The relationship between species richness and ecosystem variability is shaped by the mechanism of coexistence.
Theory relating species richness to ecosystem variability typically ignores the potential for environmental variability to promote species coexistence. Failure to account for fluctuation-dependent coexistence may explain deviations from the expected negative diversity-ecosystem variability relationship, and limits our ability to predict the consequences of increases in environmental variability. We use a consumer-resource model to explore how coexistence via the temporal storage effect and relative nonlinearity affects ecosystem variability. We show that a positive, rather than negative, diversity-ecosystem variability relationship is possible when ecosystem function is sampled across a natural gradient in environmental variability and diversity. We also show how fluctuation-dependent coexistence can buffer ecosystem functioning against increasing environmental variability by promoting species richness and portfolio effects. Our work provides a general explanation for variation in observed diversity-ecosystem variability relationships and highlights the importance of conserving regional species pools to help buffer ecosystems against predicted increases in environmental variability.


Directed differentiation of human pluripotent cells to ureteric bud kidney progenitor-like cells.
Diseases affecting the kidney constitute a major health issue worldwide. Their incidence and poor prognosis affirm the urgent need for the development of new therapeutic strategies. Recently, differentiation of pluripotent cells to somatic lineages has emerged as a promising approach for disease modelling and cell transplantation. Unfortunately, differentiation of pluripotent cells into renal lineages has demonstrated limited success. Here we report on the differentiation of human pluripotent cells into ureteric-bud-committed renal progenitor-like cells. The generated cells demonstrated rapid and specific expression of renal progenitor markers on 4-day exposure to defined media conditions. Further maturation into ureteric bud structures was accomplished on establishment of a three-dimensional culture system in which differentiated human cells assembled and integrated alongside murine cells for the formation of chimeric ureteric buds. Altogether, our results provide a new platform for the study of kidney diseases and lineage commitment, and open new avenues for the future application of regenerative strategies in the clinic.


Local foods can meet micronutrient needs for women in urban Burkina Faso, but only if rarely consumed micronutrient-dense foods are included in daily diets: A linear programming exercise.
Women of reproductive age are at nutritional risk due to their need for nutrient-dense diets. Risk is further elevated in resource-poor environments. In one such environment, we evaluated feasibility of meeting micronutrient needs of women of reproductive age using local foods alone or using local foods and supplements, while minimizing cost. Based on dietary recall data from Ouagadougou, we used linear programming to identify the lowest cost options for meeting 10 micronutrient intake recommendations, while also meeting energy needs and following an acceptable macronutrient intake pattern. We modeled scenarios with maximum intake per food item constrained at the 75th percentile of reported intake and also with more liberal maxima based on recommended portions per day, with and without the addition of supplements. Some scenarios allowed only commonly consumed foods (reported on at least 10% of recall days). We modeled separately for pregnant, lactating, and nonpregnant, nonlactating women. With maxima constrained to the 75th percentile, all micronutrient needs could be met with local foods but only when several nutrient-dense but rarely consumed items were included in daily diets. When only commonly consumed foods were allowed, micronutrient needs could not be met without supplements. When larger amounts of common animal-source foods were allowed, all needs could be met for nonpregnant, nonlactating women but not for pregnant or lactating women, without supplements. We conclude that locally available foods could meet micronutrient needs but that to achieve this, strategies would be needed to increase consistent availability in markets, consistent economic access, and demand.


HIV, HCV, HBV, HSV, and syphilis prevalence among female sex workers in Tehran, Iran, by using respondent-driven sampling.
To find out the prevalence of HIV, HCV, HBV, HSV, and syphilis infections among female sex workers (FSWs) in Tehran, a cross-sectional study by using respondent-driven sampling (RDS) method was conducted. From December 2012 to April 2013 FSWs in Tehran were recruited. Inclusion criteria consisted of trading sex during the 12 months prior to this study and selling sex for at least 6 months in participants' lifetime. Among 161 consenting participants, 5% were infected with HIV. Moreover, 8.1% of FSWs were HCV positive, 37.9% were of HSV type1/type2, 1.2% of participants were infected with HBV, and none of the participants were infected with syphilis. HIV-positive participants were significantly more likely to be co-infected with HSV type1/type2, be younger, have more sexual partners and especially more clients during seven days prior to this study and report more history of having at least one of sexually transmitted infections symptoms in 12 months prior the study. In the multiple logistic regression analysis, being infected with HSV and also being under 25 years of age were found to be independently associated with HIV infection. Compared with the prevalence of HIV among general population of Tehran, relatively high prevalence of HIV and other viral infections among FSWs should be considered. All in all, it is critical to commence effective counter-measures for this high-risk group if the aim is to prevent spreading of these viruses to general population.


