelve types of yeast and fungal isolates were detected together with other bacteria and one of these fungi measured up to 35 μm in diameter with a unique chromogen compared to other fungi. Depending on the medium type, this unique fungal isolate appeared as yeast-like fungi with different morphological forms. The isolate can ferment and assimilate nearly all of the tested carbohydrates. Furthermore, it tolerated a high concentration of salt (up to 25%) and a range of pH and temperature. ITS and 28S rRNA gene sequencing revealed a sequence similarity of 93% and 98%, respectively, with the closest genera of Eupenidiella, Hortaea, and Stenella. On the basis of its peculiar morphology, size, and genetic data, this yeast-like fungus possibly constitutes a new genus and the name Magnuscella marinae, gen nov., sp. nov., is proposed. This study is the first of its kind for the complete characterization of a yeast-like fungus from marine sponges. This novel isolate developed a symbiotic interaction with living hosts, which was not observed with other reported closest genera (they exist in a saprophytic relationship). The observed unique size and morphology may favour this new isolate to establish symbiotic interactions with living hosts.


Prognostication after cardiac arrest and hypothermia: a prospective study.
Current American Academy of Neurology (AAN) guidelines for outcome prediction in comatose survivors of cardiac arrest (CA) have been validated before the therapeutic hypothermia era (TH). We undertook this study to verify the prognostic value of clinical and electrophysiological variables in the TH setting. A total of 111 consecutive comatose survivors of CA treated with TH were prospectively studied over a 3-year period. Neurological examination, electroencephalography (EEG), and somatosensory evoked potentials (SSEP) were performed immediately after TH, at normothermia and off sedation. Neurological recovery was assessed at 3 to 6 months, using Cerebral Performance Categories (CPC). Three clinical variables, assessed within 72 hours after CA, showed higher false-positive mortality predictions as compared with the AAN guidelines: incomplete brainstem reflexes recovery (4% vs 0%), myoclonus (7% vs 0%), and absent motor response to pain (24% vs 0%). Furthermore, unreactive EEG background was incompatible with good long-term neurological recovery (CPC 1-2) and strongly associated with in-hospital mortality (adjusted odds ratio for death, 15.4; 95% confidence interval, 3.3-71.9). The presence of at least 2 independent predictors out of 4 (incomplete brainstem reflexes, myoclonus, unreactive EEG, and absent cortical SSEP) accurately predicted poor long-term neurological recovery (positive predictive value = 1.00); EEG reactivity significantly improved the prognostication. Our data show that TH may modify outcome prediction after CA, implying that some clinical features should be interpreted with more caution in this setting as compared with the AAN guidelines. EEG background reactivity is useful in determining the prognosis after CA treated with TH.


Interrater reliability of three-dimensional reconstruction of the spine : Low-dose stereoradiography for evaluating bracing in adolescent idiopathic scoliosis.
Bracing constitutes the mainstay treatment for mild scoliosis. The 3D reconstruction of the spine using low-dose stereoradiographic imaging (LSI) is increasingly being used to determine the true shape of the deformity and to assess the success of bracing. The aim of the study was to validate the measurement of 3D spinopelvic parameters and vertebral rotation in the setting of bracing treatment via a reliability study conducted in adherence to the guidelines for reporting reliability and agreement studies (GRRAS). Full spine stereoradiographs of patients with adolescent idiopathic scoliosis (AIS) who underwent Chêneau bracing were retrospectively analyzed. The 3D reconstruction was performed by two experienced operators in a blinded manner and randomized order. Rotation of every vertebra was computed in the coronal, sagittal and axial planes. Sagittal spinopelvic parameters were evaluated. All measurements were statistically compared to determine agreement of the measurement of brace correction using the intraclass correlation coefficient (ICC). In this study, 45 patients (81% females) aged 12.5 ± 2 years were included. The mean absolute difference was less than 3.5° for all measured angles, less than 4 mm for sagittal vertical axis (SVA) and less than 1.5 mm for lateral pelvic shift. The ICC was high for all parameters (ICC >0.81). Despite the overall high reliability, the reliability of axial rotation was lower in the upper and middle thoracic spine and the lower lumbar spine. Brace wearing during full spine LSI acquisition does not affect spinal measurements. The LSI under bracing treatment produces reliable measurements of spinopelvic parameters as well as vertebral rotation. These reproducible 3D data enable spine surgeons to assess the true shape of the deformity, to quantify rotation of each vertebra and enhance the understanding of the efficacy of bracing treatment.


GroEL1, from Chlamydia pneumoniae, induces vascular adhesion molecule 1 expression by p37(AUF1) in endothelial cells and hypercholesterolemic rabbit.
The expression of vascular adhesion molecule-1 (VCAM-1) by endothelial cells may play a major role in atherogenesis. The actual mechanisms of chlamydia pneumoniae (C. pneumoniae) relate to atherogenesis are unclear. We investigate the influence of VCAM-1 expression in the GroEL1 from C. pneumoniae-administered human coronary artery endothelial cells (HCAECs) and hypercholesterolemic rabbits. In this study, we constructed the recombinant GroEL1 from C. pneumoniae. The HCAECs/THP-1 adhesion assay, tube formation assay, western blotting, enzyme-linked immunosorbent assay, actinomycin D chase experiment, luciferase reporter assay, and immunohistochemical stainings were performed. The results show that GroEL1 increased both VCAM-1 expression and THP-1 cell adhesives, and impaired tube-formation capacity in the HCAECs. GroEL1 significantly increased the VCAM-1 mRNA stability and cytosolic AU-binding factor 1 (AUF1) level. Overexpression of the p37(AUF1) significantly increased VCAM-1 gene expression in GroEL1-induced bovine aortic endothelial cells (BAECs). GroEL1 prolonged the stability of VCAM-1 mRNA by increasing both p37(AUF1) and the regulation of the 5' untranslated region (UTR) of the VCAM-1 mRNA in BAECs. In hypercholesterolemic rabbits, GroEL1 administration enhanced fatty-streak and macrophage infiltration in atherosclerotic lesions, which may be mediated by elevated VCAM-1 expression. In conclusion, GroEL1 induces VCAM-1 expression by p37(AUF1) in endothelial cells and enhances atherogenesis in hypercholesterolemic rabbits.


Effectiveness of chlorhexidine dressings to prevent catheter-related bloodstream infections. Does one size fit all? A systematic literature review and meta-analysis.
To evaluate the effectiveness of chlorhexidine (CHG) dressings to prevent catheter-related bloodstream infections (CRBSIs). Systematic review and meta-analysis. We searched PubMed, CINAHL, EMBASE, and ClinicalTrials.gov for studies (randomized controlled and quasi-experimental trials) with the following criteria: patients with short- or long-term catheters; CHG dressings were used in the intervention group and nonantimicrobial dressings in the control group; CRBSI was an outcome. Random-effects models were used to obtain pooled risk ratios (pRRs). Heterogeneity was evaluated using the I2 test and the Cochran Q statistic. In total, 20 studies (18 randomized controlled trials; 15,590 catheters) without evidence of publication bias and mainly performed in intensive care units (ICUs) were included. CHG dressings significantly reduced CRBSIs (pRR, 0.71; 95% CI, 0.58-0.87), independent of the CHG dressing type used. Benefits were limited to adults with short-term central venous catheters (CVCs), including onco-hematological patients. For long-term CVCs, CHG dressings decreased exit-site/tunnel infections (pRR, 0.37; 95% CI, 0.22-0.64). Contact dermatitis was associated with CHG dressing use (pRR, 5.16; 95% CI, 2.09-12.70); especially in neonates and pediatric populations in whom severe reactions occurred. Also, 2 studies evaluated and did not find CHG-acquired resistance. CHG dressings prevent CRBSIs in adults with short-term CVCs, including patients with an onco-hematological disease. CHG dressings might reduce exit-site and tunnel infections in long-term CVCs. In neonates and pediatric populations, proof of CHG dressing effectiveness is lacking and there is an increased risk of serious adverse events. Future studies should investigate CHG effectiveness in non-ICU settings and monitor for CHG resistance.


Melatonin restores the mitochondrial production of ATP in septic mice.
To evaluate the changes in the mitochondrial ATP production during sepsis and the participation of iNOS in these changes. We also assessed the effect of melatonin administration in this experimental paradigm. The activity of ATPase, the level of adenine nucleotides, and the ATP production were measured in mitochondria of diaphragm and hind leg skeletal muscle of wild type (iNOS+/+) and knockout iNOS (iNOS-/-) mice. Three experimental groups were done: control group; group of septic mice induced by cecal ligation and puncture (CLP), and group of septic mice treated with melatonin. Mice were killed 24 hours after CLP. Melatonin was administrated in four doses (30 mg/kg b.w.) as follows: 30 min before CLP (i.p.) and 30 min, 4 h and 8 h after CLP (s.c.). Mitochondrial production of ATP decreased in iNOS+/+ but not in iNOS-/- mice after sepsis. No changes in the ATPase activity were found in any group. Melatonin treatment normalized the production of ATP in iNOS+/+ mice, without affecting iNOS-/- animals. The reduction of the ATP production in iNOS+/+ but not in iNOS-/- mice suggest the participation of iNOS in the impairment of mitochondrial function in the former. Because ATPase was unaffected by sepsis, it is suggested the ATP deficit depended on the sepsis-induced respiratory chain damage. The normalization of the production of ATP with melatonin may explain the reduction of the mortality reported elsewhere in experimental and clinical sepsis after treatment with the indoleamine.


Pilot-wave dynamics in a harmonic potential: Quantization and stability of circular orbits.
We present the results of a theoretical investigation of the dynamics of a droplet walking on a vibrating fluid bath under the influence of a harmonic potential. The walking droplet's horizontal motion is described by an integro-differential trajectory equation, which is found to admit steady orbital solutions. Predictions for the dependence of the orbital radius and frequency on the strength of the radial harmonic force field agree favorably with experimental data. The orbital quantization is rationalized through an analysis of the orbital solutions. The predicted dependence of the orbital stability on system parameters is compared with experimental data and the limitations of the model are discussed.


