Exercise training increases ERK2 activity in skeletal muscle of obese Zucker rats.
Acute exercise and training increase insulin action in skeletal muscle, but the mechanism responsible for this effect is unknown. Activation of the insulin receptor initiates signaling through both the phosphatidylinositol (PI) 3-kinase and the mitogen-activated protein kinase [MAPK, also referred to as extracellular signal-regulated kinases (ERK1/2)] pathways. Acute exercise has no effect on the PI3-kinase pathway signaling elements but does activate the MAPK pathway, which may play a role in the adaptation of muscle to exercise. It is unknown whether training produces a chronic effect on basal activity or insulin response of the MAPK pathway. The present study was undertaken to determine whether exercise training improves the activity of the MAPK pathway or its response to insulin in obese Zucker rats, a well-characterized model of insulin resistance. To accomplish this, obese Zucker rats were studied by using the hindlimb perfusion method with or without 7 wk of treadmill training. Activation of the MAPK pathway was determined in gastrocnemius muscles exposed in situ to insulin. Compared with lean Zucker rats, untrained obese Zucker rats had reduced basal and insulin-stimulated activities of ERK2 and its downstream target p90 ribosomal S6 kinase (RSK2). Seven weeks of training significantly increased basal and insulin-stimulated ERK2 and RSK2 activities, as well as insulin stimulation of MAPK kinase activity. This effect was maintained for at least 96 h in the case of ERK2. The training-induced increase in basal ERK2 activity was correlated with the increase in citrate synthase activity. Therefore, 7 wk of training increases basal and insulin-stimulated ERK2 activity. The increase in basal ERK2 activity may be related to the response of muscle to training.


Multiple oncogenic changes (K-RAS(V12), p53 knockdown, mutant EGFRs, p16 bypass, telomerase) are not sufficient to confer a full malignant phenotype on human bronchial epithelial cells.
We evaluated the contribution of three genetic alterations (p53 knockdown, K-RAS(V12), and mutant EGFR) to lung tumorigenesis using human bronchial epithelial cells (HBEC) immortalized with telomerase and Cdk4-mediated p16 bypass. RNA interference p53 knockdown or oncogenic K-RAS(V12) resulted in enhanced anchorage-independent growth and increased saturation density of HBECs. The combination of p53 knockdown and K-RAS(V12) further enhanced the tumorigenic phenotype with increased growth in soft agar and an invasive phenotype in three-dimensional organotypic cultures but failed to cause HBECs to form tumors in nude mice. Growth of HBECs was highly dependent on epidermal growth factor (EGF) and completely inhibited by EGF receptor (EGFR) tyrosine kinase inhibitors, which induced G1 arrest. Introduction of EGFR mutations E746-A750 del and L858R progressed HBECs toward malignancy as measured by soft agar growth, including EGF-independent growth, but failed to induce tumor formation. Mutant EGFRs were associated with higher levels of phospho-Akt, phospho-signal transducers and activators of transcription 3 [but not phospho-extracellular signal-regulated kinase (ERK) 1/2], and increased expression of DUSP6/MKP-3 phosphatase (an inhibitor of phospho-ERK1/2). These results indicate that (a) the HBEC model system is a powerful new approach to assess the contribution of individual and combinations of genetic alterations to lung cancer pathogenesis; (b) a combination of four genetic alterations, including human telomerase reverse transcriptase overexpression, bypass of p16/RB and p53 pathways, and mutant K-RAS(V12) or mutant EGFR, is still not sufficient for HBECs to completely transform to cancer; and (c) EGFR tyrosine kinase inhibitors inhibit the growth of preneoplastic HBEC cells, suggesting their potential for chemoprevention.


Inhibition of CCL3 abrogated precursor cell fusion and bone erosions in human osteoclast cultures and murine collagen-induced arthritis.
Macrophage inflammatory protein 1-alpha (CCL3) is a chemokine that regulates macrophage trafficking to the inflamed joint. The agonistic effect of CCL3 on osteolytic lesions in patients with multiple myeloma is recognized; however, its role in skeletal damage during inflammatory arthritis has not been established. The aim of the study was to explore the role of osteoclast-associated CCL3 upon bone resorption, and to test its pharmacological blockade for protecting against bone pathology during inflammatory arthritis. CCL3 production was studied during osteoclast differentiation from osteoclast precursor cells: human CD14-positive mononuclear cells. Mice with CIA were treated with an anti-CCL3 antibody. The effect of CCL3 blockade through mAb was studied through osteoclast number, cytokine production and bone resorption on ivory disks, and in vivo through CIA progression (clinical score, paw diameter, synovial inflammation and bone damage). Over time, CCL3 increased in parallel with the number of osteoclasts in culture. Anti-CCL3 treatment achieved a concentration-dependent inhibition of osteoclast fusion and reduced pit formation on ivory disks (P ⩽ 0.05). In CIA, anti-CCL3 treatment reduced joint damage and significantly decreased multinucleated tartrate-resistant acid phosphatase-positive osteoclasts and erosions in the wrists (P < 0.05) and elbows (P < 0.05), while also reducing joint erosions in the hind (P < 0.01) and fore paws (P < 0.01) as confirmed by X-ray. Inhibition of osteoclast-associated CCL3 reduced osteoclast formation and function whilst attenuating arthritis-associated bone loss and controlling development of erosion in murine joints, thus uncoupling bone damage from inflammation. Our findings may help future innovations for the diagnosis and treatment of inflammatory arthritis.


How do economic crises affect migrants' risk of infectious disease? A systematic-narrative review.
It is not well understood how economic crises affect infectious disease incidence and prevalence, particularly among vulnerable groups. Using a susceptible-infected-recovered framework, we systematically reviewed literature on the impact of the economic crises on infectious disease risks in migrants in Europe, focusing principally on HIV, TB, hepatitis and other STIs. We conducted two searches in PubMed/Medline, Web of Science, Cochrane Library, Google Scholar, websites of key organizations and grey literature to identify how economic changes affect migrant populations and infectious disease. We perform a narrative synthesis in order to map critical pathways and identify hypotheses for subsequent research. The systematic review on links between economic crises and migrant health identified 653 studies through database searching; only seven met the inclusion criteria. Fourteen items were identified through further searches. The systematic review on links between economic crises and infectious disease identified 480 studies through database searching; 19 met the inclusion criteria. Eight items were identified through further searches. The reviews show that migrant populations in Europe appear disproportionately at risk of specific infectious diseases, and that economic crises and subsequent responses have tended to exacerbate such risks. Recessions lead to unemployment, impoverishment and other risk factors that can be linked to the transmissibility of disease among migrants. Austerity measures that lead to cuts in prevention and treatment programmes further exacerbate infectious disease risks among migrants. Non-governmental health service providers occasionally stepped in to cater to specific populations that include migrants. There is evidence that migrants are especially vulnerable to infectious disease during economic crises. Ring-fenced funding of prevention programs, including screening and treatment, is important for addressing this vulnerability.


Does the roosting behavior of birds affect transmission dynamics of West Nile virus?
The potential role of many urban passerine birds in the transmission of West Nile virus (WNV) is well-documented by studies on host competency, seroprevalence in wild birds, and identification of vector blood meal source. In contrast, the impact of bird behavior on transmission dynamics is largely unexplored. Bird roosting (perching) behavior may be a critical component regulating WNV transmission because of the crepuscular/nocturnal feeding behavior of Culex mosquitoes, the primary vectors of WNV. We used radio telemetry to determine the roosting behavior of American crows (Corvus brachyrhynchos) and northern cardinals (Cardinalus cardinalus). On average, healthy crows moved slightly shorter distances between roosts than viremic crows, 1,038.3 meters versus 1,255.5 meters, while cardinals only moved 54.7 meters. Given the average movements of crows and cardinals between roosts, crows, which are viremic for five days, could spread the virus throughout a mean +/- SE area of 20.84 +/- 0.79 km(2), while viremic cardinals would, on average, only spread the virus over a mean +/- SE area of 0.03 +/- 0.01 km(2). Because the crow population in Illinois is decreasing at a rate of 11.5% per year and up to 35.6% per year in certain locations, crows are becoming scarce in some areas, thus reducing their role as wild bird sentinels. We suggest that if crows are important in dispersing WNV, large decreases in their abundance will shift transmission cycles to a more focal nature because of the differences in roosting behavior of crows compared with other urban birds, such as cardinals.


New technique of local ischemic preconditioning induction without repetitive aortic cross-clamping in cardiac surgery.
Several studies have demonstrated that local ischemic preconditioning can reduce myocardial ischemia-reperfusion injury in cardiac surgery patients; however, preconditioning has not become a standard cardioprotective intervention, primarily because of the increased risk of atheroembolism during repetitive aortic cross-clamping. In the present study, we aimed to describe and validate a novel technique of preconditioning induction. Patients undergoing coronary artery bypass grafting (12 women and 78 men; mean age, 56 ± 11 years) were randomized into 3 groups: (1) Controls (n = 30), (2) Perfusion (n = 30), and (3) Preconditioning (n = 30). All patients were operated under cardiopulmonary bypass using normothermic blood cardioplegia. Preconditioning was induced by subjecting the hemodynamically unloaded heart to 2 cycles of 3 min of ischemia and 3 min of reperfusion with normokalemic blood prior to cardioplegia. In the Perfusion group, the heart perfusion remained unaffected for 12 min. Troponin I (TnI) levels were analyzed before surgery, and 12, 24, 48 h, and 7 days after surgery. The secondary endpoints included the cardiac index, plasma natriuretic peptide level, and postoperative use of inotropes. Preconditioning resulted in a significant reduction in the TnI level on the 7th postoperative day only (0.10 ± 0.05 and 0.33 ± 0.88 ng/ml in Preconditioning and Perfusion groups, respectively, P < 0.05). In addition, cardiac index was significantly higher in the Preconditioning group than in the Control and Perfusion groups just after weaning from cardiopulmonary bypass. The number of patients requiring inotropic support with ≥ 2 agents after surgery was significantly lower in the Preconditioning and Perfusion group than in the Control group (P < 0.05). No complications of the procedure were recorded in the Preconditioning group. The preconditioning procedure described can be performed safely in cardiac surgery patients. The application of this technique of preconditioning was associated with certain benefits, including improved left ventricular function after weaning from cardiopulmonary bypass and a reduced need for inotropic support. However, the infarct-limiting effect of preconditioning in the early postoperative period was not evident. The procedure does not involve repetitive aortic cross-clamping, thus avoiding possible embolic complications.


