Surveillance and Outbreak Response Management System (SORMAS) to support the control of the Ebola virus disease outbreak in West Africa.
In the context of controlling the current outbreak of Ebola virus disease (EVD), the World Health Organization claimed that 'critical determinant of epidemic size appears to be the speed of implementation of rigorous control measures', i.e. immediate follow-up of contact persons during 21 days after exposure, isolation and treatment of cases, decontamination, and safe burials. We developed the Surveillance and Outbreak Response Management System (SORMAS) to improve efficiency and timeliness of these measures. We used the Design Thinking methodology to systematically analyse experiences from field workers and the Ebola Emergency Operations Centre (EOC) after successful control of the EVD outbreak in Nigeria. We developed a process model with seven personas representing the procedures of EVD outbreak control. The SORMAS system architecture combines latest In-Memory Database (IMDB) technology via SAP HANA (in-memory, relational database management system), enabling interactive data analyses, and established SAP cloud tools, such as SAP Afaria (a mobile device management software). The user interface consists of specific front-ends for smartphones and tablet devices, which are independent from physical configurations. SORMAS allows real-time, bidirectional information exchange between field workers and the EOC, ensures supervision of contact follow-up, automated status reports, and GPS tracking. SORMAS may become a platform for outbreak management and improved routine surveillance of any infectious disease. Furthermore, the SORMAS process model may serve as framework for EVD outbreak modeling.


Contribution of genes and environment to the longitudinal association between childhood impulsive-aggression and suicidality in adolescence.
Population-based and family studies showed that impulsive-aggression predicts suicidality; however, the underlying etiological nature of this association is poorly understood. The objective was to determine the contribution of genes and environment to the association between childhood impulsive-aggression and serious suicidal ideation/attempt in young adulthood. N = 862 twins (435 families) from the Quebec Newborn Twin Study were followed up from birth to 20 years. Repeated measures of teacher-assessed impulsive-aggression were modeled using a genetically informed latent growth model including intercept and slope parameters reflecting individual differences in the baseline level (age 6 years) and in the change (increase/decrease) of impulsive-aggression during childhood (6 to 12 years), respectively. Lifetime suicidality (serious suicidal ideation/attempt) was self-reported at 20 years. Associations of impulsive-aggression intercept and slope with suicidality were decomposed into additive genetic (A) and unique environmental (E) components. Additive genetic factors accounted for an important part of individual differences in impulsive-aggression intercept (A = 90%, E = 10%) and slope (A = 65%, E = 35%). Genetic (50%) and unique environmental (50%) factors equally contributed to suicidality. We found that 38% of the genetic factors accounting for suicidality were shared with those underlying impulsive-aggression slope, whereas 40% of the environmental factors accounting for suicidality were shared with those associated with impulsive-aggression intercept. The genetic correlation between impulsive-aggression slope and suicidality was 0.60, p = .027. Genetic and unique environmental factors underlying suicidality significantly overlap with those underlying childhood impulsive-aggression. Future studies should identify putative genetic and environmental factors to inform prevention.


Predicting pore water EPA-34 PAH concentrations and toxicity in pyrogenic-impacted sediments using pyrene content.
Sediment and freely dissolved pore water concentrations of the U.S. Environmental Protection Agency's list of 34 alkyl and parent PAHs (EPA-34) were measured in 335 sediment samples from 19 different sites impacted by manufactured gas plants, aluminum smelters and other pyrogenic sources. The total EPA-34 freely dissolved pore water concentration, C(pw,EPA-34), expressed as toxic units (TU) is currently considered one of the most accurate measures to assess risk at such sites; however, it is very seldom measured. With this data set, we address how accurately C(pw,EPA-34) can be estimated using limited 16 parent PAH data (EPA-16) commonly available for such sites. An exhaustive statistical analysis of the obtained data validated earlier observations that PAHs with more than 3 rings are present in similar relative abundances and their partitioning behavior typically follows Raoult's law and models developed for coal tar. As a result, sediment and freely dissolved pore water concentrations of pyrene and other 3- and 4-ring PAHs exhibit good log-log correlations (r² > 0.8) to most individual EPA-34 PAHs and also to C(pw,EPA-34). Correlations improve further by including the ratio of high to low molecular weight PAHs, as 2-ring PAHs exhibit the most variability in terms of their relative abundance. The most practical result of the current work is that log C(pw,EPA-34) estimated by the recommended pyrene-based estimation techniques was similarly well correlated to % survival of the benthic amphipods Hyalella azteca and Leptocheirus plumulosus as directly measured log C(pw,EPA-34) values (n = 211). Incorporation of the presented C(pw,EPA-34) estimation techniques could substantially improve risk assessments and guidelines for sediments impacted by pyrogenic residues, especially when limited data are available, without requiring any extra data or measurement costs.


Identification of functional endothelial protein C receptor in human plasma.
The endothelial cell protein C receptor (EPCR) binds protein C and facilitates activation by the thrombin-thrombomodulin complex. EPCR also binds activated protein C (APC) and inhibits APC anticoagulant activity. In this study, we detected a soluble form of EPCR in normal human plasma. Plasma EPCR appears to be approximately 43, 000 D, and circulates at approximately 100 ng/ml (98.4+/-27.8 ng/ml, n = 22). Plasma EPCR was purified from human citrated plasma using ion exchange, immunoaffinity, and protein C affinity chromatography. Flow cytometry experiments demonstrated that plasma EPCR bound APC with an affinity similar to that previously determined for recombinant soluble EPCR (Kdapp = 30 nM). Furthermore, plasma EPCR inhibited both protein C activation on an endothelial cell line and APC anticoagulant activity in a one-stage Factor Xa clotting assay. The physiological function of plasma EPCR is uncertain, but if the local concentrations are sufficiently high, particularly in disease states, the present data suggest that the soluble plasma EPCR could attenuate the membrane-bound EPCR augmentation of protein C activation and the anticoagulant function of APC.


Phospholipid-binding proteins differ in their capacity to induce autoantibodies and murine systemic lupus erythematosus.
We have previously shown that immunization of nonautoimmune mice with the phospholipid-binding protein β2-glycoprotein I (β2GPI), in combination with lipopolysaccharide (LPS), induces a murine model of systemic lupus erythematosus (SLE), with sequential emergence of autoantibodies and glomerulonephritis. Here, we determine whether the paradigm for induction of murine SLE extends to other phospholipid-binding proteins. Mice were immunized with a phospholipid-binding protein (prothrombin (PT), protein S, or β2GPI), or a nonphospholipid-binding protein (glu-plasminogen), in the presence of LPS. The breadth and degree of the autoantibody response, and the frequency of glomerulonephritis, varied among the three proteins, with β2GPI being the most effective in inducing SLE-like disease. The phospholipid-binding proteins also differed in the pattern of serum cytokines they elicited. The most apparent difference between β2GPI and the other phospholipid-binding proteins was in their ability to bind to LPS: β2GPI bound to LPS, while PT and protein S did not. Our data suggest that binding to phospholipid(s) is a necessary, but not sufficient, condition for full induction of murine SLE. We propose that other properties, such as physiologic function, avidity for anionic phospholipids, and degree of interaction with other cell surface and/or circulating molecules (particularly LPS) may determine the range and severity of disease.


[Are breastfeeding and complementary feeding of children of adolescent mothers different from those of adult mothers?].
To study breastfeeding during the first year of life and the kind of complementary food provided at one year of life to children of adolescent mothers. To compare these data with breastfeeding and complementary food received by children of adult mothers. A dual cohort was performed. Children were selected from the files of CAISM/UNICAMP and assessed when they were one year old. This study consisted of 122 children born from adolescent mothers and 123 children born from adult mothers--full-term births, birthweight was 2,500 g or higher. When the children were one year old, the mothers were interviewed at home or at CIPED/UNICAMP. The results were compared using the chi-square test and the Fisher's test; alpha=5%; the Kaplan-Meier method was used to analyze the duration of breastfeeding and the Wilcoxon test (Breslow) to compare the exclusive, predominant, full and total breastfeeding curves. 94.3% of children of adolescent mothers and 95.9% of children of adult mothers left the maternity hospital being breastfed (p=0.544). The median exclusive breastfeeding duration for both groups was 90 days. After completing one year, 35.3% and 28.5% of children of adolescent and adult mothers, respectively, continued breastfeeding (p=0.254): only breastfeeding 11.5% vs. 8.9% and mixed feeding 23.8% vs. 19.5% (p=0.519). Meat intake by children of adolescent mothers was lower than that of children of adult mothers (13.9% vs. 26.0%; Fisher's test: p=0.031). With regard to egg intake, 11.5% vs. 19.5% of children of adolescent mothers and adult mothers did not eat egg but the results suggested that the egg intake of children of adolescent mothers was higher (p=0.082). Duration and pattern of breastfeeding were similar between children of adolescent mothers and of adult mothers. The complementary nutrition was similar, except for a lower intake of meat and a higher intake of eggs among the children of adolescent mothers.


Kinematic Components of the Reach-to-Target Movement After Stroke for Focused Rehabilitation Interventions: Systematic Review and Meta-Analysis.
Background: Better upper limb recovery after stroke could be achieved through tailoring rehabilitation interventions directly at movement deficits. Aim: To identify potential; targets for therapy by synthesizing findings of differences in kinematics and muscle activity between stroke survivors and healthy adults performing reach-to-target tasks. Methods: A systematic review with identification of studies, data extraction, and potential risk of bias was completed independently by two reviewers. Online databases were searched from their inception to November 2017 to find studies of reach-to-target in people-with-stroke and healthy adults. Potential risk-of-bias was assessed using the Down's and Black Tool. Synthesis was undertaken via: (a) meta-analysis of kinematic characteristics utilizing the standardized mean difference (SMD) [95% confidence intervals]; and (b), narrative synthesis of muscle activation. Results: Forty-six studies met the review criteria but 14 had insufficient data for extraction. Consequently, 32 studies were included in the meta-analysis. Potential risk-of-bias was low for one study, unclear for 30, and high for one. Reach-to-target was investigated with 618 people-with-stroke and 429 healthy adults. The meta-analysis found, in all areas of workspace, that people-with-stroke had: greater movement times (seconds) e.g., SMD 2.57 [0.89, 4.25]; lower peak velocity (millimeters/second) e.g., SMD -1.76 [-2.29, -1.24]; greater trunk displacement (millimeters) e.g. SMD 1.42 [0.90, 1.93]; a more curved reach-path-ratio e.g., SMD 0.77 [0.32, 1.22] and reduced movement smoothness e.g., SMD 0.92 [0.32, 1.52]. In the ipsilateral and contralateral workspace, people-with-stroke exhibited: larger errors in target accuracy e.g., SMD 0.70 [0.39, 1.01]. In contralateral workspace, stroke survivors had: reduced elbow extension and shoulder flexion (degrees) e.g., elbow extension SMD -1.10 [-1.62, -0.58] and reduced shoulder flexion SMD -1.91 [-1.96, -0.42]. Narrative synthesis of muscle activation found that people-with-stroke, compared with healthy adults, exhibited: delayed muscle activation; reduced coherence between muscle pairs; and use of a greater percentage of muscle power. Conclusions: This first-ever meta-analysis of the kinematic differences between people with stroke and healthy adults performing reach-to-target found statistically significant differences for 21 of the 26 comparisons. The differences identified and values provided are potential foci for tailored rehabilitation interventions to improve upper limb recovery after stroke.