Dia2 controls transcription by mediating assembly of the RSC complex.
Dia2 is an F-box protein found in the budding yeast, S. cerevisiae. Together with Skp1 and Cul1, Dia2 forms the substrate-determining part of an E3 ubiquitin ligase complex, otherwise known as the SCF. Dia2 has previously been implicated in the control of replication and genome stability via its interaction with the replisome progression complex. We identified components of the RSC chromatin remodelling complex as genetic interactors with Dia2, suggesting an additional role for Dia2 in the regulation of transcription. We show that Dia2 is involved in controlling assembly of the RSC complex. RSC belongs to a group of ATP-dependent nucleosome-remodelling complexes that controls the repositioning of nucleosomes. The RSC complex is expressed abundantly and its 17 subunits are recruited to chromatin in response to both transcription activation and repression. In the absence of Dia2, RSC-mediated transcription regulation was impaired, with concomitant abnormalities in nucleosome positioning. Our findings imply that Dia2 is required for the correct assembly and function of the RSC complex. Dia2, by controlling the RSC chromatin remodeller, fine-tunes transcription by controlling nucleosome positioning during transcriptional activation and repression.


Immunocytochemical analysis of the human osteoclast: phenotypic relationship to other marrow-derived cells.
The immunocytochemistry of the osteoclast, which is known to be derived from a circulating mononuclear precursor cell of bone marrow origin, is controversial. In this study, we have determined the antigenic phenotype of human osteoclasts in fetal and adult (Paget's disease, giant cell tumour of bone) specimens using a large number of monoclonal antibodies which react with granulocytes and mononuclear phagocytes. We have identified antibodies which reacted with human osteoclasts including CD13, CD15 and several groups of anti-macrophage antibodies. All the antibodies which reacted with osteoclasts are also known to react with monocytes or macrophages. Other marrow elements such as granulocytes, megakaryocytes and platelets were also commonly stained. Expression of myeloid and platelet antigens on osteoclasts shows that they are phenotypically related to these cells and is in keeping with the origin of osteoclast precursors from the pluripotential haemopoietic stem cell. Only a proportion of osteoclasts in fetal bone preparations were stained by CD15 antibodies, suggesting that subsets or different populations of osteoclasts, which can be identified by monoclonal antibodies, may be present in bone.


Comparison of the metabolic and economic consequences of long-term treatment of schizophrenia using ziprasidone, olanzapine, quetiapine and risperidone in Canada: a cost-effectiveness analysis.
Second-generation antipsychotic agents have varying propensities to cause weight gain, elevated lipid levels and associated long-term complications. This study evaluates the cost-effectiveness of four second-generation antipsychotic agents used in Canada for the treatment of schizophrenia (ziprasidone, olanzapine, quetiapine, risperidone) with a focus on their long-term metabolic consequences. Using data from the Clinical Antipsychotic Trials of Intervention Effectiveness Study, a semi-Markov model was developed to predict the incidence and associated costs of type 2 diabetes, cardiovascular complications (e.g. angina, myocardial infarction, stroke, cardiovascular disease death), and acute psychiatric hospitalizations in patients with chronic schizophrenia treated over 5 years. Incremental costs per quality-adjusted life year (QALY) gained were calculated from the perspective of the Canadian provincial ministries of health. Scenario and probabilistic sensitivity analyses were performed. The total average cost of treatment with ziprasidone was $25,301 versus $28,563 with olanzapine, $26,233 with quetiapine and $21,831 with risperidone. Ziprasidone had the lowest predicted number of type 2 diabetes cases and cardiovascular disease events, and the highest QALY gains. Patients receiving quetiapine had the highest predicted number of hospitalizations. Ziprasidone was less costly and resulted in more QALYs compared with olanzapine and quetiapine. Compared with risperidone, ziprasidone was more costly and had higher QALYs, with an incremental cost per QALY gained of $218,060. Compared with olanzapine and quetiapine, ziprasidone produced savings to the health care system. Although ziprasidone generated incremental expenditures versus risperidone, it resulted in more QALYs. Based on this analysis, ziprasidone treatment possesses cost and therapeutic advantages compared with olanzapine and quetiapine.


Hematopoietic defects in rps29 mutant zebrafish depend upon p53 activation.
Disruption of ribosomal proteins is associated with hematopoietic phenotypes in cell culture and animal models. Mutations in ribosomal proteins are seen in patients with Diamond Blackfan anemia, a rare congenital disease characterized by red cell aplasia and distinctive craniofacial anomalies. A zebrafish screen uncovered decreased hematopoietic stem cells in embryos with mutations in ribosomal protein rps29. Here, we determined that rps29(-/-) embryos also have red blood cell defects and increased apoptosis in the head. As the p53 pathway has been shown to play a role in other ribosomal protein mutants, we studied the genetic relationship of rps29 and p53. Transcriptional profiling revealed that genes upregulated in the rps29 mutant are enriched for genes upregulated by p53 after irradiation. p53 mutation near completely rescues the rps29 morphological and hematopoietic phenotypes, demonstrating that p53 mediates the effects of rps29 knockdown. We also identified neuronal gene orthopedia protein a (otpa) as one whose expression correlates with rps29 expression, suggesting that levels of expression of some genes are dependent on rps29 levels. Together, our studies demonstrate a role of p53 in mediating the cellular defects associated with rps29 and establish a role for rps29 and p53 in hematopoietic stem cells and red blood cell development.


Campath induction in HCV and HCV/HIV-seropositive kidney transplant recipients.
Alemtuzumab (AZ) induction in hepatitis C-seropositive (HCV+) kidney transplant (KTX) recipients may negatively affect patient survival; however, available information is scant. Using US registry data from 2003 to 2010 of adult HCV+ deceased-donor KTXs (n = 4910), we examined outcomes by induction agent - AZ (n = 294), other T cell-depleting agents, (n = 2033; T cell), IL-2 receptor blockade (n = 1135; IL-2RAb), and no induction (n = 1448). On multivariate analysis, induction therapy was associated with significantly better overall patient survival with AZ [adjusted hazards ratio (aHR) 0.64, 95% confidence interval (CI) 0.45, 0.92], T cell (aHR 0.52, 95% CI 0.41, 0.65) or IL-2RAb (aHR 0.67, 95% CI 0.53, 0.87), compared to no induction. A significant protective effect was also seen with AZ (aHR 0.63, 95% CI 0.40, 0.99), T cell (aHR 0.62, 95% CI 0.49, 0.78), and IL2R-Ab (aHR 0.62, 95% CI 0.47, 0.82) in terms of death-censored graft survival relative to no induction. There were 88 HIV+/HCV+ coinfected recipients. Compared to noninduction, any induction (i.e. three induction groups combined) was associated with similar overall patient survival (P = 0.2255) on univariate analysis. Induction therapy with AZ, other T cell-depleting agents, or IL-2RAb in HCV+ KTX is associated with better patient and death-censored graft survival compared to noninduction. In HCV/HIV coinfected patients, induction is not contraindicated.


Contrast enhancement by differently sized paramagnetic MRI contrast agents in mice with two phenotypes of atherosclerotic plaque.
Interest in the use of contrast-enhanced MRI to enable in vivo specific characterization of atherosclerotic plaques is increasing. In this study the intrinsic ability of three differently sized gadolinium-based contrast agents to permeate different mouse plaque phenotypes was evaluated with MRI. A tapered cast was implanted around the right carotid artery of apoE(-/-) mice to induce two different plaque phenotypes: a thin cap fibroatheroma (TCFA) and a non-TCFA lesion. Both plaques were allowed to develop over 6 and 9 weeks, leading to an intermediate and advanced lesion, respectively. Signal enhancement in the carotid artery wall, following intravenous injection of Gd-HP-DO3A as well as paramagnetic micelles and liposomes was evaluated. In vivo T(1) -weighted MRI plaque enhancement characteristics were complemented by fluorescence microscopy and correlated to lesion phenotype. The two smallest contrast agents, i.e. Gd-HP-DO3A and micelles, were found to enhance contrast in T(1) -weighted MR images of all investigated plaque phenotypes. Maximum contrast enhancement ranged between 53 and 70% at 6 min after injection of Gd-HP-DO3A with highest enhancement and longest retention in the non-TCFA lesion. Twenty-four hours after injection of micelles maximum contrast enhancement ranged between 24 and 35% in all plaque phenotypes. Administration of the larger liposomes did not cause significant contrast enhancement in the atherosclerotic plaques. Confocal fluorescence microscopy confirmed the MRI-based differences in plaque permeation between micelles and liposomes. Plaque permeation of contrast agents was strongly dependent on size. Our results implicate that, when equipped with targeting ligands, liposomes are most suitable for the imaging of plaque-associated endothelial markers due to low background enhancement, whereas micelles, which accumulate extravascularly on a long timescale, are suited for imaging of less abundant markers inside plaques. Low molecular weight compounds may be employed for target-specific imaging of highly abundant extravascular plaque-associated targets.


European Society of Endodontology position statement: Surgical extrusion, intentional replantation and tooth autotransplantation: European Society of Endodontology developed by.
This European Society of Endodontology (ESE) position statement on surgical extrusion, intentional replantation and tooth autotransplantation represents the consensus of an expert committee, convened by the ESE. A narrative review in the International Endodontic Journal (Plotino et al. 2020, international Endodontic Journal, 53, 1636-52) formed the basis for the position statement. The review provided detailed information on the background, clinical procedures and the outcome of surgical extrusion, intentional replantation and tooth autotransplantation techniques. The aim of the current statement is to summarize the best available evidence on these clinical techniques to provide appropriate clinical guidance to undergraduate and postgraduate students, dental practitioners, clinical teachers and researchers. The current position statement will be updated by the ESE periodically to reflect new evidence as it becomes available to provide the most current treatment guidance for clinical practice.


Non-bee insects are important contributors to global crop pollination.
Wild and managed bees are well documented as effective pollinators of global crops of economic importance. However, the contributions by pollinators other than bees have been little explored despite their potential to contribute to crop production and stability in the face of environmental change. Non-bee pollinators include flies, beetles, moths, butterflies, wasps, ants, birds, and bats, among others. Here we focus on non-bee insects and synthesize 39 field studies from five continents that directly measured the crop pollination services provided by non-bees, honey bees, and other bees to compare the relative contributions of these taxa. Non-bees performed 25-50% of the total number of flower visits. Although non-bees were less effective pollinators than bees per flower visit, they made more visits; thus these two factors compensated for each other, resulting in pollination services rendered by non-bees that were similar to those provided by bees. In the subset of studies that measured fruit set, fruit set increased with non-bee insect visits independently of bee visitation rates, indicating that non-bee insects provide a unique benefit that is not provided by bees. We also show that non-bee insects are not as reliant as bees on the presence of remnant natural or seminatural habitat in the surrounding landscape. These results strongly suggest that non-bee insect pollinators play a significant role in global crop production and respond differently than bees to landscape structure, probably making their crop pollination services more robust to changes in land use. Non-bee insects provide a valuable service and provide potential insurance against bee population declines.