The effect of perioperative allergic conjunctivitis on corneal lymphangiogenesis after corneal transplantation.
Perioperative allergic conjunctivitis accelerates the speed of corneal allograft rejection. This study examines the effect of allergic conjunctivitis, with and without dexamethasone treatment, on the early inflammatory response and lymphangiogenesis in the host cornea following corneal transplantation. Allogeneic fully MHC-mismatched C57Bl/6 strain donor corneas were transplanted into naive A/J mice and into A/J mice with active allergic conjunctivitis. Further groups of allograft recipients with allergic conjunctivitis were treated post-operatively with twice daily topical dexamethasone 0.1% or phosphate-buffered saline. Mice were killed on days 2 and 6 and corneas were examined by (i) fluorescent immunohistochemistry of frozen sections using anti-CD11b, anti-F4/80 and anti-Gr-1 antibodies, or (ii) whole-mount staining with anti-LYVE-1 antibody. Lymphatic ingrowth and numbers of cells infiltrating the host cornea were compared between groups. There were significantly higher numbers of CD11b(+) cells and LYVE-1(+) vessels in the host cornea at day 2 in allergic compared with naive recipients, but no differences between naive and allergic recipients at day 6. In allergic eyes, dexamethasone treatment significantly inhibited LYVE-1 expression at days 2 and 6, and significantly improved allograft survival in recipients with allergic conjunctivitis if maintained for a week. The innate immune response to allogeneic corneal tissue is more vigorous in the presence of allergic conjunctivitis than in naive eyes and is associated with accelerated lymphatic ingrowth to host cornea. Topical dexamethasone inhibits lymphatic ingrowth and this may be one mechanism by which topical steroid enhances graft survival.


Contributions of dopaminergic drugs and disease severity to daytime sleepiness in Parkinson disease.
Excessive daytime somnolence is a common report among patients who have Parkinson disease (PD). The relative contributions of disease severity and of the various dopaminergic drugs are unclear. To separate and quantify the contributions of disease markers and drug doses. Patients seen during a 7-month period at a center for movement disorders completed the Epworth Sleepiness Scale. Treatment subgroups were compared. The relationship to sedation of age; dopaminergic drug classes and doses; Hoehn and Yahr stage; duration of disease; total score on the motor subsection of the Unified Parkinson Disease Rating Scale; and the presence or absence of dementia, depression, or hallucinations was calculated using simple and multiple regression and t tests. The Epworth Sleepiness Scale scores were higher among patients with PD (mean [SD], 10.8 [5.3]; n = 368) compared with patients with other neurological disorders (mean, 8.5 [5.1]; n = 243; P<.001). A model containing the Hoehn and Yahr stage, levodopa dose, and use of a dopamine agonist was the best at predicting the total score of Epworth Sleepiness Scale in patients who have PD, but accounted for only 9% of the interindividual variance. The parameter estimates (SE) corresponded to a 1.02 (0.03)-point increase per Hoehn and Yahr stage, a 0.14 (0.06)-point increase per 100-mg increase in levodopa dose over 24 hours, and a 2.33 (0.57)-point increase with use of an agonist. There was no statistically significant dose response for agonists. No statistically significant difference in sedation among the commonly used dopamine agonists was found. Somnolence in patients with PD, which is on average 25% higher than in other neurological diseases, is related to PD stage, levodopa dose, and the use of a dopamine agonist. However, most of the variability in sedation levels in patients with PD as well as in controls is the result of, as yet, unidentified factors.


Roles of the equatorial tyrosyl iron ligand of protocatechuate 3,4-dioxygenase in catalysis.
The active site Fe(III) of protocatechuate 3,4-dioxygenase (3,4-PCD) from Pseudomonas putida is ligated axially by Tyr447 and His462 and equatorially by Tyr408, His460, and OH(-). Tyr447 and OH(-) are displaced as protocatechuate (3,4-dihydroxybenzoate, PCA) chelates the iron and appear to serve as in situ bases to promote this process. The role(s) of Tyr408 is (are) explored here using mutant enzymes that exhibit less than 0.1% wild-type activity. The X-ray crystal structures of the mutants and their PCA complexes show that the new shorter residues in the 408 position cannot ligate the iron and instead interact with the iron through solvents. Moreover, PCA binds as a monodentate rather than a bidentate ligand, and Tyr447 fails to dissociate. Although the new residues at position 408 do not directly bind to the iron, large changes in the spectroscopic and catalytic properties are noted among the mutant enzymes. Resonance Raman features show that the Fe-O bond of the monodentate 4-hydroxybenzoate (4HB) inhibitor complex is significantly stronger in the mutants than in wild-type 3,4-PCD. Transient kinetic studies show that PCA and 4HB bind to 3,4-PCD in a fast, reversible step followed by a step in which coordination to the metal occurs; the latter process is at least 50-fold slower in the mutant enzymes. It is proposed that, in wild-type 3,4-PCD, the Lewis base strength of Tyr408 lowers the Lewis acidity of the iron to foster the rapid exchange of anionic ligands during the catalytic cycle. Accordingly, the increase in Lewis acidity of the iron caused by substitution of this residue by solvent tends to make the iron substitution inert. Tyr447 cannot be released to allow formation of the usual dianionic PCA chelate complex with the active site iron, and the rate of electrophilic attack by O(2) becomes rate limiting overall. The structures of the PCA complexes of these mutant enzymes show that hydrogen-bonding interactions between the new solvent ligand and the new second-sphere residue in position 408 allow this residue to significantly influence the spectroscopic and kinetic properties of the enzymes.