Evaluation of gamma interferon and antibody tuberculosis tests in alpacas.
We describe the performance of cell-based and antibody blood tests for the antemortem diagnosis of tuberculosis (TB) in South American camelids (SAC). The sensitivity and specificity of the gamma interferon (IFN-γ) release assay, two lateral flow rapid antibody tests (Stat-Pak and Dual Path Platform [DPP]), and two enzyme-linked immunosorbent assay (ELISA)-based antibody tests (Idexx and Enferplex) were determined using diseased alpacas from Mycobacterium bovis culture-confirmed breakdown herds and TB-free alpacas from geographical areas with no history of bovine TB, respectively. Our results show that while the sensitivities of the IFN-γ and antibody tests were similar (range of 57.7% to 66.7%), the specificity of the IFN-γ test (89.1%) was lower than those of any of the antibody tests (range of 96.4% to 97.4%). This lower specificity of the IFN-γ test was at least in part due to undisclosed Mycobacterium microti infection in the TB-free cohort, which stimulates a positive purified protein derivative (PPD) response. The sensitivity of infection detection could be increased by combining two antibody tests, but even the use of all four antibody tests failed to detect all diseased alpacas. These antibody-negative alpacas were IFN-γ positive. We found that the maximum sensitivity could be achieved only by the combination of the IFN-γ test with two antibody tests in a "test package," although this resulted in decreased specificity. The data from this evaluation of tests with defined sensitivity and specificity provide potential options for antemortem screening of SAC for TB in herd breakdown situations and could also find application in movement testing and tracing investigations.


Effects of dienogest, a synthetic steroid, on experimental endometriosis in rats.
Dienogest, a synthetic steroid with progestational activity, is used as a component of oral contraceptives and is currently being evaluated clinically for the treatment of endometriosis. The present study was conducted to confirm the effects of dienogest on experimental endometriosis in rats and to elucidate its mechanism of action. Experimental endometriosis induced by autotransplantation of endometrium in rats. Endometrial implants, immune system, and bone mineral were investigated after 3 weeks of medication. Dienogest (0.1-1 mg/kg per day, p.o.) reduced the endometrial implant volume to the same extent as danazol (100 mg/kg per day, p.o.). Simultaneously, dienogest ameliorated the endometrial implant-induced alterations of the immune system: i.e. it increased the natural killer activity of peritoneal fluid cells and splenic cells, decreased the number of peritoneal fluid cells, and decreased interleukin-1beta production by peritoneal macrophages. In contrast, danazol (100 mg/kg per day, p.o.) and buserelin (30 microg/kg per day, s.c.) had none of these immunologic effects. Additionally, combined administration of dienogest (0.1 mg/kg per day) plus buserelin (0.3 microg/kg per day) suppressed the bone mineral loss induced by buserelin alone, with no reduction of the effect on endometrial implants. In vitro studies on dienogest revealed an antiproliferative effect on rat endometrial cells due to inhibition of protein kinase C activity plus a partial progestational effect. Dienogest appears to be a potent agent with mechanisms of action different from those of danazol and GnRH agonists currently available for the treatment of endometriosis.


Botox A injection for pain after laparoscopic ventral hernia: a case report.
Laparoscopic ventral hernia repair has many advantages over open techniques: adequate visualization of the entire abdominal wall, ease of placement of preperitoneal mesh with adequate overlap, and cosmesis. Intense and activity limiting pain is often one inferior aspect of this repair. We report the case of a patient who was intolerant of narcotic pain medicine with activity limiting pain. A novel technique for postoperative pain control was instituted utilizing Botox A (Allergan Inc., Irvine, CA, USA). Botox A was diluted to 2 units per mL and three injection sites were chosen on each side of the abdominal wall. All three muscle bellies (external oblique, internal oblique, and transversus) were identified by ultrasound and 8 mL was injected in each. This resulted in three muscle layers at six sites for a total of 18 injections. A total of 300 units of Botox A were utilized. Pain scores improved from 10/10 to 2/10 and were durable at 3-month follow up. Botox A provided significant pain control for this patient after laparoscopic ventral hernia repair. Continued prospective study to define long-term outcomes, cost savings, and appropriate timing of injections is underway.


Body mass estimates of the earliest possible hominins and implications for the last common ancestor.
Many hypotheses regarding the paleobiology of the earliest possible hominins, Orrorin tugenensis and Ardipithecus ramidus, are dependent upon accurate body mass estimates for these taxa. While we have previously published body mass predictions for Orrorin and Ardipithecus, the accuracies of those estimates depend on the assumption that the postcranial skeletal dimensions and body masses of these taxa followed scaling patterns that were similar to those observed in modern humans. This assumption may not be correct because certain aspects of postcranial morphology in Orrorin and Ardipithecus differ from modern humans, and suggest that their overall body plans might be unique but more similar to modern non-human great apes than to modern humans. Here we present individual body mass predictions for O. tugenensis and Ar. ramidus assuming that they followed postcranial scaling patterns similar to those of chimpanzees. All estimates include individual prediction intervals as measures of uncertainty. In addition, we provide equations for predicting body mass from univariate postcranial measurements based on the largest sample (n = 25) yet compiled of common chimpanzee skeletons with known body masses, which is vital for calculating prediction intervals for individual fossils. Our results show that estimated body masses in Orrorin and Ardipithecus are generally larger when derived from a chimpanzee-like scaling pattern compared to estimates that assume a human-like pattern, though the prediction intervals of the two sets of estimates overlap. In addition, the more complete of the two known Orrorin femora has an overall scaling pattern that is more similar to common chimpanzees than to modern humans, supporting the application of a non-human great ape comparative model. Our new estimates fall near the male (Ardipithecus) average and in between the male and female averages (Orrorin) for wild-caught common chimpanzees. If a chimpanzee-like pattern of scaling between postcranial dimensions and body mass did exist in these earliest hominins, our results suggest the large body masses found in some early australopiths were already present in taxa near the origins of our lineage, and perhaps also in the Pan-Homo last common ancestor.


Borohydride-Scaffolded Li/Na/Mg Fast Ionic Conductors for Promising Solid-State Electrolytes.
Borohydride solid-state electrolytes with room-temperature ionic conductivity up to ≈70 mS cm-1 have achieved impressive progress and quickly taken their place among the superionic conductive solid-state electrolytes. Here, the focus is on state-of-the-art developments in borohydride solid-state electrolytes, including their competitive ionic-conductive performance, current limitations for practical applications in solid-state batteries, and the strategies to address their problems. To open, fast Li/Na/Mg ionic conductivity in electrolytes with BH4 - groups, approaches to engineering borohydrides with enhanced ionic conductivity, and later on the superionic conductivity of polyhedral borohydrides, their correlated conductive kinetics/thermodynamics, and the theoretically predicted high conductive derivatives are discussed. Furthermore, the validity of borohydride pairing with coated oxides, sulfur, organic electrodes, MgH2 , TiS2 , Li4 Ti5 O12 , electrode materials, etc., is surveyed in solid-state batteries. From the viewpoint of compatible cathodes, the stable electrochemical windows of borohydride solid-state electrolytes, the electrode/electrolyte interface behavior and battery device design, and the performance optimization of borohydride-based solid-state batteries are also discussed in detail. A comprehensive coverage of emerging trends in borohydride solid-state electrolytes is provided and future maps to promote better performance of borohydride SSEs are sketched out, which will pave the way for their further development in the field of energy storage.


Proteasome-mediated degradation and functions of hematopoietic progenitor kinase 1 in pancreatic cancer.
Hematopoietic progenitor kinase 1 (HPK1) regulates stress responses, proliferation, and apoptosis in hematopoietic cells. In this study, we examined the expression, regulation, and functions of HPK1 in pancreatic ductal adenocarcinomas (PDA). We found that loss of HPK1 protein expression correlated significantly with the progression of pancreatic intraepithelial neoplasias (P = 0.001) and development of invasive PDA. Similarly, HPK1 protein was not expressed in any of eight PDA cell lines examined but was expressed in immortalized human pancreatic duct epithelial (HPDE) cells. There was no difference in HPK1 mRNA levels in PDA cell lines or primary PDA compared with those in HPDE cells or ductal epithelium in chronic pancreatitis and normal pancreas, respectively. Treatment of Panc-1 cells with a proteasome inhibitor, MG132, increased the HPK1 protein levels in a dose-dependent manner, suggesting that alteration in proteasome activity contributes to the loss of HPK1 protein expression in pancreatic cancer. Like the endogenous HPK1, both wild-type HPK1 and its kinase-dead mutant, HPK1-M46, overexpressed in Panc-1 cells, were also targeted by proteasome-mediated degradation. After MG132 withdrawal, wild-type HPK1 protein expression was markedly decreased within 24 hours, but kinase-dead HPK1 mutant protein expression was sustained for up to 96 hours. Therefore, HPK1 kinase activities were required for the loss of HPK1 protein in PDAs. Furthermore, restoring wild-type HPK1 protein in PDA cells led to the increase in p21 and p27 protein expression and cell cycle arrest. Thus, HPK1 may function as a novel tumor suppressor and its loss plays a critical role in pancreatic cancer.