An experimental approach to measure mass diffusion in rat tumor tissue.
The objective of this research is to evaluate the usefulness of a macroscopic, fluorescent, imaging technique to quantify spatiotemporal mass transport parameters in in vitro solid tumor tissues taken from rat models. Fluorescent images captured during the experiments are digitally analyzed to determine the concentration of a fluorescent marker dye as it diffuses into tissue specimens taken from rat tumors. The collected concentration data are used to estimate local diffusion coefficients. An analysis of the distribution of the local diffusion data indicates that the local diffusion coefficient is spatially dependent within the tumor tissue. When mass transfer is restricted to one dimension, the current technique can be used to determine the concentration distribution of fluorescent molecules on the tissue surface and to estimate the mass transfer parameters within the heterogeneous tumor tissue.


Evidence for furin-type activity-mediated C-terminal processing of profibrillin-1 and interference in the processing by certain mutations.
Fibrillin-1 is a major component of the 10 nm microfibrils of the extracellular matrix (ECM). It is synthesized as an approximately 350 kDa precursor molecule, profibrillin-1, which is proteolytically processed into its biologically active approximately 320 kDa form. Furin, a calcium-dependent endoprotease of the subtilisin family, which is known to be the processing enzyme for a variety of proproteins, is believed to be responsible for the N-terminal proteolytic cleavage of profibrillin-1. In this article we provide several lines of evidence that the C-terminal trimming of profibrillin-1 also occurs via a furin-type activity. Edman degradation of a small recombinant C-terminal subdomain of fibrillin-1 revealed complete processing of the peptide immediately after the tribasic recognition sequence (R-X-K/R-R) for furin. In vitro expression experiments using another recombinant construct consisting of the C-terminal half of fibrillin-1 indicated that disruption of the putative recognition sequence for furin by site-directed mutagenesis drastically impairs proteolytic processing of the propeptide. In addition, our results suggest that the N-terminal half of fibrillin-1 is necessary for its incorporation into the ECM.


Chitinase 3 like 1 is a regulator of smooth muscle cell physiology and atherosclerotic lesion stability.
Atherosclerotic cerebrovascular disease underlies the majority of ischaemic strokes and is a major cause of death and disability. While plaque burden is a predictor of adverse outcomes, plaque vulnerability is increasingly recognized as a driver of lesion rupture and risk for clinical events. Defining the molecular regulators of carotid instability could inform the development of new biomarkers and/or translational targets for at-risk individuals. Using two independent human endarterectomy biobanks, we found that the understudied glycoprotein, chitinase 3 like 1 (CHI3L1), is up-regulated in patients with carotid disease compared to healthy controls. Further, CHI3L1 levels were found to stratify individuals based on symptomatology and histopathological evidence of an unstable fibrous cap. Gain- and loss-of-function studies in cultured human carotid artery smooth muscle cells (SMCs) showed that CHI3L1 prevents a number of maladaptive changes in that cell type, including phenotype switching towards a synthetic and hyperproliferative state. Using two murine models of carotid remodelling and lesion vulnerability, we found that knockdown of Chil1 resulted in larger neointimal lesions comprised by de-differentiated SMCs that failed to invest within and stabilize the fibrous cap. Exploratory mechanistic studies identified alterations in potential downstream regulatory genes, including large tumour suppressor kinase 2 (LATS2), which mediates macrophage marker and inflammatory cytokine expression on SMCs, and may explain how CHI3L1 modulates cellular plasticity. CHI3L1 is up-regulated in humans with carotid artery disease and appears to be a strong mediator of plaque vulnerability. Mechanistic studies suggest this change may be a context-dependent adaptive response meant to maintain vascular SMCs in a differentiated state and to prevent rupture of the fibrous cap. Part of this effect may be mediated through downstream suppression of LATS2. Future studies should determine how these changes occur at the molecular level, and whether this gene can be targeted as a novel translational therapy for subjects at risk of stroke.


The gene transfer agent of Rhodobacter capsulatus and "constitutive transduction" in prokaryotes.
Transduction, bacteriophage-mediated gene transfer, is thought to play an important role in the evolution of prokaryote genomes. Several gene transfer agents that resemble transducing phages have been found in diverse prokaryotes. This mini-review discusses these interesting agents of genetic exchange with a focus on the gene transfer agent (GTA) of Rhodobacter capsulatus, at present the only member of this group for which genetic information exists about the production of transducing particles. Production of GTA results from expression of genes that are similar to phage genes, yet transcription of these genes is dependent upon cellular (two-component) signaling proteins. The significance of these relationships, as well as the finding of GTA gene homologues in the bacterium Rhodopseudomonas palustris, is discussed.


An investigation of the transmission and attenuation of intense pulsed light on samples of human Achilles tendon and surrounding tissue.
Light therapy is a common mode of treatment for musculoskeletal injuries but the depth of penetration of light radiation is controversial. Evidence exists for the efficacy of intense pulsed light (IPL) treatment for the rejuvenation of skin (superficial tissue) but it is not known if the IPL can penetrate deeper. If the IPL can penetrate to the depth of the Achilles tendon it may provide a potential management options in the treatment of a chronic mid-body Achilles tendinopathy. To examine if any optical radiation produced by an IPL transmits to the depth of the Achilles tendon when applied cutaneously to excised samples of human Achilles tissue. A secondary aim was to establish the relative amount of optical radiation that was attenuated within the tendon. Three samples of human Achilles tendon and surrounding tissue were harvested following elective lower limb amputation operations. Each sample was irradiated 2-6 cm above the insertion into the calcaneus (area of an Achilles tendinopathy) with IPL (model iPulse; Cyden Ltd, Wales, UK) set at a single pulse of 25 millisecond, wavelength range 530-1,110 nm and fluence of 13 J/cm(2). The transmission of light radiation was evaluated using (a) standard SLR digital camera, (b) spectrometer, and (c) an external energy meter. Light radiation was found to have transmitted through each of the three tissue samples by all three instruments. There were observable differences in the color of light detected for the control photo and the IPL irradiated tissue samples photographs. The percentage of fluence that was detected to have transmitted through the tissue samples by the energy meter was 4-8.1% and wavelengths between 645 and 843 nm were detected to have transmitted through the tissue by the spectrometer. In addition, the percentage of light radiation that attenuated with the tendon was 10.2-17.32%. The results of this study provides evidence that IPL penetrates to the depth of the Achilles tendon and attenuates with the tendon. IPL has potential to produce physiological effects in the treatment of patients with a chronic mid-body Achilles tendinopathy.


Reduction of Oxidative/Nitrosative Stress in Brain and its Involvement in the Neuroprotective Effect of n-3 PUFA in Alzheimer's Disease.
Plenty of evidence has shown that an enhanced oxidative or nitrosative stress may play a central role in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD). The suppressive effect of n-3 polyunsaturated fatty acids (n-3 PUFA) against oxidative/nitrosative stressinduced injury in nervous tissues has recently received increasing interest. A number of human experimental studies have concurred to demonstrate that they may exert a substantial preventive role, especially in the very early phase of mild cognitive impairment (MCI) preceding AD. It has been suggested that they may exert an indirect antioxidant/anti-nitrosative role by modulating the expression/ activity of several proteins involved in the modulation of oxidative stress in nervous tissues. In particular, recent data have supported the hypothesis that in the early phase of MCI the light to moderate oxidative stress triggered by not cytotoxic doses of n-3 PUFA can positively regulate the transcriptional activity of nuclear factor erythroid 2-related factor 2 (Nrf2). This may result in the induced expression of heme oxygenase-1 (HO-1) and other antioxidant proteins transcriptionally regulated by Nrf2. Alternatively, the anti-inflammatory and antioxidant/anti-nitrosative effects of n-3 PUFA have been lately related to their ability to blunt microglia persistent activation occurring during chronic inflammation involved in the pathogenesis of neurodegenerative diseases. Evidences have been presented that n-3 PUFA may convert microglia from the macrophage M1 to an M2 phenotype showing lower production of neurotoxicoxidative factors and enhanced phagocytic activity toward Aβ peptide, or even to a further phenotype with neurotrophic/ protective properties.


Inferences drawn from a risk assessment compared directly with a randomized trial of a home drinking water intervention.
Risk assessments and intervention trials have been used by the U.S. Environmental Protection Agency to estimate drinking water health risks. Seldom are both methods used concurrently. Between 2001 and 2003, illness data from a trial were collected simultaneously with exposure data, providing a unique opportunity to compare direct risk estimates of waterborne disease from the intervention trial with indirect estimates from a risk assessment. Comparing the group with water treatment (active) with that without water treatment (sham), the estimated annual attributable disease rate (cases per 10,000 persons per year) from the trial provided no evidence of a significantly elevated drinking water risk [attributable risk=-365 cases/year, sham minus active; 95% confidence interval (CI) , -2,555 to 1,825]. The predicted mean rate of disease per 10,000 persons per person-year from the risk assessment was 13.9 (2.5, 97.5 percentiles: 1.6, 37.7) assuming 4 log removal due to viral disinfection and 5.5 (2.5, 97.5 percentiles: 1.4, 19.2) assuming 6 log removal. Risk assessments are important under conditions of low risk when estimates are difficult to attain from trials. In particular, this assessment pointed toward the importance of attaining site-specific treatment data and the clear need for a better understanding of viral removal by disinfection. Trials provide direct risk estimates, and the upper confidence limit estimates, even if not statistically significant, are informative about possible upper estimates of likely risk. These differences suggest that conclusions about waterborne disease risk may be strengthened by the joint use of these two approaches. Key words: drinking water, gastrointestinal, intervention trial, microbial risk assessment, waterborne pathogens.