Chronic hepatitis C, atherosclerosis and cardiovascular disease: What impact of direct-acting antiviral treatments?
Hepatitis C virus (HCV) infection is associated with extrahepatic manifestations, among these there is an increased risk of atherosclerosis and cardiovascular disease as well as an increased cardiovascular mortality. Several direct and indirect HCV pro-atherogenic mechanisms have been proposed. HCV lives and replicates within carotid plaques, promoting a local environment of pro-atherogenic factors. In addition, it causes conditions such as insulin resistance, diabetes, hepatic steatosis, cryoglobulinemia and endotoxinemia that are associated with the development of atherosclerosis and cardiovascular disease. Therapeutic regimens based on direct-acting antiviral agents (DAA) are currently available with high efficacy in HCV clearance and improvement of liver disease, but does HCV eradication also improve atherosclerosis and the risk of cardiovascular disease? Recently, a multi-center study has shown that elimination of HCV improves carotid atherosclerosis. Two studies have shown that DAA treatments significantly reduce the risk of cardiovascular events. Several studies have assessed the impact of HCV clearance on pro-atherosclerosis metabolic conditions showing improvement in cardiovascular risk biomarkers, disappearance or improvement of insulin resistance, reduction of risk of developing diabetes and improvement of glycemic control. There are also evidences that HCV clearance promotes the recovery of cytokines and inflammatory markers associated with atherosclerosis and the disappearance of cryoglobulinemia. Available data show that clearance of HCV by DAAs is associated with an improvement in atherosclerosis and metabolic and immunological conditions that promote the development of cardiovascular disease. However, the data are not sufficient to allow definitive conclusions and further studies will be needed to definitively clarify the impact of HCV clearance on atherosclerosis and cardiovascular disease.


Target organ damage in newly detected hypertensive patients.
Hypertension (HTN) is difficult to diagnose since it is asymptomatic. Most of the patients with HTN are unaware of their disease, and hence a large number of these subjects have target organ damage (TOD) on their first arrival at hospital or clinic. Hence, early detection and treatment of TOD determines the cardiovascular prognosis in hypertensive patient and can retard or prevent further damage. An observational and cross-sectional study was carried out in a tertiary care hospital and clinical profile was collected. Newly detected hypertensive men and women were recruited from outpatient and inpatient departments of medicine based on a set of inclusion and exclusion criteria. The study was carried out over a duration of 18 months from March 2014 to August 2015. A total of 150 participants were included in the study with a mean age of 51.64 ± 11.64 years. A total of 91 participants had presence of at least one TOD. In our study, retinopathy (20.67%), macroalbuminuria (MA) (44.67%), electrocardiographic left ventricular hypertrophy (LVH) (20.67%), echocardiographic LVH (29.33%), diastolic dysfunction (21.33%), and systolic dysfunction (3.33%) were particularly notable. Grade 3 retinopathy, microalbuminria, and diastolic dysfunction were associated with severity of HTN. We conclude that a strong relationship exists between HTN and TOD. The evidence for TOD was found to be greater than that expected in newly detected hypertensive patients. Hence, a tight control of blood pressure represents the first step in treating essential HTN, which not only keep the blood pressure under control and further steps to be taken to prevent or retard the onset/progression of TOD.


Social Capital and Economic Integration of Migrants in Urban China.
Based on data from a 2005 survey conducted in Shanghai, China, this research examines the role of social capital in income inequality between rural migrants and urbanites. We find strong income return on social capital, in particular on social capital from strong ties. We also observe a great disparity in social capital possession between rural migrants and urban local residents. Although social capital from strong ties seems to be more important for rural migrants than for urbanites, local ties and high-status ties do not seem to benefit rural migrants. Hence, migrants not only suffer severe social capital deficits but also capital return deficits. Given the strong income returns on social capital and the substantial differences in access to and return on social capital between migrants and urban residents, social capital is consequently found to explain a large part of the income inequality between the two groups. Overall, our findings reveal macro-structural effects on the role of social capital in labor market stratification. In China, the lack of formal labor market mechanisms continues to create both a strong need for and opportunities for economic actions to be organized around informal channels via social relations. Yet, the long-standing institutional exclusion of migrants caused by the household registration system has resulted in pervasive social exclusion and discrimination which have substantially limited rural migrants' accumulation and mobilization of social capital. Under these conditions, social capital reinforces the economic inequality between migrants and urban residents in China. Such empirical evidence adds to our understanding of the role of social capital in the economic integration of migrants and in shaping intergroup inequality in general.


Molecular analysis of asymptomatic bacteriuria Escherichia coli strain VR50 reveals adaptation to the urinary tract by gene acquisition.
Urinary tract infections (UTIs) are among the most common infectious diseases of humans, with Escherichia coli responsible for >80% of all cases. One extreme of UTI is asymptomatic bacteriuria (ABU), which occurs as an asymptomatic carrier state that resembles commensalism. To understand the evolution and molecular mechanisms that underpin ABU, the genome of the ABU E. coli strain VR50 was sequenced. Analysis of the complete genome indicated that it most resembles E. coli K-12, with the addition of a 94-kb genomic island (GI-VR50-pheV), eight prophages, and multiple plasmids. GI-VR50-pheV has a mosaic structure and contains genes encoding a number of UTI-associated virulence factors, namely, Afa (afimbrial adhesin), two autotransporter proteins (Ag43 and Sat), and aerobactin. We demonstrated that the presence of this island in VR50 confers its ability to colonize the murine bladder, as a VR50 mutant with GI-VR50-pheV deleted was attenuated in a mouse model of UTI in vivo. We established that Afa is the island-encoded factor responsible for this phenotype using two independent deletion (Afa operon and AfaE adhesin) mutants. E. coli VR50afa and VR50afaE displayed significantly decreased ability to adhere to human bladder epithelial cells. In the mouse model of UTI, VR50afa and VR50afaE displayed reduced bladder colonization compared to wild-type VR50, similar to the colonization level of the GI-VR50-pheV mutant. Our study suggests that E. coli VR50 is a commensal-like strain that has acquired fitness factors that facilitate colonization of the human bladder.


Why additional presentations help identify a stimulus.
Nosofsky (1983) reported that additional stimulus presentations within a trial increase discriminability in absolute identification, suggesting that each presentation creates an independent stimulus representation, but it remains unclear whether exposure duration or the formation of independent representations improves discrimination in such conditions. Experiment 1 replicated Nosofsky's result. Experiments 2 (masking the ISI between two-presentations) and 3 (manipulating stimulus duration without changing number of presentations or overall trial duration) ruled out an explanation in terms of extended opportunities for stimulus sampling, from either a sensory buffer during additional ISIs or increased stimulus exposure, respectively. Experiment 4 (comparing two and three-presentations, other factors controlled) provided some limited additional support for Nosofsky's original claim that additional stimulus presentations can create either independent or duplicate representations. Experiments 5 and 6 (both manipulating ISI) demonstrated that a key factor in the additional stimulus presentation effect is the overall trial duration. We discuss the results in relation to models of absolute identification, their relative emphasis on stimulus sampling versus response selection, and the mechanisms by which duplicate representations could be created.


Is the extrastriate body area part of the dorsal visuomotor stream?
The extrastriate body area (EBA) processes visual information about body parts, and it is considered one among a series of category-specific perceptual modules distributed across the occipito-temporal cortex. However, recent evidence raises the possibility that EBA might also provide an interface between perception and action, linking the ventral and dorsal streams of visual information processing. Here, we assess anatomical evidence supporting this possibility. We localise EBA in individual subjects using a perceptual task and compare the characteristics of its functional and structural connectivity to those of two perceptual areas, the lateral occipital complex (LOC) and the fusiform body area (FBA), separately for each hemisphere. We apply complementary analyses of resting-state fMRI and diffusion-weighted MRI data in a group of healthy right-handed human subjects (N = 31). Functional and structural connectivity profiles indicate that EBA interacts more strongly with dorsal-stream regions compared to other portions of the occipito-temporal cortex involved in processing body parts (FBA) and object identification (LOC). These findings provide anatomical ground for a revision of the functional role of EBA. Building on a number of recent observations, we suggest that EBA contributes to planning goal-directed actions, possibly by specifying a desired postural configuration to parieto-frontal areas involved in computing movement parameters.


Clinical Effectiveness of Direct Oral Anticoagulants vs Warfarin in Older Patients With Atrial Fibrillation and Ischemic Stroke: Findings From the Patient-Centered Research Into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) Study.
Current guidelines recommend direct oral anticoagulants (DOACs) over warfarin for stroke prevention in patients with atrial fibrillation (AF) who are at high risk. Despite demonstrated efficacy in clinical trials, real-world data of DOACs vs warfarin for secondary prevention in patients with ischemic stroke are largely based on administrative claims or have not focused on patient-centered outcomes. To examine the clinical effectiveness of DOACs (dabigatran, rivaroxaban, or apixaban) vs warfarin after ischemic stroke in patients with AF. This cohort study included patients who were 65 years or older, had AF, were anticoagulation naive, and were discharged from 1041 Get With The Guidelines-Stroke-associated hospitals for acute ischemic stroke between October 2011 and December 2014. Data were linked to Medicare claims for long-term outcomes (up to December 2015). Analyses were completed in July 2018. DOACs vs warfarin prescription at discharge. The primary outcomes were home time, a patient-centered measure defined as the total number of days free from death and institutional care after discharge, and major adverse cardiovascular events. A propensity score-overlap weighting method was used to account for differences in observed characteristics between groups. Of 11 662 survivors of acute ischemic stroke (median [interquartile range] age, 80 [74-86] years), 4041 (34.7%) were discharged with DOACs and 7621 with warfarin. Except for National Institutes of Health Stroke Scale scores (median [interquartile range], 4 [1-9] vs 5 [2-11]), baseline characteristics were similar between groups. Patients discharged with DOACs (vs warfarin) had more days at home (mean [SD], 287.2 [114.7] vs 263.0 [127.3] days; adjusted difference, 15.6 [99% CI, 9.0-22.1] days) during the first year postdischarge and were less likely to experience major adverse cardiovascular events (adjusted hazard ratio [aHR], 0.89 [99% CI, 0.83-0.96]). Also, in patients receiving DOACs, there were fewer deaths (aHR, 0.88 [95% CI, 0.82-0.95]; P < .001), all-cause readmissions (aHR, 0.93 [95% CI, 0.88-0.97]; P = .003), cardiovascular readmissions (aHR, 0.92 [95% CI, 0.86-0.99]; P = .02), hemorrhagic strokes (aHR, 0.69 [95% CI, 0.50-0.95]; P = .02), and hospitalizations with bleeding (aHR, 0.89 [95% CI, 0.81-0.97]; P = .009) but a higher risk of gastrointestinal bleeding (aHR, 1.14 [95% CI, 1.01-1.30]; P = .03). In patients with acute ischemic stroke and AF, DOAC use at discharge was associated with better long-term outcomes relative to warfarin.