A review of lawsuits related to point-of-care emergency ultrasound applications.
New medical technology brings the potential of lawsuits related to the usage of that new technology. In recent years the use of point-of-care (POC) ultrasound has increased rapidly in the emergency department (ED). POC ultrasound creates potential legal risk to an emergency physician (EP) either using or not using this tool. The aim of this study was to quantify and characterize reported decisions in lawsuits related to EPs performing POC ultrasound. We conducted a retrospective review of all United States reported state and federal cases in the Westlaw database. We assessed the full text of reported cases between January 2008 and December 2012. EPs with emergency ultrasound fellowship training reviewed the full text of each case. Cases were included if an EP was named, the patient encounter was in the emergency department, the interpretation or failure to perform an ultrasound was a central issue and the application was within the American College of Emergency Physician (ACEP) ultrasound core applications. In order to assess deferred risk, cases that involved ultrasound examinations that could have been performed by an EP but were deferred to radiology were included. We identified five cases. All reported decisions alleged a failure to perform an ultrasound study or a failure to perform it in a timely manner. All studies were within the scope of emergency medicine and were ACEP emergency ultrasound core applications. A majority of cases (n=4) resulted in a patient death. There were no reported cases of failure to interpret or misdiagnoses. In a five-year period from January 2008 through December 2012, five malpractice cases involving EPs and ultrasound examinations that are ACEP core emergency ultrasound applications were documented in the Westlaw database. All cases were related to failure to perform an ultrasound study or failure to perform a study in a timely manner and none involved failure to interpret or misdiagnosis when using of POC ultrasound.


Pharmacotherapy of attention-deficit/hyperactivity disorder reduces risk for substance use disorder.
To assess the risk for substance use disorders (SUD) associated with previous exposure to psychotropic medication in a longitudinal study of boys with attention-deficit/hyperactivity disorder (ADHD). The cumulative incidence of SUD throughout adolescence was compared in 56 medicated subjects with ADHD, 19 nonmedicated subjects with ADHD, and 137 non-ADHD control subjects. Unmedicated subjects with ADHD were at a significantly increased risk for any SUD at follow-up compared with non-ADHD control subjects (adjusted OR: 6.3 [1.8-21.6]). Subjects with ADHD medicated at baseline were at a significantly reduced risk for a SUD at follow-up relative to untreated subjects with ADHD (adjusted OR: 0.15 [0.04-0.6]). For each SUD subtype studied, the direction of the effect of exposure to pharmacotherapy was similar to that seen for the any SUD category. Consistent with findings in untreated ADHD in adults, untreated ADHD was a significant risk factor for SUD in adolescence. In contrast, pharmacotherapy was associated with an 85% reduction in risk for SUD in ADHD youth.


Human cytomegalovirus IE2 protein regulates macrophage-mediated immune escape by upregulating GRB2 expression in UL122 genetically modified mice.
Although cytomegalovirus (HCMV) infection is asymptomatic in healthy individuals, the virus can remain latent for many years due to its ability to evade host immune surveillance. However, reactivation of HCMV can lead to life-threatening disease. Recent studies have shown that HCMV infection mediates immune escape by regulating macrophage activity, although the role of the HCMV-encoded IE2 protein is unclear. A ul122 transgenic mouse model was created to stably expresses the IE2 protein, and the proportion of M1 and M2 macrophage populations in their spleen and bone marrow was compared to that in wild-type controls. In addition, the phagocytic function of the macrophages was evaluated in terms of neutral red dye uptake. Spleen and bone marrow macrophages in IE2-expressing mice were mainly of the M2 phenotype and displayed enhanced phagocytic function compared to that in control mice. The relative levels of expression of macrophage-related GRB2 and of IL-4, IFN-γ, IL-13, and TNF-α were also analyzed in the spleen and bone marrow of the two groups. The IE2-expressing mice had increased expression of GRB2 and increased expression of the M2-related cytokines IL-4 and IL-13. Taken together, the current results suggest that HCMV IE2 polarizes the host macrophages to the M2 type via a GRB2/IL-4-related pathway, which enables long-term survival of the virus in the host.


Severe lower respiratory tract infection in early infancy and pneumonia hospitalizations among children, Kenya.
Severe lower respiratory tract infection (LRTI) in infants caused by respiratory syncytial virus (RSV) has been associated with later pneumonia hospitalization among children. To determine risk for pneumonia after RSV hospitalization in infancy, we conducted a retrospective cohort analysis of 2,813 infants admitted to a hospital in Kenya and identified readmissions for pneumonia among this group during early childhood (<60 months of age). Incidence of readmission for pneumonia was higher for children whose first admission as infants was for LRTI and who were <3 months of age than for children who were first admitted as infants for non-LRTI, irrespective of RSV status. Incidence of readmission for pneumonia with wheeze was higher for children whose first admission involved RSV compared with those who had non-RSV LRTI. Excess pneumonia risk persisted for 2 years after the initial hospitalization. Close postdischarge follow-up of infants with LRTI, with or without RSV, could help prevent severe pneumonia later in childhood.


Intestinal intraepithelial lymphocytes sustain the epithelial barrier function against Eimeria vermiformis infection.
Eimeria spp. are intracellular protozoa that infect intestinal epithelia of most vertebrates, causing coccidiosis. Intestinal intraepithelial lymphocytes (IEL) that reside at the basolateral site of epithelial cells (EC) have immunoregulatory and immunoprotective roles against Eimeria spp. infection. However, it remains unknown how IEL are involved in the regulation of epithelial barrier during Eimeria sp. infection. Here, we demonstrated two distinct roles of IEL against infection with Eimeria vermiformis, a murine pathogen: production of cytokines to induce protective immunity and expression of junctional molecules to preserve epithelial barrier. The number of IEL markedly increased when oocyst production reached a peak. During infection, IEL increased production of gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) and decreased transforming growth factor beta (TGF-beta) production. Addition of IFN-gamma and TNF-alpha or supernatants obtained from cultured IEL from E. vermiformis-infected mice reduced transepithelial electrical resistance (TER) in a confluent CMT93 cell monolayer, a murine intestine-derived epithelial line, but antibodies against these cytokines suppressed the decline of TER. Moreover, TGF-beta attenuated the damage of epithelial monolayer and changes in TER caused by IFN-gamma and TNF-alpha. The expression of junctional molecules by EC was decreased when IEL produced a high level of IFN-gamma and TNF-alpha and a low level of TGF-beta in E. vermiformis-infected mice. Interestingly, IEL constantly expressed junctional molecules and a coculture of EC with IEL increased TER. These results suggest that IEL play important multifunctional roles not only in protection of the epithelium against E. vermiformis-induced change by cytokine production but also in direct interaction with the epithelial barrier when intra-EC junctions are down-regulated.


Migration and genetic structure of the grain aphid (Sitobion avenae) in Britain related to climate and clonal fluctuation as revealed using microsatellites.
Genetic structuring of populations reflects the interaction of genetic drift, mutation, migration and selection, with influences from life history. Aphids are interesting in this regard as they have the potential for unusually high levels of dispersal and natural selection, which typically counter each other. In the present study, winged grain aphids Sitobion avenae (F.) were collected in four 12.2-m high suction traps along a north-south transect in Britain in order to eliminate sampling bias from plant hosts (cereals and grasses; Poaceae), it being known that these insects show host adaptation demonstrable using molecular markers. Samples were analysed at four polymorphic microsatellite loci over two consecutive years. Population allele frequencies were similar nationally during the two years, although clonal diversity varied greatly between sites and years. In the first sampling year following a harsh winter, diversity was found to display a latitudinal clinal trend: the proportion of unique clones (genotypes) increased with latitude. However, this pattern was less apparent the following year, after a milder winter. Nonetheless, overall FST analysis showed that there was little spatial genetic structuring in either sampling year. These data support the view that the insect is highly migratory and also support a theoretical model and previous data suggesting that the reproductive mode is clinal in S. avenae. This appears to be because natural selection (reduced reproductive success of asexual genotypes under cold conditions) is sufficiently powerful to overcome the homogenizing effects of strong migration. There was no clear evidence for isolation by distance for the genetic data obtained. The data are compared with similar data from other aphid species and other insects. Only by the collection of such data sets can an accurate picture be built up relating genetic variability to flight behaviour, including migratory ambit in this group of insects since, due to their small size and rapid dilution in the air, other marking approaches are impracticable over large geographical distances.


Massively parallel sequencing and analysis of the Necator americanus transcriptome.
The blood-feeding hookworm Necator americanus infects hundreds of millions of people worldwide. In order to elucidate fundamental molecular biological aspects of this hookworm, the transcriptome of the adult stage of Necator americanus was explored using next-generation sequencing and bioinformatic analyses. A total of 19,997 contigs were assembled from the sequence data; 6,771 of these contigs had known orthologues in the free-living nematode Caenorhabditis elegans, and most of them encoded proteins with WD40 repeats (10.6%), proteinase inhibitors (7.8%) or calcium-binding EF-hand proteins (6.7%). Bioinformatic analyses inferred that the C. elegans homologues are involved mainly in biological pathways linked to ribosome biogenesis (70%), oxidative phosphorylation (63%) and/or proteases (60%); most of these molecules were predicted to be involved in more than one biological pathway. Comparative analyses of the transcriptomes of N. americanus and the canine hookworm, Ancylostoma caninum, revealed qualitative and quantitative differences. For instance, proteinase inhibitors were inferred to be highly represented in the former species, whereas SCP/Tpx-1/Ag5/PR-1/Sc7 proteins ( = SCP/TAPS or Ancylostoma-secreted proteins) were predominant in the latter. In N. americanus, essential molecules were predicted using a combination of orthology mapping and functional data available for C. elegans. Further analyses allowed the prioritization of 18 predicted drug targets which did not have homologues in the human host. These candidate targets were inferred to be linked to mitochondrial (e.g., processing proteins) or amino acid metabolism (e.g., asparagine t-RNA synthetase). This study has provided detailed insights into the transcriptome of the adult stage of N. americanus and examines similarities and differences between this species and A. caninum. Future efforts should focus on comparative transcriptomic and proteomic investigations of the other predominant human hookworm, A. duodenale, for both fundamental and applied purposes, including the prevalidation of anti-hookworm drug targets.