Potential heterogeneity in crustacean zooplankton assemblages in southern chilean saline lakes.
The Chilean saline lakes are distributed mainly in the Atacama desert in northern Chile and the southern Patagonian plains. The scarce studies are restricted mainly to northern Chilean saline lakes, and these revealed that the main component in these ecosystems are the halophylic copepod Boeckella poopoensis Marsh 1906, or the brine shrimp Artemia franciscana (Kellog, 1906), and both species do not coexist. The present study consisted of field observations in zooplankton assemblages in southern Chilean saline lakes (51-53 ºS). These first observations revealed three different patterns, one saline lake only with A. persimilis (Piccinelli and Prosdocimi, 1968), a second lake only with B. poopensis, and a third lake with A. persimilis, B. poopoensis and unidentified harpacticoid copepod. These results are different in comparison with the observations in the literature that described the non-coexistence between B. poopoensis with brine shrimps. Ecological and biogeographical topics were discussed.


Comparative and functional analysis of the archaeal cell cycle.
The temporal and spatial organization of the chromosome replication, genome segregation and cell division processes is less well understood in species belonging to the Archaea, than in those from the Bacteria and Eukarya domains. Novel insights into the regulation and key components of the Sulfolobus acidocaldarius cell cycle have been obtained through genome-wide analysis of cell cycle-specific gene expression, followed by cloning and characterization of gene products expressed at different cell cycle stages. Here, the results of the transcript profiling are further explored, and potential key players in archaeal cell cycle progression are highlighted in an evolutionary context, by comparing gene expression patterns and gene conservation between three selected microbial species from different domains of life. We draw attention to novel putative nucleases and helicases implicated in DNA replication, recombination and repair, as well as to potential genome segregation factors. Focus is also placed upon regulatory features, including transcription factors and protein kinases inferred to be involved in the execution of specific cell cycle stages, and regulation through metabolic coupling is discussed.


Clinical and Molecular Correlates of Escherichia coli Bloodstream Infection from Two Geographically Diverse Centers in Rochester, Minnesota, and Singapore.
Escherichia coli bacteremia is caused mainly by sequence type complex 131 (STc131) and two clades within its fluoroquinolone-resistance-associated H30 subclone, H30R1 and H30Rx. We examined clinical and molecular correlates of E. coli bacteremia in two geographically distinct centers. We retrospectively studied 251 unique E. coli bloodstream isolates from 246 patients (48 from the Mayo Clinic, Rochester, MN [MN], and 198 from Tan Tock Seng Hospital, Singapore [SG]), from October 2013 through March 2014. Isolates underwent PCR for phylogroup, STc, blaCTX-M type, and virulence gene profiles, and medical records were reviewed. Although STc131 accounted for 25 to 27% of all E. coli bacteremia isolates at each site, its extended-spectrum-β-lactamase (ESBL)-associated H30Rx clade was more prominent in SG than in MN (15% versus 4%; P = 0.04). In SG only, patients with STc131 (versus other E. coli STc isolates) were more likely to receive inactive initial antibiotics (odds ratio, 2.8; P = 0.005); this was true specifically for patients with H30Rx (odds ratio, 7.0; P = 0.005). H30Rx comprised 16% of community-onset bacteremia episodes in SG but none in MN. In SG, virulence scores were higher for H30Rx than for H30R1, non-H30 STc131, and non-STc131 isolates (P < 0.02 for all comparisons). At neither site did mortality differ by clonal status. The ESBL-associated H30Rx clade was more prevalent and more often of community onset in SG, where it predicted inactive empirical treatment. The clonal distribution varies geographically and has potentially important clinical implications. Rapid susceptibility testing and clonal diagnostics for H30/H30Rx might facilitate earlier prescribing of active therapy.


Surfactant alterations following donation after cardiac death donor lungs.
The use of lungs from donation after cardiac death (DCD) donors is one of the strategies to increase the donor pool. The aim of this study was to assess the surfactant alterations in DCD donor lungs. Pigs were sacrificed and left untouched for 1 (DCD1), 2 (DCD2) and 3 (DCD3) h. Lungs were then topically cooled with saline for 1, 2 or 3 h to reach a total ischemic time of 4 h. Heart-beating donors (HBD) served as control group. Bronchoalveolar lavage (BAL) samples were assessed for protein levels and surfactant function. Left lungs were prepared for ex-vivo evaluation. Pulmonary vascular resistance (PVR), oxygenation, airway pressure (AWP) and wet-to-dry weight ratio were significantly different between HBD and DCD3 groups (P < 0.05). BAL protein levels were statistically higher in DCD3 compared with HBD group (P < 0.05). Surface tension and surface tension measured at minimal bubble diameter (adsorption) were lower in HBD compared with DCD groups (P < 0.05). Adsorption was also lower in DCD1 compared with DCD2 (P < 0.05). Adsorption and surface tension were correlated with oxygenation and AWP (P < 0.05). This study has shown that lung function deteriorates with increasing warm ischemic time intervals. BAL protein, surface tension, adsorption, peak AWP and PVR increase significantly after 2 h of warm ischemia together with a significant reduction of the ratio PaO(2)/FiO(2).


Modeling the probability distribution of the bacterial burst size via a game-theoretic approach.
Based on previous studies, empirical distribution of the bacterial burst size varies even in a population of isogenic bacteria. Since bacteriophage progenies increase linearly with time, it is the lysis time variation that results in the bacterial burst size variations. Here, the burst size variation is computationally modeled by considering the lysis time decisions as a game. Each player in the game is a bacteriophage that has initially infected and lysed its host bacterium. Also, the payoff of each burst size strategy is the average number of bacteria that are solely infected by the bacteriophage progenies after lysis. For calculating the payoffs, a new version of ball and bin model with time dependent occupation probabilities (TDOP) is proposed. We show that Nash equilibrium occurs for a range of mixed burst size strategies that are chosen and played by bacteriophages, stochastically. Moreover, it is concluded that the burst size variations arise from choosing mixed lysis strategies by each player. By choosing the lysis time and also the burst size stochastically, the released bacteriophage progenies infect a portion of host bacteria in environment and avoid extinction. The probability distribution of the mixed burst size strategies is also identified.


Characterisation of the pig acute phase protein response to road transport.
The acute phase protein (APP) response was evaluated after prolonged transportation of pigs under commercial conditions. Elevated serum APP concentrations were observed in two groups of boars immediately after their arrival at a destination farm compared with within-animal control samples obtained one month later. The effect was more pronounced in the first group of pigs conveyed under average transport conditions (Transport 1, 24 h), although the second group was transported for a longer time period (Transport 2, 48 h) but in superior transport conditions. In a second trial, pigs were sampled before transport, on arrival at an abattoir (following 12 h transport), and at the slaughter-line (after 6 h lairage). Significant increases in major acute phase protein (Pig-MAP), haptoglobin, serum amyloid A, C-reactive protein, and a decrease in apolipoprotein A-I, were observed at slaughter. The results demonstrate that shipment of pigs by road can result in an APP response that is probably related to the stress of transport.


A nuclear gene encoding the beta subunit of the mitochondrial ATP synthase in Nicotiana plumbaginifolia.
The beta subunit of the mitochondrial ATP synthase in Nicotiana plumbaginifolia is encoded by two nuclear genes, atp2-1 and atp2-2, which are both expressed. The complete nucleotide sequence of atp2-1 has been determined. It contains eight introns ranging from 88 to 1453 bp. The last intron contains a putative insertion element (Inp), of 812 bp bordered by 35-bp inverted repeats which share an 11-bp homology with Agrobacterium tumefaciens T-DNA borders. Sequences homologous to Inp are present in multiple copies in the N. plumbaginifolia and the N. tabacum genome but not in more distant species. The atp2-1 encoded polypeptide is highly homologous to beta subunits from other ATP synthases but it contains an extension at the N terminus which is probably involved in mitochondrial targeting. A sequence homology between exon 4 of atp2-1 and exon 1 of the human ras genes suggests a common ancestral origin for these exons.


The human T-cell leukemia/lymphoma virus associated with American adult T-cell leukemia/lymphoma.
The human T-cell leukemia/lymphoma virus (HTLV) is a novel type-C retrovirus isolated from patients with T-lymphoproliferative malignancies. Thirteen cases of HTLV-associated malignancy from US centers were studied in detail. Ten of these cases share common clinical features and define a typical virus-associated adult T-cell leukemia/lymphoma (ATL). All ten patients presented with Ann Arbor stage IV lymphoma because of skin involvement, bone marrow involvement, or lymphomatous leptomeningitis. Lymphadenopathy occurred in 7 of 10 patients at presentation, and the malignant cells were cytologically pleomorphic. Leukemia occurred in 60% of the patients at presentation. Hypercalcemia was found initially in two-thirds of the patients, with lytic bone lesions or positive bone scans in 7 of 10. Complete remission occurred in 40%, but all have relapsed. These cases closely resemble those virus-positive cases of adult T-cell leukemia/lymphoma (ATL) reported from Japan and the Caribbean. Three additional virus-positive patients had atypical presentations and diagnoses (acute lymphocytic leukemia, Sézary's syndrome, leukemic reticuloendotheliosis), usually with less aggressive clinical courses and atypical demographic and laboratory features. Presence of HTLV serum antibodies in cases of ATL (with hypercalcemia and circulating malignant cells) appears to define a distinct clinicopathologic entity that may occur in geographic clusters.


Systematic dielectrophoretic analysis of the Ara-C-induced NB4 cell apoptosis combined with gene expression profiling.
Dielectrophoresis (DEP) can be used to noninvasively measure the dielectric state of the cell, and this data can be used to monitor cell health or apoptosis. In this study, we followed events associated with cytosine arabinoside (Ara-C)-induced apoptosis in NB4 cells using DEP analysis. Our data showed that the membrane capacitance of NB4 cells decreases from 9.42 to 7.63 mF/m(2) in the first 2 hours following treatment with Ara-C, and that this decreased capacitance persists for >12 hours. Additionally, cytoplasmic conductivity decreases from 0.217 to 0.190 S/m within 2 hours of Ara-C treatment; this level is maintained for a short period of time before decreasing. We also investigated these events molecularly at the level of gene expression using microarray analysis and showed that the expression of genes related to membrane capacitance and cytoplasmic conductivity change dramatically as early as 2 hours post-Ara-C treatment, and further demonstrated a temporal relationship between the dielectric properties and key events in apoptosis. This study, integrating physical electrical properties of the cell membrane and cytoplasm with those of conductivity-related gene networks, provides new insights into the molecular mechanisms underlying the initiation of apoptosis, establishing a systematic foundation for DEP application in follow-up drug screening and development of medicines for treating leukemia.