Maternal Body Mass Index and Use of Labor Neuraxial Analgesia: A Population-based Retrospective Cohort Study.
WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Neuraxial labor analgesia may benefit obese women by optimizing cardiorespiratory function and mitigating complications related to emergency general anesthesia. We hypothesized that obese women have a higher rate of neuraxial analgesia compared with nonobese parturients. Using U.S. natality data, our cohort comprised 17,220,680 deliveries, which accounts for 61.5% of 28 million births in the United States between 2009 and 2015. We examined the relationships between body mass index class and neuraxial labor analgesia, adjusting for sociodemographic, antenatal, pregnancy, and peripartum factors. The study cohort comprised 17,220,680 women; 0.1% were underweight, 12.7% were normal body mass index, 37% were overweight, and 28.3%, 13.5%, and 8.4% were obesity class I, II, and III, respectively. Rates of neuraxial analgesia by body mass index class were as follows: underweight, 59.7% (9,030/15,128); normal body mass index, 68.1% (1,487,117/2,182,797); overweight, 70.3% (4,476,685/6,368,656); obesity class I, 71.8% (3,503,321/4,881,938); obesity class II, 73.4% (1,710,099/2,330,028); and obesity class III, 75.6% (1,089,668/1,442,133). Compared to women with normal body mass index, the likelihood of receiving neuraxial analgesia was slightly increased for overweight women (adjusted relative risk, 1.02; 95% CI, 1.02 to 1.02), obese class I (adjusted relative risk, 1.04; 95% CI, 1.04 to 1.04), obese class II (adjusted relative risk, 1.05; 95% CI, 1.05 to 1.05), and obese class III (adjusted relative risk, 1.06; 95% CI, 1.06 to 1.06). Our findings suggest that the likelihood of receiving neuraxial analgesia is only marginally increased for morbidly obese women compared to women with normal body mass index.


The oldest old: red blood cell and plasma folate in African American and white octogenarians and centenarians in Georgia.
To determine the overall folate status of a population-based multi-ethnic sample of octogenarians and centenarians and the specific dietary, demographic and physiological factors associated with observed abnormalities. Population-based multiethnic sample of adults aged 80 to 89 and 98 and above. Northern Georgia, USA. Men and women aged 80 to 89 (octogenarians, n = 77) and 98 and older (centenarians, n = 199). Wilcoxon rank sum tests, and Chi square and logistic regression analyses were used to examine associations of low and high folate status with hematological indicators and other variables of interest. The prevalence of low red blood cell (RBC) folate was low overall, but tended to be higher in centenarians than in octogenarians (6.5% vs. 1.3%, p = 0.058; defined as RBC folate < 317 nmol/L). The risk of having lower RBC folate (< 25th vs. > 25th percentile for RBC folate for 60yr+ in NHANES 1999-2000) was greater in association with vitamin B12 deficiency (OR = 5.36; 95%CI: 2.87-10.01), African American race (OR = 4.29; 95%CI: 2.08-8.83), and residence in a skilled nursing facility (OR = 3.25; 95%CI: 1.56-6.78) but was not influenced by age, gender, B-vitamin supplement use, high/low food score or presence of atrophic gastritis. Combined high plasma folate and low vitamin B12 status was present in some individuals (n=11), but was not associated with increased prevalence of anemia or cognitive impairment in this study. Low RBC folate status (< 317 nmol/L) was rare in this post folic acid fortification sample of octogenarians and centenarians. RBC folate status (< 25th percentile) was strongly associated with 1) vitamin B12 deficiency, which has strong implications for vitamin treatment, and 2) with being African American, suggesting racial disparities exist even in the oldest old.


Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.
Angiotensin-converting-enzyme inhibitors improve the outcome among patients with left ventricular dysfunction, whether or not they have heart failure. We assessed the role of an angiotensin-converting-enzyme inhibitor, ramipril, in patients who were at high risk for cardiovascular events but who did not have left ventricular dysfunction or heart failure. A total of 9297 high-risk patients (55 years of age or older) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or heart failure were randomly assigned to receive ramipril (10 mg once per day orally) or matching placebo for a mean of five years. The primary outcome was a composite of myocardial infarction, stroke, or death from cardiovascular causes. The trial was a two-by-two factorial study evaluating both ramipril and vitamin E. The effects of vitamin E are reported in a companion paper. A total of 651 patients who were assigned to receive ramipril (14.0 percent) reached the primary end point, as compared with 826 patients who were assigned to receive placebo (17.8 percent) (relative risk, 0.78; 95 percent confidence interval, 0.70 to 0.86; P<0.001). Treatment with ramipril reduced the rates of death from cardiovascular causes (6.1 percent, as compared with 8.1 percent in the placebo group; relative risk, 0.74; P<0.001), myocardial infarction (9.9 percent vs. 12.3 percent; relative risk, 0.80; P<0.001), stroke (3.4 percent vs. 4.9 percent; relative risk, 0.68; P<0.001), death from any cause (10.4 percent vs. 12.2 percent; relative risk, 0.84; P=0.005), revascularization procedures (16.3 percent vs. 18.8 percent; relative risk, 0.85; P<0.001), cardiac arrest (0.8 percent vs. 1.3 percent; relative risk, 0.62; P=0.02), [corrected] heart failure (9.1 percent vs. 11.6 percent; relative risk, 0.77; P<0.001), and complications related to diabetes (6.4 percent vs. 7.6 percent; relative risk, 0.84; P=0.03). Ramipril significantly reduces the rates of death, myocardial infarction, and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction or heart failure.


Multiple forms of DNA polymerase from the thermo-acidophilic eubacterium Bacillus acidocaldarius: purification, biochemical characterization and possible biological role.
Two DNA polymerase isoenzymes, called DpA and DpB on the basis of their elution order from DEAE cellulose, were purified to homogeneity from the thermo-acidophilic eubacterium Bacillus acidocaldarius. The enzymes are weakly acidophilic proteins constituted by a single subunit of 117 and 103 kDa respectively. DpA and DpB differ in thermostability, in thermophilicity, in sensitivity to assay conditions and in resistance to sulphydryl-group blocking agents such as N-ethylmaleimide and p-hydroxymercuriobenzoate. They differ also in synthetic template-primer utilization, in the apparent Km for dNTPs and in processivity. In particular, DpA utilizes more effic iently synthetic templates-primers such as poly(dA).poly(dT), poly(dT). (rA)12-18 and poly(rA).(dT)12-18 and presents a greater tendency to accept dNTP analogues modified in the sugar or in the base ring, such as cytosine beta-d-arabinofuranoside 5'-triphosphate, 2',3'-dideoxyribonucleosides 5'-triphosphate, butylphenyl-dGTP and digoxigenin-conjugated dUTP. In addition, DpA presents an exonuclease activity that preferentially hydrolyses DNA in the 5'-3' direction, whereas DpB lacks this activity. The possible biological role of the enzymes is discussed.


Do influence at work and possibilities for development mitigate the impact of job demands for workers with and without depression.
Jobs characterized by low job demands and high job resources are associated with better work outcomes, yet it remains unclear whether this is the case for workers with depression. This study examined whether depression moderates the relationship between job demands, job resources, and maintaining employment. Data from the longitudinal population-based Lifelines cohort study were matched with register data on employment from Statistics Netherlands (N=55 950). Job demands included quantitative demands and work pace; job resources included influence at work and possibilities for development. The two-way interaction between job demands and depression and the three-way interaction between job demands, job resources and depression were examined in a zero-inflated Poisson regression model with path 1, including a binary employment outcome, and path 2, a count variable including months out of employment. The interaction effect of job demands and depression on being employed was significant [b=-0.22, 95% confidence interval (CI) -0.44‒0.01]. Workers without depression were more likely to be employed whereas workers with depression were less likely to be employed if they had high job demands. The three-way interaction between job demands, job resources, and depression was significant for months out of employment (b=0.15, 95% CI 0.01‒0.29), indicating that workers with depression had more months out of employment when reporting high job demands and high job resources compared to workers without depression. Discussion Although increasing influence at work and possibilities for development to prevent negative work outcomes may be beneficial for workers without depression, this approach might be limited for workers with depression.