From genes to brain development to phenotypic behavior: "dorsal-stream vulnerability" in relation to spatial cognition, attention, and planning of actions in Williams syndrome (WS) and other developmental disorders.
Visual information is believed to be processed through two distinct, yet interacting cortical streams. The ventral stream performs the computations needed for recognition of objects and faces ("what" and "who"?) and the dorsal stream the computations for registering spatial relationships and for controlling visually guided actions ("where" and "how"?). We initially proposed a model of spatial deficits in Williams syndrome (WS) in which visual abilities subserved by the ventral stream, such as face recognition, are relatively well developed (although not necessarily in exactly the same way as in typical development), whereas dorsal-stream functions, such as visuospatial actions, are markedly impaired. Since these initial findings in WS, deficits of motion coherence sensitivity, a dorsal-stream function has been found in other genetic disorders such as Fragile X and autism, and as a consequence of perinatal events (in hemiplegia, perinatal brain anomalies following very premature birth), leading to the proposal of a general "dorsal-stream vulnerability" in many different conditions of abnormal human development. In addition, dorsal-stream systems provide information used in tasks of visuospatial memory and locomotor planning, and these systems are closely coupled to networks for attentional control. We and several other research groups have previously shown deficits of frontal and parietal lobe function in WS individuals for specific attention tasks [e.g., Atkinson, J., Braddick, O., Anker, S., Curran, W., & Andrew, R. (2003). Neurobiological models of visuospatial cognition in children with Williams Syndrome: Measures of dorsal-stream and frontal function. Developmental Neuropsychology, 23(1/2), 141-174.]. We have used the Test of Everyday Attention for Children (TEA-Ch) which aims to attempt to separate components of attention with distinct brain networks (selective attention, sustained attention, and attention control-executive function) testing a group of older children with WS, but this test battery is too demanding for many children and adults with WS. Consequently, we have devised a new set of tests of attention, the Early Childhood Attention Battery (ECAB). This uses similar principles to the TEA-Ch, but adapted for mental ages younger than 6 years. The ECAB shows a distinctive attention profile for WS individuals relative to their overall cognitive development, with relative strength in tasks of sustained attention and poorer performance on tasks of selective attention and executive control. These profiles, and the characteristic developmental courses, also show differences between children with Down's syndrome and WS. This chapter briefly reviews new research findings on WS in these areas, relating the development of brain systems in WS to evidence from neuroimaging in typically developing infants, children born very preterm, and normal adults. The hypothesis of "dorsal-stream(s) vulnerability" which will be discussed includes a number of interlinked brain networks, subserving not only global visual processing and formulation of visuomotor actions but interlinked networks of attention.


Anticoagulation and Spine Surgery.
Literature review. Preoperative management of therapeutic anticoagulation in spine surgery is critical to minimize risk of thromboembolic events yet prevent postsurgical complications. Limited research is available, and most guidelines are based on drug half-lives. We aim to clarify current guidelines and available evidence for safe practice of spine surgery in this patient population. A literature search in PubMed was done encompassing comprehensive search terms to locate published literature on anticoagulation and spine surgery. Predefined inclusion and exclusion criteria were applied and data extraction was performed. A total of 17 articles met the final inclusion criteria. Of these, 12 articles were retrospective chart reviews, 3 were prospective observational studies, and 2 were systematic reviews. Current practice suggests holding warfarin until international normalized ratio <1.4, anti-Xa drugs for 48 to 72 hours, 12 to 24 hours for low-molecular-weight heparin, and 4 to 24 hours for heparin, before surgery. Antiplatelet agents can be stopped for 1 to 3 days prior to operation (81-500 mg) but must be stopped for 1 week for doses >1 g/d. For Plavix, 5 to 7 days of discontinuation advised to prevent complications. This review provides an overview of main anticoagulation agents seen in preoperative setting for spine patients. Although data is mixed and no true randomized control trials are available, there is growing evidence suggesting the aforementioned guidelines are needed to optimize anticoagulation in setting of spine surgery. Further studies are needed to elucidate risk of complications while operating under therapeutic levels of anticoagulation for a variety of comorbid conditions.


Cephalopod Hox genes and the origin of morphological novelties.
Cephalopods are a diverse group of highly derived molluscs, including nautiluses, squids, octopuses and cuttlefish. Evolution of the cephalopod body plan from a monoplacophoran-like ancestor entailed the origin of several key morphological innovations contributing to their impressive evolutionary success. Recruitment of regulatory genes, or even pre-existing regulatory networks, may be a common genetic mechanism for generating new structures. Hox genes encode a family of transcriptional regulatory proteins with a highly conserved role in axial patterning in bilaterians; however, examples highlighting the importance of Hox gene recruitment for new developmental functions are also known. Here we examined developmental expression patterns for eight out of nine Hox genes in the Hawaiian bobtail squid Euprymna scolopes, by whole-mount in situ hybridization. Our data show that Hox orthologues have been recruited multiple times and in many ways in the origin of new cephalopod structures. The manner in which these genes have been co-opted during cephalopod evolution provides insight to the nature of the molecular mechanisms driving morphological change in the Lophotrochozoa, a clade exhibiting the greatest diversity of body plans in the Metazoa.


Inhibition of cytochrome P450c11 by biogenic amines and an aziridine precursor, 2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride.
The interaction of several biogenic amines and Compound A (2-(4-acetoxyphenyl)-2-chloro- N-methyl-ethylammonium chloride), an analogue of the active substance in a HPLC fraction isolated from the shrub, Salsola tuberculatiformis Botsch., with cytochrome P450c11 was investigated. Noradrenaline, octopamine and Compound A inhibited the type I DOC induced difference spectrum of P450c11 and elicited a type II difference spectrum when added alone. The Ks-values for noradrenaline, octopamine, and Compound A were 0.8 mM, 0.16 mM and 0.36 mM, respectively. Dopamine, adrenaline and synephrine did not interact with, or inhibit, P450c11. Further investigation of Compound A indicated that it is a mixed inhibitor of sheep P450c11 with a stronger competitive (Kic = 106-110 microM) than uncompetitive (Kiu = 667-737 microM) element, and that it inhibits the conversion of deoxycorticosterone to corticosterone by human 11beta-hydroxylase and aldosterone synthase with EC50 values of 97 microM and 190 microM, respectively, in fetal calf serum.


Intravenous tissue plasminogen activator for acute ischemic stroke in patients with renal dysfunction.
This study used the Taiwan Stroke Registry data to evaluate the efficacy and safety of intravenous tissue plasminogen activator (tPA) in treating acute ischemic stroke in patients with renal dysfunction. We identified 3525 ischemic stroke patients and classified them into two groups according to the estimated glomerular filtration rate (eGFR) at the emergency department: ≥60, and <60 ml/min/1.73 m2 or on dialysis and by the propensity score from August 2006 to May 2015. The odds ratio of poor functional outcome (modified Rankin Scale ≥2) was calculated for patients with tPA treatment (N = 705), compared to those without tPA treatment (N = 2820), by eGFR levels, at 1, 3 and 6 months after ischemic stroke. We also evaluated the risks of intracerebral hemorrhage, upper gastrointestinal bleeding, mortality, between the two groups by eGFR levels. Among patients with eGFR levels of <60 ml/min/1.73 m2, tPA therapy reduced the odds ratio of poor functional outcome to 0.60 (95% confidence interval = 0.42-0.87) at 6 months after ischemic stroke. The tPA therapy was not associated with increased overall risk of upper gastrointestinal bleeding, but with increased risk of intracerebral hemorrhage. The low eGFR was not a significant risk factor of intracerebral hemorrhage among ischemic stroke patients receiving tPA treatment. tPA for acute ischemic stroke could improve functional outcomes without increasing the risks of upper gastrointestinal bleeding for patients with or without renal dysfunction. The low eGFR was not a significant risk factor for intracerebral hemorrhage among patients receiving tPA treatment.


Rib fractures in infants due to cardiopulmonary resuscitation efforts.
Although it is widely known that adults may sustain fractures of the anterior and/or lateral aspects of the ribs due to cardiopulmonary resuscitation (CPR) efforts, relatively little is written about the generation of CPR-related rib fractures in the infant age range. In a series of 70 consecutive autopsies in infants ranging in age from 2 weeks to 8 months, with no history or indications of injury, the parietal pleura of the thoracic cage was stripped and the ribs carefully examined for fracture. Subtle fractures of the anterolateral aspects of the ribs were discovered in 8 (11%) of the 70 cases. In 7 of the 8 cases, multiple ribs were fractured (ranging up to 10 rib fractures), and in 5 of these cases, the rib fractures were bilateral. All of the rib fractures were subtle, had little if any associated blood extravasation, and would have been easily missed had the parietal pleura not been stripped. These anterolateral rib fractures in infants are the likely correlate of anterolateral rib fractures that are not uncommonly seen in the adult population, resulting from resuscitation efforts. The rib fractures are subtle and may not be identified unless the parietal pleura is stripped.


Modeling Catecholaminergic Polymorphic Ventricular Tachycardia using Induced Pluripotent Stem Cell-derived Cardiomyocytes.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic cardiac disorder characterized by life-threatening arrhythmias induced by physical or emotional stress, in the absence structural heart abnormalities. The arrhythmias may cause syncope or degenerate into cardiac arrest and sudden death which usually occurs during childhood. Recent studies have shown that CPVT is caused by mutations in the cardiac ryanodine receptor type 2 (RyR2) or calsequestrin 2 (CASQ2) genes. Both proteins are key contributors to the intracellular Ca(2+) handling process and play a pivotal role in Ca(2+) release from the sarcoplasmic reticulum to the cytosol during systole. Although the molecular pathogenesis of CPVT is not entirely clear, it was suggested that the CPVT mutations promote excessive sarcoplasmic reticulum Ca(2+) leak, which initiates delayed afterdepolarizations (DADs) and triggered arrhythmias in cardiac myocytes. The recent breakthrough discovery of induced pluripotent stem cells (iPSC) generated from somatic cells (e.g. fibroblasts, keratinocytes) now enables researches to investigate mutated cardiomyocytes generated from the patient's iPSC. To this end, in the present article we review recent studies on CPVT iPSC-derived cardiomyocytes, thus demonstrating in the mutated cells catecholamine-induced DADs and triggered arrhythmias.