A conformational ensemble derived using NMR methyl chemical shifts reveals a mechanical clamping transition that gates the binding of the HU protein to DNA.
Recent improvements in the accuracy of structure-based methods for the prediction of nuclear magnetic resonance chemical shifts have inspired numerous approaches for determining the secondary and tertiary structures of proteins. Such advances also suggest the possibility of using chemical shifts to characterize the conformational fluctuations of these molecules. Here we describe a method of using methyl chemical shifts as restraints in replica-averaged molecular dynamics (MD) simulations, which enables us to determine the conformational ensemble of the HU dimer and characterize the range of motions accessible to its flexible β-arms. Our analysis suggests that the bending action of HU on DNA is mediated by a mechanical clamping mechanism, in which metastable structural intermediates sampled during the hinge motions of the β-arms in the free state are presculpted to bind DNA. These results illustrate that using side-chain chemical shift data in conjunction with MD simulations can provide quantitative information about the free energy landscapes of proteins and yield detailed insights into their functional mechanisms.


Pathogen Evasion of Chemokine Response Through Suppression of CXCL10.
Clearance of intracellular pathogens, such as Leishmania (L.) major, depends on an immune response with well-regulated cytokine signaling. Here we describe a pathogen-mediated mechanism of evading CXCL10, a chemokine with diverse antimicrobial functions, including T cell recruitment. Infection with L. major in a human monocyte cell line induced robust CXCL10 transcription without increasing extracellular CXCL10 protein concentrations. We found that this transcriptionally independent suppression of CXCL10 is mediated by the virulence factor and protease, glycoprotein-63 (gp63). Specifically, GP63 cleaves CXCL10 after amino acid A81 at the base of a C-terminal alpha-helix. Cytokine cleavage by GP63 demonstrated specificity, as GP63 cleaved CXCL10 and its homologs, which all bind the CXCR3 receptor, but not distantly related chemokines, such as CXCL8 and CCL22. Further characterization demonstrated that CXCL10 cleavage activity by GP63 was produced by both extracellular promastigotes and intracellular amastigotes. Crucially, CXCL10 cleavage impaired T cell chemotaxis in vitro, indicating that cleaved CXCL10 cannot signal through CXCR3. Ultimately, we propose CXCL10 suppression is a convergent mechanism of immune evasion, as Salmonella enterica and Chlamydia trachomatis also suppress CXCL10. This commonality suggests that counteracting CXCL10 suppression may provide a generalizable therapeutic strategy against intracellular pathogens. Leishmaniasis, an infectious disease that annually affects over one million people, is caused by intracellular parasites that have evolved to evade the host's attempts to eliminate the parasite. Cutaneous leishmaniasis results in disfiguring skin lesions if the host immune system does not appropriately respond to infection. A family of molecules called chemokines coordinate recruitment of the immune cells required to eliminate infection. Here, we demonstrate a novel mechanism that Leishmania (L.) spp. employ to suppress host chemokines: a Leishmania-encoded protease cleaves chemokines known to recruit T cells that fight off infection. We observe that other common human intracellular pathogens, including Chlamydia trachomatis and Salmonella enterica, reduce levels of the same chemokines, suggesting a strong selective pressure to avoid this component of the immune response. Our study provides new insights into how intracellular pathogens interact with the host immune response to enhance pathogen survival.


Lack of long-term effects of in utero exposure to zidovudine among uninfected children born to HIV-infected women. Pediatric AIDS Clinical Trials Group Protocol 219/076 Teams.
With the success of zidovudine chemoprophylaxis for prevention of perinatal transmission of the human immunodeficiency virus (HIV), an increasing number of HIV-exposed but uninfected children will have in utero exposure to zidovudine and other antiretroviral drugs. To evaluate the long-term effects of in utero exposure to zidovudine vs placebo among a randomized cohort of uninfected children. Prospective cohort study based on data collected during Pediatric AIDS Clinical Trials Group Protocol 076, a perinatal zidovudine HIV prevention trial, and Protocol 219, a long-term observational protocol. Pediatric research clinics in the United States. Two hundred thirty-four uninfected children born to 230 HIV-infected women enrolled in Protocol 076 and followed up through February 28, 1997, in Protocol 219 (122 in the zidovudine group and 112 in the placebo group). Physical growth measurements, immunologic parameters, cognitive/developmental function, occurrence of neoplasms, and mortality data assessed every 6 months for children younger than 24 months and yearly thereafter or as clinically indicated. Baseline echocardiogram and funduscopic evaluations were collected before 36 months of age. Median age of children at time of last follow-up visit was 4.2 years (range, 3.2-5.6 years). There were no significant differences between children exposed to zidovudine and those who received placebo in terms of sequential data on lymphocyte subsets; weight, height, and head circumference z scores; and cognitive/developmental function. No deaths or malignancies occurred. Two children (both exposed to zidovudine) are being followed up for abnormal, unexplained ophthalmic findings. One child exposed to zidovudine had a mild cardiomyopathy on echocardiogram at the age of 48 months; the child is clinically asymptomatic. No adverse effects were observed in HIV-uninfected children with in utero and neonatal exposure to zidovudine followed up for as long as 5.6 years. Continued prospective evaluations of children born to HIV-infected women who are exposed to antiretroviral or immunotherapeutic agents are critical to assess the long-term safety of interventions that prevent perinatal HIV transmission.


Appropriateness and utilization of cardiac CT: implications for development of future criteria.
The cardiac CT (CCT) appropriateness criteria (AC) were jointly published by multiple societies to ensure effective utilization of CCT. We sought to determine how these criteria apply to CCT scans performed at a tertiary-care hospital. Data were collected from medical records and interviews of 267 consecutive patients referred for CCT. Two physicians designated exam indication as appropriate, inappropriate, or uncertain as per AC, or "not known" if not listed in AC. CCT exam indication was appropriate in 47%, inappropriate in 9%, uncertain in 15%, and not known in 29%. The most common appropriate indication was evaluation of CAD in symptomatic patients with equivocal stress test, whereas the most common inappropriate referral was evaluation of asymptomatic patients with low pretest probability of CAD. Most exams (69%) were for evaluation of CAD, with the remaining exams performed to evaluate other elements of cardiac structure or function. Exams for these non-CAD indications were more likely to be appropriate and less likely to have an undetermined (uncertain or not known) level of appropriateness than those for CAD indications. There was no difference in exam appropriateness whether ordered by cardiologists or internists, but providers who completed training >25 years ago ordered fewer appropriate and more inappropriate exams than younger providers. In applying the AC to a large academic medical center, few CCT exams were inappropriate; however, many patients referred for CCT, particularly for evaluation of CAD, had an indication for which the level of appropriateness remained undetermined. Given the rapid adoption of CCT, these results emphasize the need to refine current criteria for appropriate utilization.


The control of carrier frequency in cricket calls: a refutation of the subalar-tegminal resonance/auditory feedback model.
The subalar-tegminal resonance/auditory feedback hypothesis attempts to explain how crickets control the carrier frequency (f(C)), the loudness and the spectral purity of their calls. This model contrasts with the 'clockwork cricket' or escapement model by proposing that f(C) is not controlled by the resonance of the cricket's radiators (the harps) but is instead controlled neurally. It suggests that crickets are capable of driving their harps to vibrate at any frequency and that they use a tunable Helmholtz-like resonator consisting of the tegmina and the air within the subalar space to amplify and filter the f(C). This model predicts that f(C) is variable, that call loudness is related to tegminal position (and subalar volume) and that low-density gases should cause f(C) to increase. In Anurogryllus arboreus, f(C) is not constant and varied by as much as 0.8 % between pulses. Within each sound pulse, the average f(C) typically decreased from the first to the last third of a sound pulse by 9 %. When crickets called in a mixture of heliox and air, f(C) increased 1.07- to 1.14-fold above the value in air. However, if the subalar space were part of a Helmholtz-like resonator, then its resonant frequency should have increased by 40-50 %. Moreover, similar increases occurred in species that lack a subalar space (oecanthines). Experimental reduction of the subalar volume of singing crickets resulted neither in a change in f(C) nor in a change in loudness. Nor did crickets attempt to restore the subalar volume to its original value. These results disprove the presence of a subalar-tegminal resonator. The free resonance of freshly excised Gryllus rubens tegmina shifted by 1.09-fold when moved between air and a mixture of helium and air. Auditory feedback cannot be the cause of this shift, which is similar to the f(C) shifts in intact individuals of other species. Calculations show that the harp is 3.9-1.8 times more massive than the air that moves en masse with the vibrating harps. Replacing air with heliox-air lowers the mass of the vibrating system sufficiently to account for the f(C) shifts. These results re-affirm the 'clockwork cricket' (escapement) hypothesis. However, as realized by others, the harps should be viewed as narrow-band variable-frequency oscillators whose tuning may be controlled by factors that vary the effective mass.


Vast diversity of prokaryotic virus genomes encoding double jelly-roll major capsid proteins uncovered by genomic and metagenomic sequence analysis.
Analysis of metagenomic sequences has become the principal approach for the study of the diversity of viruses. Many recent, extensive metagenomic studies on several classes of viruses have dramatically expanded the visible part of the virosphere, showing that previously undetected viruses, or those that have been considered rare, actually are important components of the global virome. We investigated the provenance of viruses related to tail-less bacteriophages of the family Tectiviridae by searching genomic and metagenomics sequence databases for distant homologs of the tectivirus-like Double Jelly-Roll major capsid proteins (DJR MCP). These searches resulted in the identification of numerous genomes of virus-like elements that are similar in size to tectiviruses (10-15 kilobases) and have diverse gene compositions. By comparison of the gene repertoires, the DJR MCP-encoding genomes were classified into 6 distinct groups that can be predicted to differ in reproduction strategies and host ranges. Only the DJR MCP gene that is present by design is shared by all these genomes, and most also encode a predicted DNA-packaging ATPase; the rest of the genes are present only in subgroups of this unexpectedly diverse collection of DJR MCP-encoding genomes. Only a minority encode a DNA polymerase which is a hallmark of the family Tectiviridae and the putative family "Autolykiviridae". Notably, one of the identified putative DJR MCP viruses encodes a homolog of Cas1 endonuclease, the integrase involved in CRISPR-Cas adaptation and integration of transposon-like elements called casposons. This is the first detected occurrence of Cas1 in a virus. Many of the identified elements are individual contigs flanked by inverted or direct repeats and appear to represent complete, extrachromosomal viral genomes, whereas others are flanked by bacterial genes and thus can be considered as proviruses. These contigs come from metagenomes of widely different environments, some dominated by archaea and others by bacteria, suggesting that collectively, the DJR MCP-encoding elements have a broad host range among prokaryotes. The findings reported here greatly expand the known host range of (putative) viruses of bacteria and archaea that encode a DJR MCP. They also demonstrate the extreme diversity of genome architectures in these viruses that encode no universal proteins other than the capsid protein that was used as the marker for their identification. From a supposedly minor group of bacterial and archaeal viruses, these viruses are emerging as a substantial component of the prokaryotic virome.