Encephalization of Australian and New Guinean marsupials.
Encephalization of Australian marsupials was analyzed using the endocranial volume (ECV) of 52 species of Dasyuromorphia and Notoryctemorphia, 14 species of Peramelemorphia and 116 species of Diprotodontia from Australia and New Guinea and compared with 16 species of Ameridelphian marsupials and 3 species of native and recently introduced Australian eutherian carnivores (dingo, feral cat and feral fox). Linear regression analysis of the relationship between ECV and body weight for marsupials revealed that allometric parameters for these groups are different from those previously derived for samples of (mainly eutherian) mammals, with higher slopes for Dasyuromorphia and Diprotodontia and lower slopes for Ameridelphians and Peramelemorphia. Absolute ECV for small Australian and New Guinea marsupial carnivores (Antechinus and Sminthopsis) were found to be comparable to eutherians of similar body weight, but large marsupial carnivores such as the Tasmanian devil and thylacine had substantially smaller ECVs than eutherian carnivores of similar body weight. Similarly, members of some superfamilies within Diprotodontia (Burramyoidea, Petauroidea, Tarsipedoidea) had ECVs comparable to prosimians, whereas bandicoots, bilbies and many macropods were found to be poorly encephalized. When both encephalization quotient (EQ) and residuals from regression analysis were used to compare relative ECV of extinct/threatened species with common species there were no significant differences for any of the orders of Australian marsupials, suggesting that encephalization is not a major factor in the current extinction crisis for Australian marsupials. Similarly there were no consistent differences in relative ECV between marsupials from New Guinea and associated islands compared to Australia or between arid and non-arid Australian regions for any of the marsupial orders. The results indicate that marsupials are not uniformly poorly encephalized and that small marsupial carnivores and some members of Diprotodontia are of comparable encephalization to eutherians of similar body weight. In particular, honey possums and some gliders show an encephalization level comparable to prosimians, perhaps reflecting convergence in adaptation to similar arboreal niches.


Voriconazole as therapy for systemic Penicillium marneffei infections in AIDS patients.
The objective of this study was to evaluate the triazole anti-fungal agent, voriconazole, as therapy for systemic Penicillium marneffei infections in patients with advanced HIV infection. Patients with systemic P. marneffei infection were enrolled into a study of voriconazole for the treatment of less common, emerging, or refractory fungal infections. Patients were eligible for inclusion in the study on the basis that no anti-fungal agents have received regulatory approval specifically for P. marneffei infections. Patients were treated in the hospital setting with intravenous voriconazole (6 mg/kg every 12 hours on Day 1 and then 4 mg/kg every 12 hours for at least 3 days, after which patients could switch to oral therapy at 200 mg twice a day) or as outpatients with oral voriconazole (400 mg twice a day on Day 1 and then 200 mg twice a day) for a maximum of 12 weeks. Eleven patients received treatment with voriconazole. Two received short courses of intravenous therapy followed by the oral formulation; nine were treated with oral voriconazole only. At the end of therapy, eight of the nine evaluable patients had favorable response to therapy, based on mycological and clinical findings. There were no relapses of P. marneffei infection in the six patients who were seen at follow-up within 4 weeks of the end of therapy. Treatment with voriconazole was well tolerated, with no discontinuations caused by drug-related adverse events. The results of this study suggest that voriconazole is an effective, well-tolerated, and convenient option for the treatment of systemic infections with P. marneffei.


Impact of interfacial coupling of oxygen octahedra on ferromagnetic order in La0.7Sr0.3MnO3/SrTiO3 heterostructures.
La0.7Sr0.3MnO3, a half-metallic ferromagnet with full spin polarization, is generally used as a standard spin injector in heterostructures. However, the magnetism of La0.7Sr0.3MnO3 is strongly modified near interfaces, which was addressed as "dead-layer" phenomenon whose origin is still controversial. Here, both magnetic and structural properties of La0.7Sr0.3MnO3/SrTiO3 heterostructures were investigated, with emphasis on the quantitative analysis of oxygen octahedral rotation (OOR) across interfaces using annular-bright-field imaging. OOR was found to be significantly altered near interface for both La0.7Sr0.3MnO3 and SrTiO3, as linked to the magnetism deterioration. Especially in La0.7Sr0.3MnO3/SrTiO3 superlattices, the almost complete suppression of OOR in 4 unit-cell-thick La0.7Sr0.3MnO3 results in a canted ferromagnetism. Detailed comparisons between strain and OOR relaxation and especially the observation of an unexpected La0.7Sr0.3MnO3 lattice c expansion near interfaces, prove the relevance of OOR for the magnetic properties. These results indicate the capability of tuning the magnetism by engineering OOR at the atomic scale.


Acquired hemophilia masked by warfarin therapy: report on two cases.
Spontaneous appearance of acquired anticoagulants is a rare phenomenon. We present two cases, where such antibodies against factor VIII were masked by warfarin therapy. The two patients were anticoagulated with warfarin due to mechanical heart valve and recurrent thromboembolic events, respectively. Different therapies against the inhibitor of factor VIII were used in the two cases. One patient received corticosteroids and high-dose gammaglobulin with temporary effect and was then effectively treated with cyclophosphamide. The other patient was successfully treated with cyclosporine. The special problems of keeping the balance between thrombosis and bleeding in this group of patients with need of anticoagulation due to mechanical heart valves or other thrombogenic factors are discussed.


Montmorency Tart cherries (Prunus cerasus L.) modulate vascular function acutely, in the absence of improvement in cognitive performance.
Cerebral blood volume and metabolism of oxygen decline as part of human ageing, and this has been previously shown to be related to cognitive decline. There is some evidence to suggest that polyphenol-rich foods can play an important role in delaying the onset or halting the progression of age-related health disorders such as CVD and Alzheimer's disease and to improve cognitive function. In the present study, an acute, placebo-controlled, double-blinded, cross-over, randomised Latin-square design study with a washout period of at least 14 d was conducted on twenty-seven, middle-aged (defined as 45-60 years) volunteers. Participants received either a 60 ml dose of Montmorency tart cherry concentrate (MC), which contained 68·0 (sd 0·26) mg cyanidin-3-glucoside/l, 160·75 (sd 0·55) mean gallic acid equivalent/l and 0·59 (sd 0·02) mean Trolox equivalent/l, respectively, or a placebo. Cerebrovascular responses, cognitive performance and blood pressure were assessed at baseline and 1, 2, 3 and 5 h following consumption. There were significant differences in concentrations of total Hb and oxygenated Hb during the task period 1 h after MC consumption (P≤0·05). Furthermore, MC consumption significantly lowered systolic blood pressure (P≤0·05) over a period of 3 h, with peak reductions of 6±2 mmHg at 1 h after MC consumption relative to the placebo. Cognitive function and mood were not affected. These results show that a single dose of MC concentrate can modulate certain variables of vascular function; however, this does not translate to improvements in cognition or mood.


THE INTRA- AND INTER-RATER RELIABILITY OF THE SOCCER INJURY MOVEMENT SCREEN (SIMS).
The growing volume of movement screening research reveals a belief among practitioners and researchers alike that movement quality may have an association with injury risk. However, existing movement screening tools have not considered the sport-specific movement and injury patterns relevant to soccer. The present study introduces the Soccer Injury Movement Screen (SIMS), which has been designed specifically for use within soccer. Furthermore, the purpose of the present study was to assess the intra- and inter-rater reliability of the SIMS and determine its suitability for use in further research. The study utilized a test-retest design to discern reliablility. Twenty-five (11 males, 14 females) healthy, recreationally active university students (age 25.5 ± 4.0 years, height 171 ± 9 cm, weight 64.7 ± 12.6 kg) agreed to participate. The SIMS contains five sub-tests: the anterior reach, single-leg deadlift, in-line lunge, single-leg hop for distance and tuck jump. Each movement was scored out of 10 points and summed to produce a composite score out of 50. The anterior reach and single-leg hop for distance were scored in real-time while the remaining tests were filmed and scored retrospectively. Three raters conducted the SIMS with each participant on three occasions separated by an average of three and a half days (minimum one day, maximum seven days). Rater 1 re-scored the filmed movements for all participants on all occasions six months later to establish the 'pure' intra-rater (intra-occasion) reliability for those movements. Intraclass correlation coefficient (ICC) values for intra- and inter-rater composite score reliability ranged from 0.66-0.72 and 0.79-0.86 respectively. Weighted kappa values representing the intra- and inter-rater reliability of the individual sub-tests ranged from 0.35-0.91 indicating fair to almost perfect agreement. Establishing the reliability of the SIMS is a prerequisite for further research seeking to investigate the relationship between test score and subsequent injury. The present results indicate acceptable reliability for this purpose; however, room for further development of the intra-rater reliability exists for some of the individual sub-tests. 2b.


Men's Sheds: enabling environments for Australian men living with and without long-term disabilities.
The health of Australian men has recently received greater attention. Men's Sheds are named in national policy as an exemplar community-based organisation for the betterment of men's psychosocial health; yet, the evidence base to support this is limited. This study investigates the comparative experience of men with long-term disabilities and men without long-term disabilities who go to a Men's Shed and to what extent this provides these men with an enabling, as opposed to disabling, environment. Data were collected from 12 individual interviews with men with long-term disabilities (5) and men without long-term disabilities (6), including 1 interview with the male Men's Shed Coordinator (MSC); participant observation within the shed; and a document received from the female MSC regarding the funding the Shed receives. Interviews explored the men's experiences at the Shed and their sense of belonging and social inclusion. Participants had any type of long-term disability and had been attending the shed for a minimum of 1 month. Data were collected between May and September 2013 and were analysed using the constant comparative method of grounded theory. The core theme that emerged was an enabling community space. The four sub-themes were: a community and social hub; an equalising space; a safe and supportive male environment; and meaningful male activities. The current literature exemplifies Men's Sheds to be important community-based organisations beneficial to men's health and well-being. For men living with long-term disabilities, this study illuminates that Men's Sheds offer an environment of equality, facilitating a collegial and egalitarian culture. Men can partake in enabling activities and enjoy the company of other men enhancing their sense of belonging and social inclusion as well as interact with other community groups that occupy the same space as the Men's Shed.


Diagnosis and treatment of heart failure in primary health care among elderly patients with non-insulin-dependent diabetes mellitus, with special reference to use of echocardiography.
The aim of the present study was to describe how the diagnosis of heart failure (HF) was assessed, aetiology and management in elderly patients with non-insulin-dependent diabetes mellitus (NIDDM) in primary health care, with special reference to use of echocardiography. Descriptive retrospective investigation. Ronneby and Karlskrona communities, both situated on the Swedish south-east coast, 28,600 and 60,600 inhabitants, respectively. 279 patients with NIDDM, mean age 77 years (range 70-85). Prevalence, aetiology, diagnostic procedures and management of HF. The majority of patients were given the diagnosis of HF mainly as a result of clinical examination, ECG and chest X-ray, or of hospitalisation for HF. The diagnosis of HF by the primary care physicians was based on an objective evaluation of cardiac function in 8% of the patients. Hypertension was the predominant associated disease, followed by ischaemic heart disease (IHD). Therapy included diuretics (91%), angiotensin-converting enzyme (ACE) inhibitors (43%) and digoxin (53%). There is still a gap between current management of HF in primary care and guidelines, particularly in the case of diagnosis that is not generally based on an objective evaluation of cardiac function.