Fever of Unknown Origin in US Soldier: Telemedical Consultation Limitations in a Deployment to West Africa.
Review the application of telemedicine support for managing a patient with possible sepsis, suspected malaria, and unusual musculoskeletal symptoms. Clinical Context: Regionally Aligned Forces (RAF) supporting US Army Africa/Southern European Task Force (USARAF/ SETAF) in the Africa Command area of responsibility. Care provided by a small Role I facility on the compound. Organic Medical Expertise: Five 68W combat medics (one is the patient); one SOCM trained 68W combat medic. No US provider present in country. Closest Medical Support: Organic battalion physician assistant (PA) located in the USA; USARAF PA located in Italy; French Role II located in bordering West African country; medical consultation sought via telephone, WhatsApp® (communication with French physician) or over unclassified, encrypted e-mail. Earliest Evacuation: Estimated at 12 to 24 hours with appropriate country clearances and approval to fly from three countries including French forces support approval.


[Clinical observasion of acupuncture in patients with depression and its impact on serum 5-HT].
To observe the clinical effect of acupuncture for depression and to discuss its impact on the content of 5-HT in patients with depression. Eighty patients with depression were randomly divided into an acupuncture group and a western medication group,40 cases in each one. Acupuncture was applied in the acupuncture group,Siman(KI 14),Shenshu(BL 23),Guanyuan(CV 4),Dazhui(GV 14),Yinlingquan(SP 9), Zusanli(ST 36),Taichong(LR 3),Yanglingquan(GB 34) and Jingming(BL 1) were selected, the intensive moxibustion was applied at G(uanyuan(CV 4). Fluoxetine was treated with oral administration in the western medication group. The treatments of six weeks were required in each group. The Hamilton depression rating scale (HAMD) was applied to evaluate efficacy and serum 5-HT was detected before and after treatment in the two groups. After treatment,the scores of HAMD were decreased obviously in the two groups compared with those before treatment (scores in the acupuncture group: 24. 48 ± 0. 28 vs 8. 95 ± 2. 24; scores in the western medication group: 24. 14±0. 24 vs 10. 29±1. 30),and the differences were statistically significant (both P<0. 05). Between the two groups,the scores of HAMD in the acupuncture group at the end of the lst,2nd,4th,6th weeks were superior to those in the western medication group (all P<0. 05). The content of serum 5-HT after treatment was increased markedly compared with that before treatment [the content in the acupuncture group: (26. 21 2. 36)pg/mL vs (52. 07 ± 0. 56)pg/mL, the content in the western medication group:(26. 26±2. 31)pg/mL vs (51. 70±0. 52)pg/ mL, both P<0. 05]. But there was no statistic significance between the two groups(P >0.05). The efficacy of acupuncture for depression is superior to that of western medication with fluoxetine.


Modeling of gas absorption cross sections by use of principal-component-analysis model parameters.
Monitoring the amount of gaseous species in the atmosphere and exhaust gases by remote infrared spectroscopic methods calls for the use of a compilation of spectral data, which can be used to match spectra measured in a practical application. Model spectra are based on time-consuming line-by-line calculations of absorption cross sections in databases by use of temperature as input combined with path length and partial and total pressure. It is demonstrated that principal component analysis (PCA) can be used to compress the spectrum of absorption cross sections, which depend strongly on temperature, into a reduced representation of score values and loading vectors. The temperature range from 300 to 1000 K is studied. This range is divided into two subranges (300-650 K and 650-1000K), and separate PCA models are constructed for each. The relationship between the scores and the temperature values is highly nonlinear. It is shown, however, that because the score-temperature relationships are smooth and continuous, they can be modeled by polynomials of varying degrees. The accuracy of the data compression method is validated with line-by-line-calculated absorption data of carbon monoxide and water vapor. Relative deviations between the absorption cross sections reconstructed from the PCA model parameters and the line-by-line-calculated values are found to be smaller than 0.15% for cross sections exceeding 1.27 x 10(-21) cm(-1) atm(-1) (CO) and 0.20% for cross sections exceeding 4.03 x 10(-21) cm(-1) atm(-1) (H2O). The computing time is reduced by a factor of 10(4).


Identification of infection by Chikungunya, Zika, and Dengue in an area of the Peruvian coast. Molecular diagnosis and clinical characteristics.
To assess the presence of Dengue, Chikungunya, and Zika in serum samples of patients with acute febrile illness in Piura, Peru and describe the most common clinical features. Dengue was the most common arbovirus detected in 170/496 (34.3%), followed by Zika in 39/496 (7.9%) and Chikungunya in 23/496 (4.6%). Among the 170 samples positive for Dengue, serotype 2 was the most predominant type present in 97/170 (57.1%) of samples, followed by the serotype 3 in 9/170 (5.3%). Headaches, muscle pain, and joint pain were the most common symptoms associated with fever in patients with Dengue and Zika. No symptoms predominance was observed in patients with Chikungunya.Dengue is considered the most frequent arbovirus in Peru and the number of cases has increased dramatically in the last 5 years. However, it is not the only arbovirus that circulates along the northern coast of Peru. It has also been determined the presence of Zika and Chikungunya in our population, which may suggest the circulation of other arboviruses that have not been detected.


The effect of physical exercise on bone density in middle-aged and older men: a systematic review.
Although trials have shown that exercise has positive effects on bone mineral density (BMD), the majority of exercise trials have been conducted in older women. The aim of this study was to systematically review trials examining the effect of weight-bearing and resistance-based exercise modalities on the BMD of hip and lumbar spine of middle-aged and older men. Eight electronic databases were searched in August 2012. Randomised controlled or controlled trials that assessed the effect of weight-bearing and resistance-based exercise interventions on BMD measured by dual-energy x-ray absorptiometry, and reported effects in middle-aged and older men were included. Eight trials detailed in nine papers were included. The interventions included walking (n = 2), resistance training (n = 3), walking + resistance training (n = 1), resistance training + impact-loading activities (n = 1) and resistance training + Tai Chi (n = 1). Five of the eight trials achieved a score of less than 50% on the modified Delphi quality rating scale. Further, there was heterogeneity in the type, intensity, frequency and duration of the exercise regimens. Effects of exercise varied greatly among studies, with six interventions having a positive effect on BMD and two interventions having no significant effect. It appears that resistance training alone or in combination with impact-loading activities are most osteogenic for this population, whereas the walking trials had limited effect on BMD. Therefore, regular resistance training and impact-loading activities should be considered as a strategy to prevent osteoporosis in middle-aged and older men. High quality randomised controlled trials are needed to establish the optimal exercise prescription.


Implementation of maternal and perinatal death reviews: a scoping review protocol.
Maternal and perinatal death surveillance and response (MPDSR), or any related form of audit, is a systematic process used to prevent future maternal and perinatal deaths. While the existence of MPDSR policies is routinely measured, measurement and understanding of policy implementation has lagged behind. In this paper, we present a theory-based conceptual framework for understanding MPDSR implementation as well as a scoping review protocol to understand factors influencing MPDSR implementation in low/ middle-income countries (LMIC). The Consolidated Framework for Implementation Research will inform the development of a theory-based conceptual framework for MPDSR implementation. The methodology for the scoping review will be guided by an adapted Arksey and O'Malley approach. Documents will include published and grey literature sourced from electronic databases (PubMed, CINAHL, SCOPUS, Web of Science, JSTOR, LILACS), the WHO Library, Maternal Death Surveillance and Response Action Network, Google, the reference lists of key studies and key experts. Two reviewers will independently screen titles, abstracts and full studies for inclusion. All discrepancies will be resolved by an independent third party. We will include studies published in English from 2004 to July 2018 that present results on factors influencing implementation of MPDSR, or any related form. Qualitative content and thematic analysis will be applied to extracted data according to the theory-based conceptual framework. Stakeholders will be consulted at various stages of the process. The scoping review will synthesise implementation factors relating to MPDSR in LMIC as described in the literature. This review will contribute to the work of the Countdown to 2030 Drivers Group, which seeks to explore key contextual drivers for equitable and effective coverage of maternal and child health interventions. Ethics approval is not required. The results will be disseminated through various channels, including a peer-reviewed publication.


How to report and interpret screening test properties: guidelines for driving researchers.
One important goal of driving research is the development of a short but valid office-based screening test for fitness to drive of aging drivers. Several candidate tests have been proposed already, and no doubt others will be proposed in the future. It might seem obvious that authors advocating for the adoption of a particular screening test or procedure should report sensitivity, specificity, and other common screening test properties. Unfortunately, driving researchers have frequently failed to report any screening test properties. Others have reported screening test properties but have made basic mistakes such as calculating predictive values of positive and negative tests but reporting them incorrectly as sensitivity and specificity. These omissions and errors suggest that some driving researchers may be unaware of the importance of accurately reporting test properties when proposing a screening procedure and that others may need a refresher on how to calculate and interpret the most common screening test properties. Many good learning resources for screening and diagnostic tests are available, but most of them are intended for students and researchers in medicine, epidemiology, or public health. We hope that this tutorial in a prominent transportation journal will help lead to improved reporting and interpretation of screening test properties in articles that assess the usefulness of potential screening tools for fitness to drive.


In vitro novel combinations of psychotropics and anti-cancer modalities in U87 human glioblastoma cells.
Glioblastoma multiforme (GBM) is a highly aggressive malignant brain tumor. Despite some recent improvement in the treatment of this malignancy, life expectancy of GBM patients remains extremely low. Therefore, continuous efforts to develop new treatment modalities are mandatory. A novel approach to cancer treatment is the use of targeted treatments, alone and in combination with other therapies. In this study, we evaluated the effects of novel combinations of conventional anti-cancer treatments (temozolomide or irradiation) with the targeted drug, imatinib, or with psychotropic drugs, belonging to the selective serotonin reuptake inhibitors (SSRIs) and phenothiazine subclasses, as well as combination of imatinib with psychotropic agents, on a human U87 glioblastoma cell line. The combination of temozolomide with imatinib or the psychotropic drugs resulted in an additive anti-proliferative effect, while the combination of irradiation and the psychotropic agents resulted in a less than additive effect on cell proliferation. A marked synergistic anti-proliferative effect of imatinib combined with the psychotropic drugs fluoxetine, sertraline or perphenazine was demonstrated. None of the single or combined treatments led to a reduction in the expression of phosphorylated MAP kinase. However, a marked synergistic reduction in the expression of the key regulatory molecule, pAKT, was detected, following the combined treatment of the cells with the imatinib/psychotropics combination. This down-regulation of pAKT may mediate the synergistic anti-proliferative interaction of imatinib with the psychotropic agents. Although the concentrations of the psychotropic agents used in this and other in vitro studies were beyond the clinically relevant blood levels in humans, recent studies have demonstrated anti-proliferative effects in vivo, using sertraline in a human colon cancer model. Thus, it seems that further in vivo studies combining imatinib with psychotropic agents, especially fluoxetine and sertraline, are warranted.