Robot Assisted Surgical Ward Rounds: Virtually Always There.
While an explosion in technological sophistication has revolutionized surgery within the operating theatre, delivery of surgical ward-based care has seen little innovation. Use of telepresence allowing off-site clinicians communicate with patients has been largely restricted to outpatient settings or use of complex, expensive, static devices. We designed a prospective study to ascertain feasibility and face validity of a remotely controlled mobile audiovisual drone (LUCY) to access inpatients. This device is, uniquely, lightweight, freely mobile and emulates 'human' interaction by swiveling and adjusting height to patients' eye-level. METHODS: Robot-assisted ward rounds(RASWR) were conducted over 3 months. A remotely located consultant surgeon communicated with patients/bedside teams via encrypted audiovisual telepresence robot (DoubleRoboticstm, California USA). Likert-scale satisfaction questionnaires, incorporating free-text sections for mixed-methods data collection, were disseminated to patient and staff volunteers following RASWRs. The same cohort completed a linked questionnaire following conventional (gold-standard) rounds, acting as control group. Data were paired, and non-parametric analysis performed. RESULTS: RASWRs are feasible (>90% completed without technical difficulty). The RASWR(n=52 observations) demonstrated face validity with strong correlations (r>0.7; Spearman, p-value <0.05) between robotic and conventional ward rounds among patients and staff on core themes, including dignity/confidentiality/communication/satisfaction with management plan. Patients (96.08%, n=25) agreed RASWR were a satisfactory alternative when consultant physical presence was not possible. There was acceptance of nursing/NCHD cohort (100% (n=11) willing to regularly partake in RASWR). CONCLUSION: RASWRs receive high levels of patient and staff acceptance, and offer a valid alternative to conventional ward rounds when a consultant cannot be physically present.


A germinal center-associated microenvironmental signature reflects malignant phenotype and outcome of DLBCL.
Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell malignancy, with varying prognosis after the gold standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Several prognostic models have been established by focusing primarily on characteristics of lymphoma cells themselves, including cell-of-origin (COO), genomic alterations, and gene/protein expressions. However, the prognostic impact of the lymphoma microenvironment and its association with characteristics of lymphoma cells are not fully understood. Using the nCounter-based gene expression profiling of untreated DLBCL tissues, we assess the clinical impact of lymphoma microenvironment on the clinical outcomes and pathophysiological, molecular signatures in DLBCL. The presence of normal germinal center (GC)-microenvironmental cells, including follicular T cells, macrophage/dendritic cells, and stromal cells in lymphoma tissue indicates a positive therapeutic response. Our prognostic model, based on quantitation of transcripts from distinct GC-microenvironmental cell markers, clearly identified patients with graded prognosis independently of existing prognostic models. We observed increased incidences of genomic alterations and aberrant gene expression associated with poor prognosis in DLBCL tissues lacking GC-microenvironmental cells relative to those containing these cells. These data suggest that the loss of GC-associated microenvironmental signature dictates clinical outcomes of DLBCL patients reflecting the accumulation of "unfavorable" molecular signatures.


GPU-BLAST: using graphics processors to accelerate protein sequence alignment.
The Basic Local Alignment Search Tool (BLAST) is one of the most widely used bioinformatics tools. The widespread impact of BLAST is reflected in over 53,000 citations that this software has received in the past two decades, and the use of the word 'blast' as a verb referring to biological sequence comparison. Any improvement in the execution speed of BLAST would be of great importance in the practice of bioinformatics, and facilitate coping with ever increasing sizes of biomolecular databases. Using a general-purpose graphics processing unit (GPU), we have developed GPU-BLAST, an accelerated version of the popular NCBI-BLAST. The implementation is based on the source code of NCBI-BLAST, thus maintaining the same input and output interface while producing identical results. In comparison to the sequential NCBI-BLAST, the speedups achieved by GPU-BLAST range mostly between 3 and 4. The source code of GPU-BLAST is freely available at http://archimedes.cheme.cmu.edu/biosoftware.html.


Estren behaves as a weak estrogen rather than a nongenomic selective activator in the mouse uterus.
A proposed membrane-mediated mechanism of rapid nongenomic response to estrogen has been the intense focus of recent research. Estren, a synthetic steroid, is reported to act selectively through a rapid membrane-mediated pathway, rather than through the classical nuclear estrogen receptor (ER)-mediated pathway, to maintain bone density in ovariectomized mice without uterotropic effects. To evaluate the mechanism and physiological effects of estren, we studied responses in adult ovariectomized mice. In a 3-d uterine bioassay, we found that 300 microg estren significantly increased uterine weight; in comparison, a more maximal response was seen with 1 mug estradiol (E2). The estren response was partly ERalpha independent, because ERalpha knockout (alphaERKO) uteri also exhibited a more moderate weight increase. Estren induced epithelial cell proliferation in wild-type, but not alphaERKO, mice, indicating ERalpha dependence of the epithelial growth response. Examination of estren-regulated uterine genes by microarray indicated that early (2 h) changes in gene expression are similar to the early responses to E2. These gene responses are ERalpha dependent, because they are not seen in alphaERKO mice. Later estren-induced changes in gene expression (24 h) are blunted compared with those seen 24 h after E2. In contrast to early genes, these later estren responses are independent of ERalpha, because the alphaERKO shows a similar response to estren at 24 h. We found that E2 or estren treatments lead to depletion of ERalpha in the uterine cytosol fraction and accumulation in the nuclear fraction within 30-60 min, consistent with the ability of estren to regulate genes through a nuclear ERalpha rather than a nongenomic mechanism. Interestingly, estren, but not E2, induces accumulation of androgen receptor (AR) in the nuclear fraction of both wild-type and alphaERKO samples, suggesting that AR might be involved in the later ERalpha-independent genomic responses to estren. In conclusion, our studies suggest that estren is weakly estrogenic in the mouse uterus and might induce nuclear ERalpha- and AR-mediated responses. Given its activity in our uterine model, the use of estren as a bone-selective clinical compound needs to be reconsidered.


Abacavir/lamivudine versus tenofovir/emtricitabine in virologically suppressed patients switching from ritonavir-boosted protease inhibitors to raltegravir.
There are few clinical data on the combination abacavir/lamivudine plus raltegravir. We compared the outcomes of patients from the SPIRAL trial receiving either abacavir/lamivudine or tenofovir/emtricitabine at baseline who had taken at least one dose of either raltegravir or ritonavir-boosted protease inhibitors. For the purpose of this analysis, treatment failure was defined as virological failure (confirmed HIV-1 RNA ≥50 copies/ml) or discontinuation of abacavir/lamivudine or tenofovir/emtricitabine because of adverse events, consent withdrawal, or lost to follow-up. There were 143 (72.59%) patients with tenofovir/emtricitabine and 54 (27.41%) with abacavir/lamivudine. In the raltegravir group, there were three (11.11%) treatment failures with abacavir/lamivudine and eight (10.96%) with tenofovir/emtricitabine (estimated difference 0.15%; 95% CI -17.90 to 11.6). In the ritonavir-boosted protease inhibitor group, there were four (14.81%) treatment failures with abacavir/lamivudine and 12 (17.14%) with tenofovir/emtricitabine (estimated difference -2.33%; 95% CI -16.10 to 16.70). Triglycerides decreased and HDL cholesterol increased through the study more pronouncedly with abacavir/lamivudine than with tenofovir/emtricitabine and differences in the total-to-HDL cholesterol ratio between both combinations of nucleoside reverse transcriptase inhibitors (NRTIs) tended to be higher in the raltegravir group, although differences at 48 weeks were not significant. While no patient discontinued abacavir/lamivudine due to adverse events, four (2.80%) patients (all in the ritonavir-boosted protease inhibitor group) discontinued tenofovir/emtricitabine because of adverse events (p=0.2744). The results of this analysis do not suggest that outcomes of abacavir/lamivudine are worse than those of tenofovir/emtricitabine when combined with raltegravir in virologically suppressed HIV-infected adults.


If Stigmatized, Self-Esteem Is not Enough: Effects of Sexism, Self-Esteem and Social Identity on Leadership Aspiration.
Ambivalent sexism has many pernicious consequences. Since gender stereotypes also affect leadership roles, the present research investigated the effects of ambivalent sexism on envisioning oneself as a leader. Our studies tested the influence of sexist attitudes (toward women - Study 1 - and men - Study 2) on leadership aspiration, taking into account the interaction among ambivalent attitudes, personal characteristics (e.g. self-esteem), and group processes (e.g. level of identification with gender). Specifically, the current study used a 3 (sexism: hostile, benevolent, control) x 2 (social identification: high, low) x 2 (self-esteem: high, low) factorial design. 178 women participated in Study 1. Results showed that, although sexism was not recognised as a form of prejudice and did not trigger negative emotions, in sexist conditions high-identified women increase their leadership aspiration. In Study 2 men (N = 184) showed to recognise hostility as a form of prejudice, to experience more negative emotions, but to be not influenced in leadership aspiration. For both men and women self-esteem had a significant main effect on leadership aspiration.