Precaution or Integrated Responsibility Approach to Nanovaccines in Fish Farming? A Critical Appraisal of the UNESCO Precautionary Principle.
Nanoparticles have multifaceted advantages in drug administration as vaccine delivery and hence hold promises for improving protection of farmed fish against diseases caused by pathogens. However, there are concerns that the benefits associated with distribution of nanoparticles may also be accompanied with risks to the environment and health. The complexity of the natural and social systems involved implies that the information acquired in quantified risk assessments may be inadequate for evidence-based decisions. One controversial strategy for dealing with this kind of uncertainty is the precautionary principle. A few years ago, an UNESCO expert group suggested a new approach for implementation of the principle. Here we compare the UNESCO principle with earlier versions and explore the advantages and disadvantages by employing the UNESCO version to the use of PLGA nanoparticles for delivery of vaccines in aquaculture. Finally, we discuss whether a combined scientific and ethical analysis that involves the concept of responsibility will enable approaches that can provide a supplement to the precautionary principle as basis for decision-making in areas of scientific uncertainty, such as the application of nanoparticles in the vaccination of farmed fish.


Value computations underlying human proposer behavior in the ultimatum game.
Interacting with others to decide how finite resources should be allocated between potentially competing parties is an important part of social life. Considering that not all of our proposals to others are always accepted, the outcomes of such social interactions are probabilistic and risky. Here, we highlight cognitive processes related to value computations in human social interactions, based on mathematical modeling of the proposer behavior in the Ultimatum Game. Our results suggest that the perception of risk is an overarching process across nonsocial and social decision-making domains, whereas the nonlinear weighting of others' acceptance probabilities appears to be more closely associated with social interactive decision-making situations in which others' valuation processes needs to be inferred. Despite the complexity of social interactive decision-making, human participants adjust their risk and probability weighting parameters while interacting with opponents with different social value orientations, and these parameters governing participants' decision-making strategies are influenced by the inferences participants make about their opponents (e.g., how prosocial they think their opponent is relative to themselves), as well as their own social value orientation. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


State-of-the-art review: Hemostats, sealants, and adhesives II: Update as well as how and when to use the components of the surgical toolbox.
The goal of this submission is to describe how and when to best use hemostats, sealants, and adhesives as well as to compare their characteristics and to update the surgical toolbox with respect to any new products approved by the Food and Drug Administration (FDA) as of this date (November 2009). The materials will be presented in 3 major groups each containing specific categories: (1) hemostats; mechanical, active, flowable, and fibrin sealant, (2) sealants; fibrin sealant, polyethylene glycol polymer, and albumin and glutaraldehyde, (3) adhesives; cyanoacrylate, albumin and glutaraldehyde, and fibrin sealant. The categories will be used for comparisons based on safety, efficacy, usability, and cost. Recommendations with respect to how and when to best use these materials will be presented. A review of the recent literature is also provided with respect to the most recent uses of these materials in specific surgical specialties.


Resource limitation in a competitive context determines complex plant responses to experimental resource additions.
Almost all models of plant resource limitation are grounded in either one or both of two simple conceptual models: Liebig's Minimum Hypothesis (LMH), the idea that plants are limited by the resource in shortest supply, and the Multiple Limitation Hypothesis (MLH), the idea that plants should adjust to their environment so that all essential resources are equally limiting. Despite the differences in their predictions, experiments have so far failed to discriminate between them. In a simple factorial nitrogen and water addition experiment in a Minnesota grassland, we observed shifts in allocation that, as in previous studies, are not all explained by a single theory. We found that leaf biomass responded positively to nitrogen additions but did not respond to water additions. We found that fine-root biomass increased in response to water additions, but only at low nitrogen levels, and that fine-root biomass decreased in response to nitrogen additions, but only at high water levels. To understand these responses we built a physiologically based model of plant competition for water, nitrogen, and space to predict plant allocation to fine roots and leaves. Critically, we include in our model the inherent variability of soil moisture and treat light, water, and nitrogen as resources with distinct mechanistic roles. Experimental results showed that plants were nitrogen and water limited. The model explains the experimental results, under conditions of co-limitation, as follows. Foliage increases with nitrogen additions but not water additions because leaf construction is constrained by nitrogen uptake. When water is added, plants spend a larger fraction of the growing season limited by light (and effectively nitrogen) than by water. Thus, water additions cause fine-root biomass to increase because of the increased importance of nitrogen limitation. The response of fine-root biomass to water additions decreases with nitrogen additions because these additions reduce nitrogen limitation. In general, our results are explained by sequential resource limitation. The rate of carbon assimilation may be limited by a single resource at any one moment, but the identity of the limiting resource(s) changes throughout the growing season.


Sustained virologic response rates with telaprevir by response after 4 weeks of lead-in therapy in patients with prior treatment failure.
For hepatitis C virus (HCV)-infected patients who have not responded to previous PegIFN/ribavirin treatment, it is unclear whether subsequent direct-acting antiviral therapy outcomes are better predicted by prior treatment response or by on-treatment response to a PegIFN/ribavirin lead-in. In REALIZE, treatment-experienced patients randomized to the lead-in telaprevir arm received 4 weeks of PegIFN-α-2a (180 μg/week) and ribavirin (1000-1200 mg/day), then 12 weeks of telaprevir (750 mg every 8h) plus PegIFN-α-2a/ribavirin, followed by 32 weeks of PegIFN-α-2a/ribavirin. This subanalysis only included patients in the lead-in telaprevir arm with available week 4 on-treatment response data (n=240). After 4weeks of PegIFN/ribavirin, 90% of relapsers, 60% of partial responders, and 41% of null responders in the lead-in telaprevir arm had ⩾1 log(10) HCV RNA reduction. Sustained virologic response (SVR) rates for telaprevir-treated patients with ≥1 versus <1 log(10) HCV RNA reduction after the PegIFN/ribavirin lead-in were 94% versus 62% in relapsers, 59% versus 56% in partial responders and 54% versus 15% in null responders. In prior relapsers and partial responders there is no apparent benefit of assessing response after a PegIFN/ribavirin lead-in with the aim of guiding telaprevir-based treatment. For patients known to be prior null responders, on-treatment response after a 4-week PegIFN/ribavirin lead-in may provide clinically useful prognostic information. However, withholding telaprevir-containing therapy in uncategorised treatment-experienced patient populations (i.e., that could include prior relapsers or partial responders), using response after a PegIFN/ribavirin lead-in could potentially exclude some patients with a high chance of SVR.


Using discrete choice experiments to value informal care tasks: exploring preference heterogeneity.
While informal care is a significant part of non-market economic activity, its value is rarely acknowledged, perhaps reflecting a lack of market data. Traditional methods to value such care include opportunity and replacement cost. This study is the first to employ the discrete choice experiment methodology to value informal care tasks. A monetary value is estimated for three tasks (personal care, supervising and household tasks). The relationship between time spent on formal and informal care is also modelled and preference heterogeneity investigated using the Latent Class Model. Complementarity between supervising tasks and formal care is observed. Monetary compensation is important, with willingness to accept per hour values ranging from £0.38 to £0.83 for personal care, £0.75 for supervising and £0.31 to £0.6 for household tasks. Heterogeneity in preferences is observed, with monetary compensation being important for younger people, but insignificant for older individuals. Such heterogeneity is important at the policy level. Values are lower than those generated by opportunity cost and replacement cost methods, perhaps because of the limited ability of revealed preference methods to capture broader aspect of utility. Differences with contingent valuation methods are also observed, suggesting future research should investigate the external validity of the different methods.


Single high-dose (45 mg) infusions of aminohydroxypropylidene diphosphonate for severe malignant hypercalcemia.
A 3-hour single intravenous infusion of aminohydroxypropylidene diphosphonate (APD) 45 mg was given to 25 patients with malignant hypercalcemia. There were seven patients with breast cancer, eight with lung cancer, and ten with a variety of other cancers. Twenty-four patients responded to a single APD 45 mg infusion, 18 of whom (75%) had falls in plasma calcium to below the upper limit of normal (less than or equal to 2.75 mmol/l). Of 15 patients who had severe hypercalcemia, i.e., plasma calcium levels greater than 3.5 mmol/l, 14 responded and 9 (60%) achieved normocalcemia. Five patients developed hypocalcemia. One patient with lung cancer developed spontaneously reversible acute dyspnea after APD which was considered to be an idiosyncratic drug reaction. Single short-duration infusions of APD 45 mg are very effective in correcting malignant hypercalcemia in the majority of patients and are particularly suitable for patients with pre-APD plasma calcium levels greater than 3.5 mmol/l, who are less likely to develop hypocalcemia.


Intimate partner violence among African American and African Caribbean women: prevalence, risk factors, and the influence of cultural attitudes.
Women of African descent are disproportionately affected by intimate partner abuse; yet, limited data exist on whether the prevalence varies for women of African descent in the United States and those in the US territories. In this multisite study, we estimated lifetime and 2-year prevalence of physical, sexual, and psychological intimate partner abuse (IPA) among 1,545 women of African descent in the United States and US Virgin Islands (USVI). We also examined how cultural tolerance of physical and/or sexual intimate partner violence (IPV) influences abuse. Between 2009 and 2011, we recruited African American and African Caribbean women aged 18-55 from health clinics in Baltimore, MD, and St. Thomas and St. Croix, USVI, into a comparative case-control study. Screened and enrolled women completed an audio computer-assisted self-interview. Screening-based prevalence of IPA and IPV were stratified by study site and associations between tolerance of IPV and abuse experiences were examined by multivariate logistic regression analysis. Most of the 1,545 screened women were young, of low-income, and in a current intimate relationship. Lifetime prevalence of IPA was 45% in St. Thomas, 38% in St. Croix, and 37% in Baltimore. Lifetime prevalence of IPV was 38% in St. Thomas, 28% in St. Croix, and 30% in Baltimore. Past 2-year prevalence of IPV was 32% in St. Thomas, 22% in St. Croix, and 26% in Baltimore. Risk and protective factors for IPV varied by site. Community and personal acceptance of IPV were independently associated with lifetime IPA in Baltimore and St. Thomas. Variance across sites for risk and protective factors emphasizes cultural considerations in sub-populations of women of African descent when addressing IPA and IPV in given settings. Individual-based interventions should be coupled with community/societal interventions to shape attitudes about use of violence in relationships and to promote healthy relationships.