Age-related changes following in vitro stimulation with Rhodococcus equi of peripheral blood leukocytes from neonatal foals.
Rhodococcus equi is an intracellular bacterium primarily known as an equine pathogen that infects young foals causing a pyogranulomatuous pneumonia. The molecular mechanisms mediating the immune response of foals to R. equi are not fully elucidated. Hence, global genomic high-throughput tools like gene expression microarrays might identify age-related gene expression signatures and molecular pathways that contribute to the immune mechanisms underlying the inherent susceptibility of foals to disease caused by R. equi. The objectives of this study were 2-fold: 1) to compare the expression profiles at specific ages of blood leukocytes from foals stimulated with virulent R. equi with those of unstimulated leukocytes; and, 2) to characterize the age-related changes in the gene expression profile associated with blood leukocytes in response to stimulation with virulent R. equi. Peripheral blood leukocytes were obtained from 6 foals within 24 hours (h) of birth (day 1) and 2, 4, and 8 weeks after birth. The samples were split, such that half were stimulated with live virulent R. equi, and the other half served as unstimulated control. RNA was extracted and the generated cDNA was labeled with fluorescent dyes for microarray hybridizations using an equine microarray. Our findings suggest that there is age-related differential expression of genes involved in host immune response and immunity. We found induction of genes critical for host immunity against pathogens (MHC class II) only at the later time-points (compared to birth). While it appears that foals up to 8-weeks of age are able to initiate a protective inflammatory response against the bacteria, relatively decreased expression of various other immune-related genes points toward inherent diminished immune responses closer to birth. These genes and pathways may contribute to disease susceptibility in foals if infected early in life, and might thus be targeted for developing preventative or therapeutic strategies.


Construction of a detailed molecular map of the mouse X chromosome by microcloning and interspecific crosses.
A large number of microclones obtained by microdissection of the mouse X chromosome have been mapped using an interspecific Mus domesticus/Mus spretus cross. Clones displaying close linkage to a number of loci of known phenotype but unknown gene product, such as mdx (X-linked muscular dystrophy), have been obtained. Over a central 30 cM span of the mouse X chromosome, 17 clones have been mapped and ordered at a sufficient density to contemplate the complete physical mapping of this region that will aid in the isolation of a number of unidentified genes. Some of the mapped microclones detect moderately repetitive sequences that were clustered in several discrete regions of the mouse X chromosome.


Examination of the change in latent statuses in bullying behaviors across time.
Involvement in bullying and victimization has been mostly studied using cross-sectional data from 1 time point. As such, much of our understanding of bullying and victimization has not captured the dynamic experiences of youth over time. To examine the change of latent statuses in bullying and victimization, we applied latent transition analysis examining self-reported bullying involvement from 1,180 students in 5th through 9th grades across 3 time points. We identified unobserved heterogeneous subgroups (i.e., latent statuses) and investigated how students transition between the unobserved subgroups over time. For victimization, 4 latent statuses were identified: frequent victim (11.23%), occasional traditional victim (28.86%), occasional cyber and traditional victim (10.34%), and infrequent victim (49.57%). For bullying behavior, 3 latent statuses were identified: frequent perpetrator (5.12%), occasional verbal/relational perpetrator (26.04%), and infrequent perpetrator (68.84%). The characteristics of the transitions were examined. The multiple-group effects of gender, grade, and first language learned on transitions across statuses were also investigated. The infrequent victim and infrequent perpetrator groups were the most stable, and the frequent victim and frequent perpetrator groups were the least stable. These findings suggest instability in perpetration and victimization over time, as well as significant changes, especially during school transition years. Findings suggest that school-based interventions need to address the heterogeneity in perpetrator and victim experiences in adolescence.


Audience preferences are predicted by temporal reliability of neural processing.
Naturalistic stimuli evoke highly reliable brain activity across viewers. Here we record neural activity from a group of naive individuals while viewing popular, previously-broadcast television content for which the broad audience response is characterized by social media activity and audience ratings. We find that the level of inter-subject correlation in the evoked encephalographic responses predicts the expressions of interest and preference among thousands. Surprisingly, ratings of the larger audience are predicted with greater accuracy than those of the individuals from whom the neural data is obtained. An additional functional magnetic resonance imaging study employing a separate sample of subjects shows that the level of neural reliability evoked by these stimuli covaries with the amount of blood-oxygenation-level-dependent (BOLD) activation in higher-order visual and auditory regions. Our findings suggest that stimuli which we judge favourably may be those to which our brains respond in a stereotypical manner shared by our peers.


Deciphering cellular signals in adult mouse sinoatrial node cells.
Sinoatrial node (SAN) cells are the pacemakers of the heart. This study describes a method for culturing and infection of adult mouse SAN cells with FRET-based biosensors that can be exploited to examine signaling events. SAN cells cultured in media with blebbistatin or (S)-nitro-blebbistatin retain their morphology, protein distribution, action potential (AP) waveform, and cAMP dynamics for at least 40 h. SAN cells expressing targeted cAMP sensors show distinct β-adrenergic-mediated cAMP pools. Cyclic GMP, protein kinase A, Ca2+/CaM kinase II, and protein kinase D in SAN cells also show unique dynamics to different stimuli. Heart failure SAN cells show a decrease in cAMP and cGMP levels. In summary, a reliable method for maintaining adult mouse SAN cells in culture is presented, which facilitates studies of signaling networks and regulatory mechanisms during physiological and pathological conditions.


Insulin inhibits AMPA-induced neuronal damage via stimulation of protein kinase B (Akt).
We designed a series of experiments to explore the neuroprotective effects of insulin. Insulin significantly inhibited the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-induced neuronal cell damage as evidenced by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide (MTT) assay. However, insulin had little affect on the AMPA-induced glial cell damage. To determine whether insulin inhibits AMPA-induced excitotoxicity, we performed grease-gap recording assays using rat brain slices. In these experiments, insulin also significantly inhibited AMPA-induced depolarization. Flow cytometry and DNA fragmentation assays showed that insulin inhibits AMPA-induced apoptosis and DNA fragmentation, respectively. Insulin stimulated protein kinase B (Akt) activity, whereas AMPA pretreatment did not alter the insulin-stimulated Akt activity. On the contrary, insulin blocked induction of SAPK/JNK, which AMPA stimulated. Taken together, these results suggest that insulin exerts neuroprotective effects by inhibiting AMPA-induced excitotoxicity and apoptosis, possibly by activating Akt and blocking SAPK/JNK.


UGT2B10 genotype influences nicotine glucuronidation, oxidation, and consumption.
Tobacco exposure is routinely assessed by quantifying nicotine metabolites in plasma or urine. On average, 80% of nicotine undergoes C-oxidation to cotinine. However, interindividual variation in nicotine glucuronidation is substantial, and glucuronidation accounts for from 0% to 40% of total nicotine metabolism. We report here the effect of a polymorphism in a UDP-glucuronsyltransferase, UGT2B10, on nicotine metabolism and consumption. Nicotine, cotinine, their N-glucuronide conjugates, and total trans-3'-hydroxycotinine were quantified in the urine (n = 327) and plasma (n = 115) of smokers. Urinary nicotine N-oxide was quantified in 105 smokers. Nicotine equivalents, the sum of nicotine and all major metabolites, were calculated for each smoker. The relationship of the UGT2B10 Asp67Tyr allele to nicotine equivalents, N-glucuronidation, and C-oxidation was determined. Individuals heterozygous for the Asp67Tyr allele excreted less nicotine or cotinine as their glucuronide conjugates than did wild-type, resulting in a 60% lower ratio of cotinine glucuronide to cotinine, a 50% lower ratio of nicotine glucuronide to nicotine, and increased cotinine and trans-3'-hydroxycotinine. Nicotine equivalents, a robust biomarker of nicotine intake, were lower among Asp67Tyr heterozygotes compared with individuals without this allele: 58.2 (95% confidence interval, 48.9-68.2) versus 69.2 nmol/mL (95% confidence interval, 64.3-74.5). Individuals heterozygous for UGT2B10 Asp67Tyr consume less nicotine than do wild-type smokers. This striking observation suggests that variations in nicotine N-glucuronidation, as reported for nicotine C-oxidation, may influence smoking behavior. UGT2B10 genotype influences nicotine metabolism and should be taken into account when characterizing the role of nicotine metabolism on smoking.


Score statistic to test for genetic correlation for proband-family design.
In genetic epidemiological studies informative families are often oversampled to increase the power of a study. For a proband-family design, where relatives of probands are sampled, we derive the score statistic to test for clustering of binary and quantitative traits within families due to genetic factors. The derived score statistic is robust to ascertainment scheme. We considered correlation due to unspecified genetic effects and/or due to sharing alleles identical by descent (IBD) at observed marker locations in a candidate region. A simulation study was carried out to study the distribution of the statistic under the null hypothesis in small data-sets. To illustrate the score statistic, data from 33 families with type 2 diabetes mellitus (DM2) were analyzed. In addition to the binary outcome DM2 we also analyzed the quantitative outcome, body mass index (BMI). For both traits familial aggregation was highly significant. For DM2, also including IBD sharing at marker D3S3681 as a cause of correlation gave an even more significant result, which suggests the presence of a trait gene linked to this marker. We conclude that for the proband-family design the score statistic is a powerful and robust tool for detecting clustering of outcomes.