Cannabis use and risks of respiratory and all-cause morbidity and mortality: a population-based, data-linkage, cohort study.
Although cannabis is frequently used worldwide, its impact on respiratory health is characterised by controversy. To evaluate the association between cannabis use and respiratory-related emergency room (ER) visits and hospitalisations. A retrospective, population-based, cohort study was carried out, linking health survey and health administrative data for residents of Ontario, Canada, aged 12-65 years, between January 2009 and December 2015. Individuals self-reporting cannabis use within the past year were matched to control individuals (people who reported never using cannabis, or used cannabis only once, and more than 12 months ago) in upwards of a 1:3 ratio on 31 different variables, using propensity score matching methods. Respiratory-related and all-cause ER visits or hospitalisations, and all-cause mortality, were evaluated up to 12 months following the index date. We identified 35 114 individuals who had either used cannabis in the past year or were controls, of whom 6425 (18.3%) used cannabis in the past year. From this group, 4807 (74.8%) were propensity-score matched to 10 395 control individuals. In the propensity score matched cohort, there was no significant difference in odds of respiratory-related ER visit or hospitalisation between cannabis users and the control group (OR 0.91, 95% CI 0.77 to 1.09). Compared with control individuals, cannabis users had significantly increased odds of all-cause ER visit or hospitalisation (OR 1.22, 95% CI 1.13 to 1.31) and there was no significant difference with respect to all-cause mortality (OR 0.99, 95% CI 0.49 to 2.02). Although no significant association was observed between cannabis use and respiratory-related ER visits or hospitalisations, the risk of an equally important morbidity outcome, all-cause ER visit or hospitalisation, was significantly greater among cannabis users than among control individuals. Therefore, cannabis use is associated with increased risk for serious adverse health events and its recreational consumption is not benign.


FS4JK farm safety day camps: who learns the most?
Farm Safety 4 Just Kids uses daylong community-based farm safety day camps as a primary method to instruct children about the hazards in farm environments. This article describes children's knowledge about farm safety before and after a day camp experience and assesses differences in knowledge gain by farm residency status and by gender as a result of their attendance at the camps. Data collection focused on three high-risk farm exposures: tractors, powered equipment, and large animals. A 32-item pre- and post-camp survey developed by the research team measured children's knowledge scores in these three focal areas. The sample consisted of 1,233 children, ranging from 8 to 12 years of age. Mixed models were used to test for changes in knowledge over time and for differences by gender and by farm/nonfarm status of the child. The results were encouraging: both farm and nonfarm children increased their knowledge about farm injury risk. Overall, girls demonstrated greater knowledge than boys on both the pre- and post-tests. Based on these findings, farm safety day camps appear to improve the knowledge of children about the injury risks associated with the farm environment. Refinements to the camp structure may foster greater knowledge gain of children attending the camps. While education of children about farm safety is not the sole answer to decreasing injury, it is a key component that should not be discounted.


Frequency analysis of wavefront curvature sensing: optimum propagation distance and multi-z wavefront curvature sensing.
In this paper we determine the optimum propagation distance between measurement planes and the plane of the lens in a wavefront curvature sensor with the diffraction optics approach. From the diffraction viewpoint, the measured wavefront aberration can be decomposed into Fourier harmonics at various frequencies. The curvature signal produced by a single harmonic is analyzed with the wave propagation transfer function approach, which is the frequency analysis of wavefront curvature sensing. The intensity of the curvature signal is a sine function of the product of the propagation distance and the squared frequency. To maximize the curvature signal, the optimum propagation distance is proposed as one quarter of the Talbot length at the critical frequency (average power point at which the power spectrum density is the average power spectrum density). Following the determination of the propagation distance, the intensity of the curvature signal varies sinusoidally with the squared frequencies, vanishing at some higher frequency bands just like a comb filter. To cover these insensitive bands, wavefront curvature sensing with dual propagation distances or with multi-propagation distances is proposed.


Highly sensitive silicon microreactor for catalyst testing.
A novel microfabricated chemical reactor for highly sensitive measurements of catalytic activity and surface kinetics is presented. The reactor is fabricated in a silicon chip and is intended for gas-phase reactions at pressures ranging from 0.1 to 5.0 bar. A high sensitivity is obtained by directing the entire gas flow through the catalyst bed to a mass spectrometer, thus ensuring that nearly all reaction products are present in the analyzed gas flow. Although the device can be employed for testing a wide range of catalysts, the primary aim of the design is to allow characterization of model catalysts which can only be obtained in small quantities. Such measurements are of significant fundamental interest but are challenging because of the low surface areas involved. The relationship between the reaction zone gas flow and the pressure in the reaction zone is investigated experimentally. A corresponding theoretical model is presented, and the gas flow through an on-chip flow-limiting capillary is predicted to be in the intermediate regime. The experimental data for the gas flow are found to be in good agreement with the theoretical model. At typical experimental conditions, the total gas flow through the reaction zone is around 3x10(14) molecules s(-1), corresponding to a gas residence time in the reaction zone of about 11 s. To demonstrate the operation of the microreactor, CO oxidation on low-area platinum thin film circles is employed as a test reaction. Using temperature ramping, it is found that platinum catalysts with areas as small as 15 microm(2) are conveniently characterized with the device.


Austronesian genetic signature in East African Madagascar and Polynesia.
The dispersal of the Austronesian language family from Southeast Asia represents the last major diaspora leading to the peopling of Oceania to the East and the Indian Ocean to the West. Several theories have been proposed to explain the current locations, and the linguistic and cultural diversity of Austronesian populations. However, the existing data do not support unequivocally any given migrational scenario. In the current study, the genetic profile of 15 autosomal STR loci is reported for the first time for two populations from opposite poles of the Austronesian range, Madagascar at the West and Tonga to the East. These collections are also compared to geographically targeted reference populations of Austronesian descent in order to investigate their current relationships and potential source population(s) within Southeast Asia. Our results indicate that while Madagascar derives 66.3% of its genetic makeup from Africa, a clear connection between the East African island and Southeast Asia can be discerned. The data suggest that although geographic location has influenced the phylogenetic relationships between Austronesian populations, a genetic connection that binds them beyond geographical divides is apparent.


Rapid detection of cfiA metallo-β-lactamase-producing Bacteroides fragilis by the combination of MALDI-TOF MS and CarbaNP.
Carbapenem resistance in Bacteroides fragilis is emerging and is mainly attributed to insertion sequence (IS)-mediated activation of the carbapenemase gene cfiA. We investigated the use of matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS) and the CarbaNP assay for the rapid identification of these strains. This study used the Bruker MALDI Biotype system and the mass spectra models generated by 20 B. fragilis reference strains (10 cfiA-positive and 10 cfiA-negative) in the ClinProTools software to identify 404 B. fragilis (71 cfiA-positive and 333 cfiA-negative) clinical isolates. The ability of the CarbaNP assay to detect IS-mediated activation of the cfiA gene was assessed and the results obtained by molecular analysis were used as reference methods. The support vector machine model generated by ClinProTools was found to be the most reliable algorithm for differentiation of cfiA-positive and cfiA-negative B. fragilis subgroups. Using the direct transfer method, all but one cfiA-negative isolates were correctly identified to the two subgroups by the model. The correct identification of the cfiA-negative isolate was obtained upon retesting by the extraction method. Of the 81 cfiA-positive isolates, PCR and sequencing showed that 30 had an IS element providing the promoter for activation of cfiA. With regard to the presence of the IS element, the CarbaNP test in the cfiA upstream region had 100% sensitivity, 80.4% specificity, 75.0% positive predictive value and 100% negative predictive value. The combination of MALDI-TOF MS and the CarbaNP assay can be applied in diagnostic clinical laboratory for rapid identification of B. fragilis with IS element-activated cfiA gene.


Low bone mineral density is associated with dyslipidemia in South Korean men: the 2008-2010 Korean National Health and Nutrition Examination Survey.
This study examined the relationship between bone mineral density (BMD) and dyslipidemia in South Korean men. Data from 6,300 men who participated in the Korean National Health and Nutrition Examination Survey from 2008 to 2010 were analyzed, including serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) after 8 hours of fasting and mean BMD measured at the lumbar spine (LS), total hip (TH), and femoral neck (FN). Dyslipidemia was defined according to the criteria of the National Cholesterol Education Program Adult Treatment Panel III. Other parameters of dyslipidemia were also calculated, such as TG/HDL-C, TC/HDL-C, non-HDL-C (NHDL-C), and LDL-C/HDL-C. Men with dyslipidemia and high levels of TG, TG/HDL-C, TC/HDL-C, NHDL-C, and LDL-C/HDL-C had lower BMD than men without dyslipidemia at the LS, TH, and FN after adjustment for age and body mass index (all p<0.01). On multivariable regression analysis, all odds ratios for high levels of TG, TG/HDL-C, TC/HDL-C, NHDL-C, and LDL-C/HDL-C with an increase in BMD (per standard deviation) were <1 at all 3 sites after adjustment for age and body mass index (model 1). After adjustment for all covariates, only odds ratios for high levels of TG, TG/HDL-C, TC/HDL-C, and NHDL-C were <1 at all 3 sites (model 2), but an increase in BMD was not associated with high LDL-C levels in models 1 and 2. In conclusion, BMD was inversely correlated with parameters of atherogenic dyslipidemia in South Korean men.


Structure of the Helicase Domain of DNA Polymerase Theta Reveals a Possible Role in the Microhomology-Mediated End-Joining Pathway.
DNA polymerase theta (Polθ) has been identified as a crucial alternative non-homologous end-joining factor in mammalian cells. Polθ is upregulated in a range of cancer cell types defective in homologous recombination, and knockdown has been shown to inhibit cell survival in a subset of these, making it an attractive target for cancer treatment. We present crystal structures of the helicase domain of human Polθ in the presence and absence of bound nucleotides, and a characterization of its DNA-binding and DNA-stimulated ATPase activities. Comparisons with related helicases from the Hel308 family identify several unique features. Polθ exists as a tetramer both in the crystals and in solution. We propose a model for DNA binding to the Polθ helicase domain in the context of the Polθ tetramer, which suggests a role for the helicase domain in strand annealing of DNA templates for subsequent processing by the polymerase domain.