Pulsed electromagnetic field therapy for management of osteoarthritis-related pain, stiffness and physical function: clinical experience in the elderly.
Pulsed electromagnetic field (PEMF) therapy has shown promising therapeutic effectiveness on bone- and cartilage-related pathologies, being also safe for management of knee osteoarthritis. The aim of this study was to investigate the clinical efficacy of a PEMF device for management of knee osteoarthritis in elderly patients. A total of 33 patients were screened, and 28 patients, aged between 60 and 83 and affected by bilateral knee osteoarthritis, were enrolled in this study. They received PEMF therapy on the right leg for a total of three 30-minute sessions per week for a period of 6 weeks, while the left leg did not receive any treatment and served as control. An intravenous drip containing ketoprofen, sodium clodronate, glucosamine sulfate, calcitonin, and ascorbic acid, for a total volume of 500 mL, was administered during PEMF therapy. At baseline and 3 months post-PEMF therapy, Visual Analog Scale (VAS) was used to assess knee pain and Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) was used to measure knee pain, stiffness and physical function. Changes in VAS and WOMAC scores were calculated for both knees as baseline minus post-treatment. A two sample Student's t-test, comparing change in knee-related VAS pain for PEMF-treated leg (49.8 ± 2.03) vs control leg (11 ± 1.1), showed a significant difference in favor of PEMF therapy (P < 0.001). A two sample Student's t-test comparing change in knee-related WOMAC pain, stiffness, and physical function for PEMF-treated leg (8.5 ± 0.4, 3.5 ± 0.2, 38.5 ± 2.08, respectively) vs control leg (2.6 ± 0.2; 1.6 ± 0.1; 4.5 ± 0.5 respectively), also showed a significant difference in favor of PEMF therapy (P < 0.001). No adverse reactions to therapy were observed. The present study shows that PEMF therapy improves pain, stiffness and physical function in elderly patients affected by knee osteoarthritis.


Polycomblike 2 facilitates the recruitment of PRC2 Polycomb group complexes to the inactive X chromosome and to target loci in embryonic stem cells.
Polycomb group (PcG) proteins play an important role in the control of developmental gene expression in higher organisms. In mammalian systems, PcG proteins participate in the control of pluripotency, cell fate, cell cycle regulation, X chromosome inactivation and parental imprinting. In this study we have analysed the function of the mouse PcG protein polycomblike 2 (Pcl2), one of three homologues of the Drosophila Polycomblike (Pcl) protein. We show that Pcl2 is expressed at high levels during early embryogenesis and in embryonic stem (ES) cells. At the biochemical level, Pcl2 interacts with core components of the histone H3K27 methyltransferase complex Polycomb repressive complex 2 (PRC2), to form a distinct substoichiometric biochemical complex, Pcl2-PRC2. Functional analysis using RNAi knockdown demonstrates that Pcl2-PRC2 facilitates both PRC2 recruitment to the inactive X chromosome in differentiating XX ES cells and PRC2 recruitment to target genes in undifferentiated ES cells. The role of Pcl2 in PRC2 targeting in ES cells is critically dependent on a conserved PHD finger domain, suggesting that Pcl2 might function through the recognition of a specific chromatin configuration.


Familial predisposition to recurrent mutations causing Huntington's disease: genetic risk to sibs of sporadic cases.
Huntington's disease (HD) is associated with expansion of a CAG repeat in a new gene. We have recently defined a premutation in a paternal allele of 30 to 38 CAG repeats in the HD gene which is greater than that seen in the general population (< 30 repeats) but below the range seen in patients with HD (> 38). These intermediate alleles are unstable during transmission through the germline and in sporadic cases expand to the full mutation associated with the clinical phenotype of HD. Here we have analysed three new mutation families where, in each, the proband and at least one sib have CAG sizes in the HD range. In one of these families, two sibs with expanded CAG repeats are both clinically affected with HD, thus presenting a pseudorecessive pattern of inheritance. In all three families the parental intermediate allele has expanded in more than one offspring, thus showing a previously unrecognised risk of inheriting HD to sibs of sporadic cases of HD.


Full-Length Recombinant hSP-D Binds and Inhibits SARS-CoV-2.
SARS-CoV-2 infection of host cells is driven by binding of the SARS-CoV-2 spike-(S)-protein to lung type II pneumocytes, followed by virus replication. Surfactant protein SP-D, member of the front-line immune defense of the lungs, binds glycosylated structures on invading pathogens such as viruses to induce their clearance from the lungs. The objective of this study is to measure the pulmonary SP-D levels in COVID-19 patients and demonstrate the activity of SP-D against SARS-CoV-2, opening the possibility of using SP-D as potential therapy for COVID-19 patients. Pulmonary SP-D concentrations were measured in bronchoalveolar lavage samples from patients with corona virus disease 2019 (COVID-19) by anti-SP-D ELISA. Binding assays were performed by ELISAs. Protein bridge and aggregation assays were performed by gel electrophoresis followed by silver staining and band densitometry. Viral replication was evaluated in vitro using epithelial Caco-2 cells. Results indicate that COVID-19 patients (n = 12) show decreased pulmonary levels of SP-D (median = 68.9 ng/mL) when compared to levels reported for healthy controls in literature. Binding assays demonstrate that SP-D binds the SARS-CoV-2 glycosylated spike-(S)-protein of different emerging clinical variants. Binding induces the formation of protein bridges, the critical step of viral aggregation to facilitate its clearance. SP-D inhibits SARS-CoV-2 replication in Caco-2 cells (EC90 = 3.7 μg/mL). Therefore, SP-D recognizes and binds to the spike-(S)-protein of SARS-CoV-2 in vitro, initiates the aggregation, and inhibits viral replication in cells. Combined with the low levels of SP-D observed in COVID-19 patients, these results suggest that SP-D is important in the immune response to SARS-CoV-2 and that rhSP-D supplementation has the potential to be a novel class of anti-viral that will target SARS-CoV-2 infection.


HIV-1-specific CD4+ T lymphocyte turnover and activation increase upon viral rebound.
HIV-specific CD4+ T helper lymphocytes are preferred targets for infection. Although complete interruption of combination antiretroviral therapy (ART) can form part of therapeutic manipulations, there is grave concern that the resumption of viral replication might destroy, perhaps irreversibly, these T helper populations. High viremia blocks the proliferation capacity of HIV-specific helper cells. However, cytokine production assays imply that some antigen-specific effector function is retained. Despite this careful work, it remains unclear whether the return of HIV-1 replication physically destroys HIV-1-specific T helper cells in the peripheral blood. Difficulties in producing stable peptide-MHC class II complexes and the very low frequencies of antigen-specific CD4+ T cells have delayed the application of this powerful technique. Here we employ HLA class II tetramers and validate a sensitive, quantitative cell-enrichment technique to detect HIV-1 T helper cells. We studied patients with early-stage HIV infection who were given a short, fixed course of ART as part of a clinical study. We did not find significant deletion of these cells from the peripheral circulation when ART was stopped and unfettered HIV replication returned. The turnover of these virus-specific cells increased and they adopted an effector phenotype when viremia returned.


Microfabricated endoscopic probe integrated MEMS micromirror for optical coherence tomography bioimaging.
In this paper, we present a miniaturized endoscopic probe, consisted of MEMS micromirror, silicon optical bench (SiOB), grade index (GRIN) lens, single mode optical fiber (SMF) and transparent housing, for optical coherence tomography (OCT) bioimaging. Due to the use of the MEMS micromirror, the endoscopic OCT system is highly suitable for non-invasive imaging diagnosis of a wide variety of inner organs. The probe engineering and proof of concept were demonstrated by obtaining the two-dimensional OCT images with a cover slide and an onion used as standard samples and the axial resolution was around 10µm.


Engineering a Synthesis-Friendly Constitutive Promoter for Mammalian Cell Expression.
Since cell-based therapies require the constitutive and stable expression of therapeutic transgenes, lentiviral infection is commonly used to integrate gene material regulated by standard constitutive promoters. Unfortunately, none of the standard or synthetic constitutive promoters can be easily synthesized at low cost due to the presence of repeated subsequences. Thus, in this paper, we designed a synthetic constitutive promoter (named SFCp) that can drive the expression of fluorescent proteins that subsequently trafficked to intended subcellular localizations and the expression of synthetic proteins that rewired the cellular response of Ca2+ to cell morphology changes. Furthermore, SFCp can be used to avoid sequence homology that can theoretically result in loss of genetic material by homologous recombination in tandem constructs. As gene synthesis becomes an indispensable tool in the arsenal of synthetic biology, it is essential to develop a toolbox of gene synthesis friendly components for cell engineering such as constitutive promoters.


A proteomics approach to the identification of biomarkers for psoriasis utilising keratome biopsy.
The discovery of plasma biomarkers for psoriasis vulgaris may aid clinicians in disease grading and monitoring of treatment response. We have therefore developed a proteomics/mass spectrometry based workflow which enables biomarker discovery from psoriasis patient samples. We have utilised keratome skin biopsy, which results in reduced cellular complexity compared to punch biopsy. Furthermore, we applied short term ex vivo culture in order to enrich for a "secretome" sub-proteome reflective of the disease and enriched in potential biomarkers. Using these sample preparation techniques we performed a quantitative proteomics screen of four patients with psoriasis using stable isotope dimethyl labelling and identified over 50 proteins consistently altered in abundance in psoriasis lesional versus non-lesional skin. This includes several canonical psoriasis related proteins (e.g. S100A7 [Psoriasin] and FABP5 [Epidermal Fatty Acid Binding Protein]) and more than 30 novel alterations. From this disease localised dataset we further assessed several proteins as potential biomarkers in the plasma of patients with psoriasis versus healthy controls utilising selected reaction monitoring mass spectrometry (SRM-MS/MS). The significance of this study for proteome research in psoriasis and dermal disease is threefold. 1) A novel sample preparation method for isolation of dermal proteomes enriched in extracellular proteins is described, which may be of interest to other researchers in the field. 2) Novel psoriasis associated alterations in protein abundance are described at the disease site, bolstering knowledge in an area dominated by transcript level studies and 3) Profilin 1 is described as a candidate plasma biomarker of psoriasis, this is of value in itself and it proves that our workflow can yield results in terms of biomarker discovery.