Calcium Microdomain Formation at the Perisynaptic Cradle Due to NCX Reversal: A Computational Study.
It has recently been proposed using a multi-compartmental mathematical model that negatively fixed charged membrane-associated sites constrain the flow of cations in perisynaptic astroglial processes. This restricted movement of ions between the perisynaptic cradle (PsC), principal astroglial processes and the astrocyte soma gives rise to potassium (K+) and sodium (Na+) microdomains at the PsC. The present paper extends the above model to demonstrate that the formation of an Na+ microdomain can reverse the Na+/Ca2+ exchanger (NCX) thus providing an additional source of calcium (Ca2+) at the PsC. Results presented clearly show that reversal of the Na+/Ca2+ exchanger is instigated by a glutamate transporter coupled increase in concentration of cytoplasmic [Na+]i at the PsC, which and instigates Ca2+ influx through the NCX. As the flow of Ca2+ along the astrocyte process and away from the PsC is also constrained by Ca2+ binding proteins, then a Ca2+ microdomain forms at the PsC. The paper also serves to demonstrate that the EAAT, NKA, and NCX represent the minimal requirement necessary and sufficient for the development of a Ca2+ microdomain and that these mechanisms directly link neuronal activity and glutamate release to the formation of localized Na+ and Ca2+ microdomains signals at the PsC. This local source of Ca2+ can provide a previously underexplored form of astroglial Ca2+ signaling.


Decadal land cover change dynamics in Bhutan.
Land cover (LC) is one of the most important and easily detectable indicators of change in ecosystem services and livelihood support systems. This paper describes the decadal dynamics in LC changes at national and sub-national level in Bhutan derived by applying object-based image analysis (OBIA) techniques to 1990, 2000, and 2010 Landsat (30 m spatial resolution) data. Ten LC classes were defined in order to give a harmonized legend land cover classification system (LCCS). An accuracy of 83% was achieved for LC-2010 as determined from spot analysis using very high resolution satellite data from Google Earth Pro and limited field verification. At the national level, overall forest increased from 25,558 to 26,732 km(2) between 1990 and 2010, equivalent to an average annual growth rate of 59 km(2)/year (0.22%). There was an overall reduction in grassland, shrubland, and barren area, but the observations were highly dependent on time of acquisition of the satellite data and climatic conditions. The greatest change from non-forest to forest (277 km(2)) was in Bumthang district, followed by Wangdue Phodrang and Trashigang, with the least (1 km(2)) in Tsirang. Forest and scrub forest covers close to 75% of the land area of Bhutan, and just over half of the total area (51%) has some form of conservation status. This study indicates that numerous applications and analyses can be carried out to support improved land cover and land use (LCLU) management. It will be possible to replicate this study in the future as comparable new satellite data is scheduled to become available.


Amplitude filter and Zernike polynomial expansion method for quality control of microlens arrays.
This paper deals with a computer simulation and an experimental realization of an optical setup for automatic quality control of microlens arrays. The method is based on a 4f coherent light correlator setup with an amplitude filter placed in the Fourier plane. The output intensity signal is proportional to the first derivative of the distortion of the input wavefront. An analysis can be carried out with the use of the Zernike polynomial expansion method. It must be carried out separately for each lens, but it allows for a more precise, quantitative assessment of their quality. What is important is that the analysis is computer-based and performed on the basis of the initial single optical measurement.


Geographical accessibility and spatial coverage modeling of the primary health care network in the Western Province of Rwanda.
Primary health care is essential in improving and maintaining the health of populations. It has the potential to accelerate achievement of the Millennium Development Goals and fulfill the "Health for All" doctrine of the Alma-Ata Declaration. Understanding the performance of the health system from a geographic perspective is important for improved health planning and evidence-based policy development. The aims of this study were to measure geographical accessibility, model spatial coverage of the existing primary health facility network, estimate the number of primary health facilities working under capacity and the population underserved in the Western Province of Rwanda. This study uses health facility, population and ancillary data for the Western Province of Rwanda. Three different travel scenarios utilized by the population to attend the nearest primary health facility were defined with a maximum travelling time of 60 minutes: Scenario 1--walking; Scenario 2--walking and cycling; and Scenario 3--walking and public transportation. Considering these scenarios, a raster surface of travel time between primary health facilities and population was developed. To model spatial coverage and estimate the number of primary health facilities working under capacity, the catchment area of each facility was calculated by taking into account population coverage capacity, the population distribution, the terrain topography and the travelling modes through the different land categories. Scenario 2 (walking and cycling) has the highest degree of geographical accessibility followed by Scenario 3 (walking and public transportation). The lowest level of accessibility can be observed in Scenario 1 (walking). The total population covered differs depending on the type of travel scenario. The existing primary health facility network covers only 26.6% of the population in Scenario 1. In Scenario 2, the use of a bicycle greatly increases the population being served to 58% of inhabitants. When considering Scenario 3, the total population served is 34.3%. Significant spatial variations in geographical accessibility and spatial coverage were observed across the three travel scenarios. The analysis demonstrates that regardless of which travel scenario is used, the majority of the population in the Western Province does not have access to the existing primary health facility network. Our findings also demonstrate the usefulness of GIS methods to leverage multiple datasets from different sources in a spatial framework to provide support to evidence-based planning and resource allocation decision-making in developing countries.


Molecular imaging of EGFR and CD44v6 for prediction and response monitoring of HSP90 inhibition in an in vivo squamous cell carcinoma model.
Heat shock protein 90 (HSP90) is essential for the activation and stabilization of numerous oncogenic client proteins. AT13387 is a novel HSP90 inhibitor promoting degradation of oncogenic proteins upon binding, and may also act as a radiosensitizer. For optimal treatment there is, however, the need for identification of biomarkers for patient stratification and therapeutic response monitoring, and to find suitable targets for combination treatments. The aim of this study was to assess the response of surface antigens commonly expressed in squamous cell carcinoma to AT13387 treatment, and to find suitable biomarkers for molecular imaging and radioimmunotherapy in combination with HSP90 inhibition. Cancer cell proliferation and radioimmunoassays were used to evaluate the effect of AT13387 on target antigen expression in vitro. Inhibitor effects were then assessed in vivo in mice-xenografts. Animals were treated with AT13387 (5 × 50 mg/kg), and were imaged with PET using either (18)F-FDG or (124)I-labelled tracers for EGFR and CD44v6, and this was followed by ex-vivo biodistribution analysis and immunohistochemical staining. AT13387 exposure resulted in high cytotoxicity and possible radiosensitization with IC50 values below 4 nM. Both in vitro and in vivo AT13387 effectively downregulated HSP90 client proteins. PET imaging with (124)I-cetuximab showed a significant decrease of EGFR in AT13387-treated animals compared with untreated animals. In contrast, the squamous cell carcinoma-associated biomarker CD44v6, visualized with (124)I-AbD19384 as well as (18)F-FDG uptake, were not significantly altered by AT13387 treatment. We conclude that AT13387 downregulates HSP90 client proteins, and that molecular imaging of these proteins may be a suitable approach for assessing treatment response. Furthermore, radioimmunotherapy targeting CD44v6 in combination with AT13387 may potentiate the radioimmunotherapy outcome due to radiosensitizing effects of the drug, and could potentially lead to a lower dose to normal tissues.


The Cytoophidium and Its Kind: Filamentation and Compartmentation of Metabolic Enzymes.
Compartmentation is essential for the localization of biological processes within a cell. In 2010, three groups independently reported that cytidine triphosphate synthase (CTPS), a metabolic enzyme for de novo synthesis of the nucleotide CTP, is compartmentalized in cytoophidia (Greek for "cellular snakes") in bacteria, yeast, and fruit flies. Subsequent studies demonstrate that CTPS can also form filaments in human cells. Thus, the cytoophidium represents a new type of intracellular compartment that is strikingly conserved across prokaryotes and eukaryotes. Multiple lines of evidence have recently suggested that polymerization of metabolic enzymes such as CTPS and inosine monophosphate dehydrogenase into filamentous cytoophidia modulates enzymatic activity. With many more metabolic enzymes found to form the cytoophidium and its kind, compartmentation via filamentation may serve as a general mechanism for the regulation of metabolism.


Dual orexin receptor antagonists - promising agents in the treatment of sleep disorders.
Insomnia is a serious medical and social problem, its prevalence in the general population ranges from 9 to 35% depending on the country and assessment method. Often, patients are subject to inappropriate and therefore dangerous pharmacotherapies that include prolonged administration of hypnotic drugs, benzodiazepines and other GABAA receptor modulators. This usually does not lead to a satisfactory improvement in patients' clinical states and may cause lifelong drug dependence. Brain state transitions require the coordinated activity of numerous neuronal pathways and brain structures. It is thought that orexin-expressing neurons play a crucial role in this process. Due to their interaction with the sleep-wake-regulating neuronal population, they can activate vigilance-promoting regions and prevent unwanted sleep intrusions. Understanding the multiple orexin modulatory effects is crucial in the context of pathogenesis of insomnia and should lead to the development of novel treatments. An important step in this process was the synthesis of dual antagonists of orexin receptors. Crucially, these drugs, as opposed to benzodiazepines, do not change the sleep architecture and have limited side-effects. This new pharmacological approach might be the most appropriate to treat insomnia.


Differential roles of amygdala and posterior superior temporal sulcus in social scene understanding.
Neuropsychology and neuroimaging studies provide distinct views on the key neural underpinnings of social scene understanding (SSU): the amygdala and multimodal neocortical areas such as the posterior superior temporal sulcus (pSTS), respectively. This apparent incongruity may stem from the difference in the assumed cognitive processes of the situation-response association and the integrative or creative processing of social information. To examine the neural correlates of different SSU types using functional magnetic resonance imaging (fMRI), we devised a clothing recommendation task in three types of client's standpoint. Situation-response association was induced by a situation-congruent standpoint (ecological SSU), whereas the integrative and creative processing of social information was elicited by a lack and situation incongruence of the standpoint (perceptual and elaborative SSUs, respectively). Activation characteristic of the ecological SSU was identified in the right amygdala, while that of the perceptual SSU and elaborative SSU demand was identified in the right pSTS and left middle temporal gyrus (MTG), respectively. Thus, the current results provide evidence for the conceptual and neural distinction of the three types of SSU, with basic ecological SSU being supported by a limbic structure while sophisticated integrative or creative SSUs being developed in humans by multimodal association cortices.