Morphometric differentiation in Cornops aquaticum (Orthoptera: Acrididae): associations with sex, chromosome, and geographic conditions.
The water-hyacinth grasshopper Cornops aquaticum (Bruner) (Orthoptera: Acrididae) is native to South America and inhabits lowlands from southern Mexico to central Argentina and Uruguay. This grasshopper feeds and lays eggs on species from the genera Eichhornia and Pontederia. Particularly, Eichhornia crassipes is considered "the world's worst water weed," and the release of C. aquaticum was proposed as a form of biological control. Morphometric variation on the chromosomally differentiated populations from the middle and lower Paraná River and its possible association with geographic, sex, and chromosomal conditions was analyzed. Significant phenotype variation in C. aquaticum population was detected. C. aquaticum presents body-size sexual dimorphism, females being bigger than males. Female-biased sexual size dimorphism for all five analyzed traits was detected. The assessment of variation in sexual size dimorphism for tegmen length showed that this trait scaled allometrically, indicating that males and females did not vary in a similar fashion. The detected allometry was consistent with Rensch's rule demonstrating greater evolutionary divergence in male size than in female size and suggests that males are more sensitive to environmental condition. The analysis of morphometric variation in the context of chromosome constitution showed that the presence of fusion 1/6 was related to body-size variation. Fusion carriers displayed bigger body size than standard homozygotes. Besides, a positive relationship between tegmen length and the number of fused chromosomes was detected, showing a chromosome dose effect. Because the highest frequency of fusions has been found in the lower Paraná River, a marginal environment for this species, the results found would support the hypothesis that some supergenes located in the fusions may be favored in the southern populations, thus contributing to the establishment and maintenance of the polymorphism.


Design and synthesis of a new dimeric xanthone derivative: enhancement of G-quadruplex selectivity and telomere damage.
Following the results we previously reported on a series of xanthene and xanthone derivatives as G-quadruplex stabilizing ligands, in order to obtain a more selective compound with respect to the previous generation of derivatives, we decided to modify the structure of the core ligand, specifically its aromatic extension. In particular, here we report the design, synthesis and activity data of a new compound obtained by dimerization of the xanthene core (HELIXA4C). The reported results show that extension of the aromatic core and the increase of the number of polar side chains led to a great enhancement of G-quadruplex selectivity and telomere damage capability, as derived using ESI-MS evaluation, in vitro cancer screening and specific immunofluorescence assays.


Ruthenium-106 plaque brachytherapy for thick posterior uveal melanomas.
Ruthenium-106 brachytherapy is an effective method for treating small to medium uveal melanomas. The purpose of this study was to examine its effectiveness and safety in the management of thick posterior uveal melanoma (apical height >/=8.0 mm) and to compare it with enucleation. 126 consecutive patients with thick uveal melanoma were included. 63 patients treated with Ruthenium-106 brachytherapy were compared with 63 patients treated with enucleation. The main outcome measures were visual acuity, eye retention, local recurrence, metastases, all-cause mortality and melanoma-related mortality. Patients treated with brachytherapy were significantly younger and had significantly smaller tumours, compared with patients treated with enucleation. Tumour thickness in the brachytherapy group was 9.3 (SD 0.9) mm compared with 12.2 (1.9) mm in the enucleation group. The 5- and 10-year melanoma-related mortality was 20.5% and 46.2% for brachytherapy patients and 28.1% and 44.0% for enucleation patients (p = 0.6 and p = 0.9). When comparing 15 brachytherapy with 15 matched enucleation patients, the 5-year melanoma-related mortalities were similar, 28.6% and 33.3% respectively (p = 0.7). Complications associated with brachytherapy included tumour regrowth (n = 15), scleral melt (n = 3), neovascular glaucoma (n = 5) and vitreous haemorrhage (n = 3). In the brachytherapy group, no significant difference in survival was noted between patients who did and did not develop local recurrence (p = 0.9). Of the eyes that were initially treated with brachytherapy, 71.4% were saved from enucleation. Of these, 70.8% had a final visual acuity of 20/200 or better. Ruthenium-106 brachytherapy is an alternative to enucleation in some thick posterior uveal melanomas.


Chemotherapy principles of managing stage IV breast cancer in the United States.
The therapeutic landscape for metastatic breast cancer (MBC) has expanded greatly over the last three decades with an increasing availability of targeted therapies for specific breast cancer subtypes. However, cytotoxic chemotherapy remains an essential component for the management of endocrine refractory or triple negative MBC. Multiple chemotherapy agents have demonstrated activity in MBC as single agents and in combination. While taxanes are frequently recommended as the initial treatment of metastatic disease, capecitabine is a convenient oral therapy with well received toxicity profile. Eribulin is the only agent that demonstrated overall survival (OS) benefit in a phase III clinical trial when compared to treatment of physician choice in heavily pre-treated patients. Ixabepilone, gemcitabine, vinorelbine and platinum agents have demonstrated activity and, therefore, constitute additional therapeutic options. In this review, we will discuss the data supporting the use of different cytotoxic agents and the general principles in guiding the use of chemotherapy.


Autophosphorylation sites participate in the activation of the double-stranded-RNA-activated protein kinase PKR.
The interferon-induced RNA-dependent protein kinase PKR is found in cells in a latent state. In response to the binding of double-stranded RNA, the enzyme becomes activated and autophosphorylated on several serine and threonine residues. Consequently, it has been postulated that autophosphorylation is a prerequisite for activation of the kinase. We report the identification of PKR sites that are autophosphorylated in vitro concomitantly with activation and examine their roles in the activation of PKR. Mutation of one site, threonine 258, results in a kinase that is less efficient in autophosphorylation and in phosphorylating its substrate, the initiation factor eIF2, in vitro. The mutant kinase is also impaired in vivo, displaying reduced ability to inhibit protein synthesis in yeast and mammalian cells and to induce a slow-growth phenotype in Saccharomyces cerevisiae. Mutations at two neighboring sites, serine 242 and threonine 255, exacerbated the effect. Taken together with earlier results (S. B. Lee, S. R. Green, M. B. Mathews, and M. Esteban, Proc. Natl. Acad. Sci. USA 91:10551-10555, 1994), these data suggest that the central part of the PKR molecule, lying between its RNA-binding and catalytic domains, regulates kinase activity via autophosphorylation.


Choice Under Risk: How Occupation Influences Preferences.
In the last decade, a number of studies in the behavioral sciences, particularly in psychology and economics, have explored the complexity of individual risk behavior and its underlying factors. Most previous studies have examined the influences of various socio-economic, cognitive, biological and psychological factors on human decision-making, however, the relationship between the decision-makers' risk preferences and occupational background has not received much empirical attention. Accordingly, in the current study, we investigated how occupational background, together with decision-making framing (e.g., variations in decision domain, context, presentation of risk, and utility ratios), influence participants' risk preferences for decision options with equivalent expected utility. Our novel findings indicate that risk preferences may vary among individuals from different occupational backgrounds. As such, when the task was framed in gain terms, participants who mostly deal with health/safety-related risks on a day-to-day basis (high-risk occupations) were predominantly risk-averse (avoiding risky options), while participants who mostly deal with financial/social risks (white-collar occupations) were prone to risk-seeking behavior (avoiding certain options). Specifically, in "high-risk" occupations, participants' pattern of choices changed from risk-averse in gain scenarios to risk-seeking in loss scenarios. However, the opposite pattern of risk preferences was found in participants with "white-collar" occupations. Our findings indicate that decision-makers' occupational backgrounds influence risk preferences under some circumstances.


Foxm1 transcription factor is required for maintenance of pluripotency of P19 embryonal carcinoma cells.
Transcription factor Foxm1 plays a critical role during embryonic development and its expression is repressed during retinoic acid (RA)-induced differentiation of pluripotent P19 embryonal carcinoma cells at the early stage, correlated with downregulation of expression of pluripotency markers. To study whether Foxm1 participates in the maintenance of pluripotency of stem cells, we knock down Foxm1 expression in P19 cells and identify that Oct4 are regulated directly by Foxm1. Knockdown of Foxm1 also results in spontaneous differentiation of P19 cells to mesodermal derivatives, such as muscle and adipose tissues. Maintaining Foxm1 expression prevents the downregulation of pluripotency-related transcription factors such as Oct4 and Nanog during P19 cell differentiation. Furthermore, overexpression of FOXM1 alone in RA-differentiated P19 cells (4 days) or human newborn fibroblasts restarts the expression of pluripotent genes Oct4, Nanog and Sox2. Together, our results suggest a critical involvement of Foxm1 in maintenance of stem cell pluripotency.


Atrial and ventricular function after cardioversion of atrial fibrillation.
Previous studies on atrial recovery after cardioversion of atrial fibrillation have not taken into account new knowledge about the pathophysiology of transmitral and transtricuspid flow velocity patterns. It is possible to shed further light on this problem if atrioventricular inflow velocity, venous filling pattern, and atrioventricular annulus motion are recorded and interpreted together. Prospective examinations of mitral and tricuspid transvalvar flow velocities, superior caval and pulmonary venous filling, and mitral and tricuspid annulus motion were recorded using Doppler echocardiography. Examinations were performed before and 24 hours, 1 month, and 20 months after cardioversion. Tertiary referral centre for cardiac disease with facilities for invasive and non-invasive investigation. 16 patients undergoing cardioversion of atrial fibrillation in whom sinus rhythm had persisted for 24 hours or more. Before conversion there was no identifiable A wave in transvalvar flow recordings. The total motion of the tricuspid and mitral annulus was subnormal and there was no identifiable atrial component. Venous flow patterns in general showed a low systolic velocity. After conversion, A waves and atrial components were seen in all patients and increased significantly (P < 0.01) with time. There was a similar time course for the amplitude of annulus atrial components, an increased systolic component of venous inflow, an increased A wave velocity, and a decreased E/A ratio of the transvalvar velocity curves. The ventricular component of annulus motion was unchanged. Changes in general occurred earlier on the right side than the left. This study indicates that, in addition to the previously known electromechanical dissociation of atrial recovery that exists after cardioversion of atrial fibrillation, there may also be a transient deterioration of ventricular function modulating the transvalvar inflow velocity recordings. Function on the right side generally becomes normal earlier than on the left. Integration of information from transvalvar inflow curves, annulus motion, and venous filling patterns gives additional insight into cardiac function.