Cardiovascular Complications in Patients with Klinefelter's Syndrome.
More than 70 years have passed since the first description of Klinefelter Syndrome (KS), the most frequent chromosome disorder causing male infertility and hypogonadism. KS is associated with increased cardiovascular (CV) mortality due to several comorbidities, including hypogonadism, as well as metabolic syndrome and type 2 diabetes, which are highly prevalent in these patients. Aside from metabolic disturbances, patients with KS suffer from both acquired and congenital CV abnormalities, cerebrovascular thromboembolic disease, subclinical atherosclerosis and endothelial dysfunction, which may all contribute to increased CV mortality. The mechanisms involved in this increased risk of CV morbidity and mortality are not entirely understood. More research is needed to better characterise the CV manifestations, elucidate the pathophysiological mechanisms and define the contribution of testosterone replacement to restoring CV health in KS patients. This review explores the complex association between KS, metabolic syndrome and CV risk in order to plan future studies and improve strategies to reduce mortality in this high-risk population.


Biallelic ADPRHL2 mutations in complex neuropathy affect ADP ribosylation and DNA damage response.
ADP ribosylation is a reversible posttranslational modification mediated by poly(ADP-ribose)transferases (e.g., PARP1) and (ADP-ribosyl)hydrolases (e.g., ARH3 and PARG), ensuring synthesis and removal of mono-ADP-ribose or poly-ADP-ribose chains on protein substrates. Dysregulation of ADP ribosylation signaling has been associated with several neurodegenerative diseases, including Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Recessive ADPRHL2/ARH3 mutations are described to cause a stress-induced epileptic ataxia syndrome with developmental delay and axonal neuropathy (CONDSIAS). Here, we present two families with a neuropathy predominant disorder and homozygous mutations in ADPRHL2 We characterized a novel C26F mutation, demonstrating protein instability and reduced protein function. Characterization of the recurrent V335G mutant demonstrated mild loss of expression with retained enzymatic activity. Although the V335G mutation retains its mitochondrial localization, it has altered cytosolic/nuclear localization. This minimally affects basal ADP ribosylation but results in elevated nuclear ADP ribosylation during stress, demonstrating the vital role of ADP ribosylation reversal by ARH3 in DNA damage control.


Flexibility in the Periplasmic Domain of BamA Is Important for Function.
The β-barrel assembly machine (BAM) mediates the biogenesis of outer membrane proteins (OMPs) in Gram-negative bacteria. BamA, the central BAM subunit composed of a transmembrane β-barrel domain linked to five polypeptide transport-associated (POTRA) periplasmic domains, is thought to bind nascent OMPs and undergo conformational cycling to catalyze OMP folding and insertion. One model is that conformational flexibility between POTRA domains is part of this conformational cycling. Nuclear magnetic resonance (NMR) spectroscopy was used here to study the flexibility of the POTRA domains 1-5 in solution. NMR relaxation studies defined effective rotational correlational times and together with residual dipolar coupling data showed that POTRA1-2 is flexibly linked to POTRA3-5. Mutants of BamA that restrict flexibility between POTRA2 and POTRA3 by disulfide crosslinking displayed impaired function in vivo. Together these data strongly support a model in which conformational cycling of hinge motions between POTRA2 and POTRA3 in BamA is required for biological function.


Factors influencing lysis time stochasticity in bacteriophage λ.
Despite identical genotypes and seemingly uniform environments, stochastic gene expression and other dynamic intracellular processes can produce considerable phenotypic diversity within clonal microbes. One trait that provides a good model to explore the molecular basis of stochastic variation is the timing of host lysis by bacteriophage (phage). Individual lysis events of thermally-inducible λ lysogens were observed using a temperature-controlled perfusion chamber mounted on an inverted microscope. Both mean lysis time (MLT) and its associated standard deviation (SD) were estimated. Using the SD as a measure of lysis time stochasticity, we showed that lysogenic cells in controlled environments varied widely in lysis times, and that the level of lysis time stochasticity depended on allelic variation in the holin sequence, late promoter (pR') activity, and host growth rate. In general, the MLT was positively correlated with the SD. Both lower pR' activities and lower host growth rates resulted in larger SDs. Results from premature lysis, induced by adding KCN at different time points after lysogen induction, showed a negative correlation between the timing of KCN addition and lysis time stochasticity. Taken together with results published by others, we conclude that a large fraction of λ lysis time stochasticity is the result of random events following the expression and diffusion of the holin protein. Consequently, factors influencing the timing of reaching critical holin concentrations in the cell membrane, such as holin production rate, strongly influence the mean lysis time and the lysis time stochasticity.


Mindfulness and reduced cognitive reactivity to sad mood: evidence from a correlational study and a non-randomized waiting list controlled study.
Cognitive Reactivity (CR) refers to the degree to which a mild dysphoric state reactivates negative thinking patterns, and it has been found to play a key causal role in depressive relapse. Although Mindfulness-Based Cognitive Therapy (MBCT) directly aims to address this mechanism of CR, the relationship between mindfulness and CR has not been tested to date. Using a cross-sectional design (Study 1; n = 164) and a non-randomized waiting list controlled design (Study 2; MBCT [n = 18] vs. waiting list [n = 21]), the authors examined the relationship between naturally occurring levels of mindfulness (Study 1) and MBCT (Study 2) on the one hand, and CR on the other hand. In line with predictions, it was found that (a) trait mindfulness is significantly negatively correlated with CR, even when controlled for current depressive symptoms and prior history of depression (Study 1), and that (b) MBCT, compared to a matched control group, significantly reduces CR, and that this effect of MBCT on reduction of CR is mediated by a positive change in mindfulness skills (Study 2). Results provide first evidence for the claim that mindfulness practices in MBCT are designed to address the process of CR.


Source partitioning using stable isotopes: coping with too many sources.
Stable isotopes are increasingly being used as tracers in environmental studies. One application is to use isotopic ratios to quantitatively determine the proportional contribution of several sources to a mixture, such as the proportion of various pollution sources in a waste stream. In general, the proportional contributions of n+1 different sources can be uniquely determined by the use of n different isotope system tracers (e.g., delta13C, delta15N, delta18O) with linear mixing models based on mass balance equations. Often, however, the number of potential sources exceeds n+1, which prevents finding a unique solution of source proportions. What can be done in these situations? While no definitive solution exists, we propose a method that is informative in determining bounds for the contributions of each source. In this method, all possible combinations of each source contribution (0-100%) are examined in small increments (e.g., 1%). Combinations that sum to the observed mixture isotopic signatures within a small tolerance (e.g., +/-0.1 per thousand ) are considered to be feasible solutions, from which the frequency and range of potential source contributions can be determined. To avoid misrepresenting the results, users of this procedure should report the distribution of feasible solutions rather than focusing on a single value such as the mean. We applied this method to a variety of environmental studies in which stable isotope tracers were used to quantify the relative magnitude of multiple sources, including (1) plant water use, (2) geochemistry, (3) air pollution, and (4) dietary analysis. This method gives the range of isotopically determined source contributions; additional non-isotopic constraints specific to each study may be used to further restrict this range. The breadth of the isotopically determined ranges depends on the geometry of the mixing space and the similarity of source and mixture isotopic signatures. A sensitivity analysis indicated that the estimated ranges vary only modestly with different choices of source increment and mass balance tolerance parameter values. A computer program (IsoSource) to perform these calculations for user-specified data is available at http://www.epa.gov/wed/pages/models.htm.


Small is the new big: assessing the population structure of microorganisms.
Microorganisms are a tremendously large and diverse group spanning multiple kingdoms, yet they have been considerably under-studied by ecologists and evolutionary biologists compared to their larger relatives. Although a few microbial species have become the stars of laboratory experiments, relatively few studies have examined microbial species in their natural habitats. As such, the question of whether microbial diversity parallels that of larger bodied species is contentious (Lachance 2004; Fenchel & Finlay 2004). It has been suggested that large population sizes, high dispersal potential and low extinction rates lead to genetically homogeneous populations of microbial species over large geographical scales—arguments that bring to mind discussions about speciation and population structure in the marine environment. In this issue of Molecular Ecology, Herrera et al. (2011) add to this debate by examining 91 isolates of the flower-living yeast Metschnikowia gruessii from southeastern Spain. Their AFLP results support both spatial structuring of genetic diversity across the region, as well as microsite-dependent diversifying selection within single flowers. This study adds to a growing body of literature suggesting that although microbes have much larger population sizes and many differ in their principal mode of reproduction (primarily clonal rather than sexual), patterns of genetic diversity and phylogenetic structure for some microbial species may be similar to that of larger species. This study highlights the need for vastly more research that specifically examines biogeographic structure in this under-utilized group of organisms.


How I treat LGL leukemia.
Large granular lymphocyte (LGL) leukemia is characterized by a clonal expansion of either CD3(+) cytotoxic T or CD3(-) NK cells. Prominent clinical features of T-LGL leukemia include neutropenia, anemia and rheumatoid arthritis (RA). The terminal effector memory phenotype (CD3(+)/CD45RA(+)/CD62L(-)CD57(+)) of T-LGL suggests a pivotal chronic antigen-driven immune response. LGL survival is then promoted by platelet-derived growth factor and interleukin-15, resulting in global dysregulation of apoptosis and resistance to normal pathways of activation-induced cell death. These pathogenic features explain why treatment of T-LGL leukemia is based on immunosuppressive therapy. The majority of these patients eventually need treatment because of severe or symptomatic neutropenia, anemia, or RA. No standard therapy has been established because of the absence of large prospective trials. The authors use low-dose methotrexate initially for T-LGL leukemia patients with neutropenia and/or RA. We recommend either methotrexate or oral cyclophosphamide as initial therapy for anemia. If treatment is not successful, patients are switched to either the other agent or cyclosporine. The majority of patients experience an indolent clinical course. Deaths infrequently occur because of infections related to severe neutropenia. As there are no curative therapeutic modalities for T-LGL leukemia, new treatment options are needed.