Distribution of brain metastases: implications for non-uniform dose prescriptions.
The aim of this study was to determine the disease-specific distribution of brain metastases and, using radiobiological modelling, estimate how these anatomical tendencies might be exploited when delivering prophylactic whole-brain radiotherapy for small cell lung cancer in complete remission. Disease-specific brain metastasis atlases were created by mapping brain metastases to a standard image set from a database of patients who were to receive external beam radiation therapy. The specific diseases investigated included lung (both small cell and non-small cell), breast, renal and gynaecological cancers as well as melanoma. Radiobiological modelling was used to estimate how much improvement, in terms of the metastasis-free rate at 3 years, might be possible with non-uniform dose distributions if there are spatial biases in the incidence of micrometastases from small cell lung cancer. For lung and breast cancer, there was an increased probability of cerebellar metastases compared with what would be predicted based solely on brain volume. This trend was not evident for renal cancer, gynaecological malignancies or melanoma. Radiobiological models suggest that if there is a non-uniform distribution of microscopic brain metastases in patients with small cell lung cancer, higher population-based metastasis-free rates might be achievable with non-uniform irradiation compared with the same integral whole-brain dose delivered as a uniform prescription.


Dysregulation of RUNX2/Activin-A Axis upon miR-376c Downregulation Promotes Lymph Node Metastasis in Head and Neck Squamous Cell Carcinoma.
Epigenetic correlates of the head and neck cancer may illuminate its pathogenic roots. Through a gene set enrichment analysis, we found that the oncogenic transcription factor RUNX2 is widely upregulated in the head and neck squamous cell carcinoma (HNSCC) with lymph node metastasis, where it also predicts poor prognosis in patients with HNSCC. Enforced expression of ectopic RUNX2 promoted the metastatic capabilities of HNSCC, whereas RUNX2 silencing inhibited these features. Mechanistic investigations showed that manipulating levels of activin A (INHBA) could rescue or compromise the RUNX2-mediated metastatic capabilities of HNSCC cells. Furthermore, we found that miR-376c-3p encoded within the 3'-untranslated region of RUNX2 played a pivotal role in regulating RUNX2 expression in highly metastatic HNSCC cells, where it was downregulated commonly. Restoring miR-376c expression in this setting suppressed expression of RUNX2/INHBA axis along with metastatic capability. Clinically, we observed an inverse relationship between miR-376c-3p expression and the RUNX2/INHBA axis in HNSCC specimens. In summary, our results defined a novel pathway in which dysregulation of the RUNX2/INHBA axis due to miR-376c downregulation fosters lymph node metastasis in HNSCC. Cancer Res; 76(24); 7140-50. ©2016 AACR.


Dislocations in SrTiO3: easy to reduce but not so fast for oxygen transport.
The effect of dislocations on the chemical, electrical and transport properties in oxide materials is important for electrochemical devices, such as fuel cells and resistive switches, but these effects have remained largely unexplored at the atomic level. In this work, by using large-scale atomistic simulations, we uncover how a ⟨100⟩{011} edge dislocation in SrTiO3, a prototypical perovskite oxide, impacts the local defect chemistry and oxide ion transport. We find that, in the dilute limit, oxygen vacancy formation energy in SrTiO3 is lower at sites close to the dislocation core, by as much as 2 eV compared to that in the bulk. We show that the formation of a space-charge zone based on the redistribution of charged oxygen vacancies can be captured quantitatively at atomistic level by mapping the vacancy formation energies around the dislocation. Oxide-ion diffusion was studied for a low vacancy concentration regime (ppm level) and a high vacancy concentration regime (up to 2.5%). In both cases, no evidence of pipe-diffusion, i.e., significantly enhanced mobility of oxide ions, was found as determined from the calculated migration barriers, contrary to the case in metals. However, in the low vacancy concentration regime, the vacancy accumulation at the dislocation core gives rise to a higher diffusion coefficient, even though the oxide-ion mobility itself is lower than that in the bulk. Our findings have important implications for applications of perovskite oxides for information and energy technologies. The observed lower oxygen vacancy formation energy at the dislocation core provides a quantitative and direct explanation for the electronic conductivity of dislocations in SrTiO3 and related oxides studied for red-ox based resistive switching. Reducibility and electronic transport at dislocations can also be quantitatively engineered into active materials for fuel cells, catalysis, and electronics.


Factors affecting attainment of paid employment after lung transplantation.
Limited data exist regarding return to or attainment of paid employment after lung transplantation. Accordingly, the purpose of our study was to identify the issues relating to paid employment after this procedure. We conducted a mailed survey using Dillman's protocol. We mailed questionnaires to surviving Toronto General Hospital lung transplant recipients (n = 190). We used descriptive statistics, t-tests, and chi-square tests to analyze the data. A total of 117 lung transplant recipients completed the questionnaires (70% response rate). The mean age of respondents was 51 +/- 13 years. Fifty-one percent of the sample were women and 72% were married. Cystic fibrosis and chronic obstructive pulmonary disease were the most frequent pre-transplant diagnoses. Fifty-six percent of participants had paid employment at some point before transplant. After transplant, 37% of respondents obtained employment. Individuals who obtained paid employment were more likely to be younger (p = 0.002), to have university degrees (p = 0.02), to report higher health ratings (p = 0.001), and to feel physically able to work (p = 0.01). They also were more likely to express a desire to enter the paid workforce (p < 0.0001); to describe receiving physician encouragement to work (p < 0.0001); to identify the possibility of obtaining paid employment as a primary motivator for the transplantation (p = 0.01); and to report that their previous jobs were available after transplantation (p = 0.01). All individuals who did not obtain paid employment cited personal or transplant-related factors. Medical and social factors influence attainment of paid employment after lung transplantation. Important components of the pre-transplant assessment are discussion of expectations about attaining employment and openly exploring the recipient's motivation for employment.


Effect of the supramolecular interactions on the nanostructure of halloysite/biopolymer hybrids: a comprehensive study by SANS, fluorescence correlation spectroscopy and electric birefringence.
The structural properties of halloysite/biopolymer aqueous mixtures were firstly investigated by means of combining different techniques, including small-angle neutron scattering (SANS), electric birefringence (EBR) and fluorescence correlation spectroscopy (FCS). Among the biopolymers, non-ionic hydroxypropylcellulose and polyelectrolytes (anionic alginate and cationic chitosan) were selected. On this basis, the specific supramolecular interactions were correlated to the structural behavior of the halloysite/biopolymer mixtures. SANS data were analyzed in order to investigate the influence of the biopolymer adsorption on the halloysite gyration radius. In addition, a morphological description of the biopolymer-coated halloysite nanotubes (HNTs) was obtained by the simulation of SANS curves. EBR experiments evidenced that the orientation dynamics of the nanotubes in the electric field is influenced by the specific interactions with the polymers. Namely, both variations of the polymer charge and/or wrapping mechanisms strongly affected the HNT alignment process and, consequently, the rotational mobility of the nanotubes. FCS measurements with fluorescently labeled biopolymers allowed us to study the aqueous dynamic behavior of ionic biopolymers after their adsorption onto the HNT surfaces. The combination of EBR and FCS results revealed that the adsorption process reduces the mobility in water of both components. These effects are strongly enhanced by HNT/polyelectrolyte electrostatic interactions and wrapping processes occurring in the halloysite/chitosan mixture. The attained findings can be useful for designing halloysite/polymer hybrids with controlled structural properties.


Gastrointestinal dysfunction in patients and mice expressing the autism-associated R451C mutation in neuroligin-3.
Gastrointestinal (GI) problems constitute an important comorbidity in many patients with autism. Multiple mutations in the neuroligin family of synaptic adhesion molecules are implicated in autism, however whether they are expressed and impact GI function via changes in the enteric nervous system is unknown. We report the GI symptoms of two brothers with autism and an R451C mutation in Nlgn3 encoding the synaptic adhesion protein, neuroligin-3. We confirm the presence of an array of synaptic genes in the murine GI tract and investigate the impact of impaired synaptic protein expression in mice carrying the human neuroligin-3 R451C missense mutation (NL3R451C ). Assessing in vivo gut dysfunction, we report faster small intestinal transit in NL3R451C compared to wild-type mice. Using an ex vivo colonic motility assay, we show increased sensitivity to GABAA receptor modulation in NL3R451C mice, a well-established Central Nervous System (CNS) feature associated with this mutation. We further show increased numbers of small intestine myenteric neurons in NL3R451C mice. Although we observed altered sensitivity to GABAA receptor modulators in the colon, there was no change in colonic neuronal numbers including the number of GABA-immunoreactive myenteric neurons. We further identified altered fecal microbial communities in NL3R451C mice. These results suggest that the R451C mutation affects small intestinal and colonic function and alter neuronal numbers in the small intestine as well as impact fecal microbes. Our findings identify a novel GI phenotype associated with the R451C mutation and highlight NL3R451C mice as a useful preclinical model of GI dysfunction in autism. Autism Res 2019, 12: 1043-1056. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: People with autism commonly experience gastrointestinal problems, however the cause is unknown. We report gut symptoms in patients with the autism-associated R451C mutation encoding the neuroligin-3 protein. We show that many of the genes implicated in autism are expressed in mouse gut. The neuroligin-3 R451C mutation alters the enteric nervous system, causes gastrointestinal dysfunction, and disrupts gut microbe populations in mice. Gut dysfunction in autism could be due to mutations that affect neuronal communication.


Searching for superspreaders of information in real-world social media.
A number of predictors have been suggested to detect the most influential spreaders of information in online social media across various domains such as Twitter or Facebook. In particular, degree, PageRank, k-core and other centralities have been adopted to rank the spreading capability of users in information dissemination media. So far, validation of the proposed predictors has been done by simulating the spreading dynamics rather than following real information flow in social networks. Consequently, only model-dependent contradictory results have been achieved so far for the best predictor. Here, we address this issue directly. We search for influential spreaders by following the real spreading dynamics in a wide range of networks. We find that the widely-used degree and PageRank fail in ranking users' influence. We find that the best spreaders are consistently located in the k-core across dissimilar social platforms such as Twitter, Facebook, Livejournal and scientific publishing in the American Physical Society. Furthermore, when the complete global network structure is unavailable, we find that the sum of the nearest neighbors' degree is a reliable local proxy for user's influence. Our analysis provides practical instructions for optimal design of strategies for "viral" information dissemination in relevant applications.