Treatment with PEG-interferon and ribavirin for chronic hepatitis C increases neutrophil and monocyte chemotaxis.
The incidence of infections increases during treatment with pegylated interferon (PEG-IFN) and ribavirin (RBV) for chronic hepatitis C (CHC). Despite a reduction in neutrophil count, there is no clear relationship between infection occurrence and neutropenia. In the present study we investigated whether HCV treatment alters leukocyte function. We studied cell chemotaxis, reactive oxygen species, neutrophil phagocytosis, CR3 expression, and plasma colony stimulating factors (CSF) in 20 healthy subjects and 20 patients with CHC (10 with cirrhosis) at baseline, during antiviral treatment (at 4, 12, 24 weeks), and 12 weeks after discontinuation. Our results demonstrate that neutrophil chemotaxis and oxidative burst significantly increased during treatment and returned to baseline at the end of therapy. CR3 neutrophil expression was enhanced in baseline CHC compared to controls but did not change during antiviral treatment. Chemotaxis, oxidative burst, phagocytosis, and CSF levels did not differ significantly between patients before treatment and control subjects or among CHC cases according to the presence of cirrhosis in either cell subpopulation. In conclusion, the innate immune cell activity is enhanced in patients with CHC during antiviral treatment and returns to normal after its discontinuation thus possibly playing a role in their susceptibility to infections.


Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the management of schizophrenia and related disorders.
This guideline provides recommendations for the clinical management of schizophrenia and related disorders for health professionals working in Australia and New Zealand. It aims to encourage all clinicians to adopt best practice principles. The recommendations represent the consensus of a group of Australian and New Zealand experts in the management of schizophrenia and related disorders. This guideline includes the management of ultra-high risk syndromes, first-episode psychoses and prolonged psychoses, including psychoses associated with substance use. It takes a holistic approach, addressing all aspects of the care of people with schizophrenia and related disorders, not only correct diagnosis and symptom relief but also optimal recovery of social function. The writing group planned the scope and individual members drafted sections according to their area of interest and expertise, with reference to existing systematic reviews and informal literature reviews undertaken for this guideline. In addition, experts in specific areas contributed to the relevant sections. All members of the writing group reviewed the entire document. The writing group also considered relevant international clinical practice guidelines. Evidence-based recommendations were formulated when the writing group judged that there was sufficient evidence on a topic. Where evidence was weak or lacking, consensus-based recommendations were formulated. Consensus-based recommendations are based on the consensus of a group of experts in the field and are informed by their agreement as a group, according to their collective clinical and research knowledge and experience. Key considerations were selected and reviewed by the writing group. To encourage wide community participation, the Royal Australian and New Zealand College of Psychiatrists invited review by its committees and members, an expert advisory committee and key stakeholders including professional bodies and special interest groups. The clinical practice guideline for the management of schizophrenia and related disorders reflects an increasing emphasis on early intervention, physical health, psychosocial treatments, cultural considerations and improving vocational outcomes. The guideline uses a clinical staging model as a framework for recommendations regarding assessment, treatment and ongoing care. This guideline also refers its readers to selected published guidelines or statements directly relevant to Australian and New Zealand practice. This clinical practice guideline for the management of schizophrenia and related disorders aims to improve care for people with these disorders living in Australia and New Zealand. It advocates a respectful, collaborative approach; optimal evidence-based treatment; and consideration of the specific needs of those in adverse circumstances or facing additional challenges.


Factors related to building loss due to wildfires in the conterminous United States.
Wildfire is globally an important ecological disturbance affecting biochemical cycles and vegetation composition, but also puts people and their homes at risk. Suppressing wildfires has detrimental ecological effects and can promote larger and more intense wildfires when fuels accumulate, which increases the threat to buildings in the wildland-urban interface (WUI). Yet, when wildfires occur, typically only a small proportion of the buildings within the fire perimeter are lost, and the question is what determines which buildings burn. Our goal was to examine which factors are related to building loss when a wildfire occurs throughout the United States. We were particularly interested in the relative roles of vegetation, topography, and the spatial arrangement of buildings, and how their respective roles vary among ecoregions. We analyzed all fires that occurred within the conterminous United States from 2000 to 2010 and digitized which buildings were lost and which survived according to Google Earth historical imagery. We modeled the occurrence as well as the percentage of buildings lost within clusters using logistic and linear regression. Overall, variables related to topography and the spatial arrangement of buildings were more frequently present in the best 20 regression models than vegetation-related variables. In other words, specific locations in the landscape have a higher fire risk, and certain development patterns can exacerbate that risk. Fire policies and prevention efforts focused on vegetation management are important, but insufficient to solve current wildfire problems. Furthermore, the factors associated with building loss varied considerably among ecoregions suggesting that fire policy applied uniformly across the United States will not work equally well in all regions and that efforts to adapt communities to wildfires must be regionally tailored.


Genome Re-Sequencing of Diverse Sweet Cherry (Prunus avium) Individuals Reveals a Modifier Gene Mutation Conferring Pollen-Part Self-Compatibility.
The S-RNase-based gametophytic self-incompatibility (GSI) reproduction barrier is important for maintaining genetic diversity in species of the families Solanaceae, Plantaginaceae and Rosaceae. Among the plant taxa with S-RNase-based GSI, Prunus species in the family Rosaceae exhibit Prunus-specific self-incompatibility (SI). Although pistil S and pollen S determinants have been identified, the mechanism underlying SI remains uncharacterized in Prunus species. A putative pollen-part modifier was identified in this study. Disruption of this modifier supposedly confers self-compatibility (SC) to sweet cherry (Prunus avium) 'Cristobalina'. To identify the modifier, genome re-sequencing experiments were completed involving sweet cherry individuals from 18 cultivars and 43 individuals in two segregating populations. Cataloging of subsequences (35 bp kmers) from the obtained genomic reads, while referring to the mRNA sequencing data, enabled the identification of a candidate gene [M locus-encoded GST (MGST)]. Additionally, the insertion of a transposon-like sequence in the putative MGST promoter region in 'Cristobalina' down-regulated MGST expression levels, probably leading to the SC of this cultivar. Phylogenetic, evolutionary and gene expression analyses revealed that MGST may have undergone lineage-specific evolution, and the encoded protein may function differently from the corresponding proteins encoded by GST orthologs in other species, including members of the subfamily Maloideae (Rosaceae). Thus, MGST may be important for Prunus-specific SI. The identification of this novel modifier will expand our understanding of the Prunus-specific GSI system. We herein discuss the possible functions of MGST in the Prunus-specific GSI system.


Health consequences of female genital mutilation/cutting in the Gambia, evidence into action.
Female Genital Mutilation/Cutting (FGM/C) is a harmful traditional practice with severe health complications, deeply rooted in many Sub-Saharan African countries. In The Gambia, the prevalence of FGM/C is 78.3% in women aged between 15 and 49 years. The objective of this study is to perform a first evaluation of the magnitude of the health consequences of FGM/C in The Gambia. Data were collected on types of FGM/C and health consequences of each type of FGM/C from 871 female patients who consulted for any problem requiring a medical gynaecologic examination and who had undergone FGM/C in The Gambia. The prevalence of patients with different types of FGM/C were: type I, 66.2%; type II, 26.3%; and type III, 7.5%. Complications due to FGM/C were found in 299 of the 871 patients (34.3%). Even type I, the form of FGM/C of least anatomical extent, presented complications in 1 of 5 girls and women examined. This study shows that FGM/C is still practiced in all the six regions of The Gambia, the most common form being type I, followed by type II. All forms of FGM/C, including type I, produce significantly high percentages of complications, especially infections.


Genetic signature of differentiated thyroid carcinoma susceptibility: a machine learning approach.
To identify a peculiar genetic combination predisposing to differentiated thyroid carcinoma (DTC), we selected a set of single nucleotide polymorphisms (SNPs) associated with DTC risk, considering polygenic risk score (PRS), Bayesian statistics and a machine learning (ML) classifier to describe cases and controls in three different datasets. Dataset 1 (649 DTC, 431 controls) has been previously genotyped in a genome-wide association study (GWAS) on Italian DTC. Dataset 2 (234 DTC, 101 controls) and dataset 3 (404 DTC, 392 controls) were genotyped. Associations of 171 SNPs reported to predispose to DTC in candidate studies were extracted from the GWAS of dataset 1, followed by replication of SNPs associated with DTC risk (P < 0.05) in dataset 2. The reliability of the identified SNPs was confirmed by PRS and Bayesian statistics after merging the three datasets. SNPs were used to describe the case/control state of individuals by ML classifier. Starting from 171 SNPs associated with DTC, 15 were positive in both datasets 1 and 2. Using these markers, PRS revealed that individuals in the fifth quintile had a seven-fold increased risk of DTC than those in the first. Bayesian inference confirmed that the selected 15 SNPs differentiate cases from controls. Results were corroborated by ML, finding a maximum AUC of about 0.7. A restricted selection of only 15 DTC-associated SNPs is able to describe the inner genetic structure of Italian individuals, and ML allows a fair prediction of case or control status based solely on the individual genetic background.


Human neural stem cells genetically modified to overexpress brain-derived neurotrophic factor promote functional recovery and neuroprotection in a mouse stroke model.
Intracerebral hemorrhage (ICH) is a lethal stroke type; mortality approaches 50%, and current medical therapy against ICH shows only limited effectiveness, so an alternative approach is required, such as stem cell-based cell therapy. Previously we have shown that intravenously transplanted human neural stem cells (NSCs) selectively migrate to the brain and promote functional recovery in rat ICH model, and others have shown that intracerebral infusion of brain-derived neurotrophic factor (BDNF) results in improved structural and functional outcome from cerebral ischemia. We postulated that human NSCs overexpressing BDNF transplanted into cerebral cortex overlying ICH lesion could provide improved survival of grafted NSCs and increased angiogenesis and behavioral recovery in mouse ICH model. ICH was induced in adult mice by injection of bacterial collagenase into striatum. The HB1.F3.BDNF (F3.BDNF) human NSC line produces sixfold higher amounts of BDNFF over the parental F3 cell line in vitro, induces behavioral improvement, and produces a threefold increase in cell survival at 2 weeks and 8 weeks posttransplantation. Brain transplantation of human NSCs overexpressing BDNF provided differentiation and survival of grafted human NSCs and renewed angiogenesis of host brain and functional recovery of ICH animals. These results indicate that the F3.BDNF human NSCs should be of great value as a cellular source for experimental studies involving cellular therapy for human neurological disorders, including ICH.