Multivariable regression analysis of list experiment data on abortion: results from a large, randomly-selected population based study in Liberia.
The list experiment is a promising measurement tool for eliciting truthful responses to stigmatized or sensitive health behaviors. However, investigators may be hesitant to adopt the method due to previously untestable assumptions and the perceived inability to conduct multivariable analysis. With a recently developed statistical test that can detect the presence of a design effect - the absence of which is a central assumption of the list experiment method - we sought to test the validity of a list experiment conducted on self-reported abortion in Liberia. We also aim to introduce recently developed multivariable regression estimators for the analysis of list experiment data, to explore relationships between respondent characteristics and having had an abortion - an important component of understanding the experiences of women who have abortions. To test the null hypothesis of no design effect in the Liberian list experiment data, we calculated the percentage of each respondent "type," characterized by response to the control items, and compared these percentages across treatment and control groups with a Bonferroni-adjusted alpha criterion. We then implemented two least squares and two maximum likelihood models (four total), each representing different bias-variance trade-offs, to estimate the association between respondent characteristics and abortion. We find no clear evidence of a design effect in list experiment data from Liberia (p = 0.18), affirming the first key assumption of the method. Multivariable analyses suggest a negative association between education and history of abortion. The retrospective nature of measuring lifetime experience of abortion, however, complicates interpretation of results, as the timing and safety of a respondent's abortion may have influenced her ability to pursue an education. Our work demonstrates that multivariable analyses, as well as statistical testing of a key design assumption, are possible with list experiment data, although with important limitations when considering lifetime measures. We outline how to implement this methodology with list experiment data in future research.


Daily versus weekly iron supplementation and prevention of iron deficiency anaemia in lactating women.
To demonstrate the effectiveness and social feasibility of weekly versus daily iron supplementation in preventing and treating iron deficiency anaemia among anaemic mothers. A longitudinal in nature. Seven urban slum communities in Teklehaimanot Wereda, Addis Ababa, Ethiopia. Two hundred seven eligible mothers were assigned to the daily supplementation, weekly supplementation or control groups following randomisation between March and May 2001. The daily supplemented groups (n=71) received 60 mg of elemental iron containing 300 mg ferrous sulphate and 400 microg folic acid from Monday to Friday. The weekly group (n=68) received one tablet once a week every Monday supervised while the control group (n=68) was advised to take no medications without the knowledge of the investigators until the completion of the study. To eliminate a major source of variation, subjects participating in the study were de-wormed at the beginning of the study. Haemoglobin and serum ferritin concentrations were compared before and after the intervention among the groups. The mean haemoglobin (Hgb), and serum ferritin concentration (SFC) at baseline were practically similar among the groups. Haemoglobin levels significantly increased at the end of the study in all the groups and the proportion of anaemia decreased from 6.9% to 1.6% in the daily, 6.7% to 1.7% in the weekly supplemented and 6.7% to 6.1% in the control groups. The difference noted between the daily and weekly supplemented groups was not significant. The improvement of SFC concentration was better in the daily than the weekly group but not statistically significant. Daily supplementation schedule caused more side effects and lower compliance level than the weekly supplementation schedule. Weekly supplementation is simple, comparable to daily supplementation and economically advantageous. Thus, it is recommended to adopt the strategy for controlling anaemia. Further because of higher compliance rate and lower side effects, it is deemed to be socially feasible.


Comparing and visualizing titanium implant integration in rat bone using 2D and 3D techniques.
The aim was to compare the osseointegration of grit-blasted implants with and without a hydrogen fluoride treatment in rat tibia and femur, and to visualize bone formation using state-of-the-art 3D visualization techniques. Grit-blasted implants were inserted in femur and tibia of 10 Sprague-Dawley rats (4 implants/rat). Four weeks after insertion, bone implant samples were retrieved. Selected samples were imaged in 3D using Synchrotron Radiation-based μCT (SRμCT). The 3D data was quantified and visualized using two novel visualization techniques, thread fly-through and 2D unfolding. All samples were processed to cut and ground sections and 2D histomorphometrical comparisons of bone implant contact (BIC), bone area (BA), and mirror image area (MI) were performed. BA values were statistically significantly higher for test implants than controls (p < 0.05), but BIC and MI data did not differ significantly. Thus, the results partly indicate improved bone formation at blasted and hydrogen fluoride treated implants, compared to blasted implants. The 3D analysis was a valuable complement to 2D analysis, facilitating improved visualization. However, further studies are required to evaluate aspects of 3D quantitative techniques, with relation to light microscopy that traditionally is used for osseointegration studies.


The clinical effectiveness and cost-effectiveness of point-of-care tests (CoaguChek system, INRatio2 PT/INR monitor and ProTime Microcoagulation system) for the self-monitoring of the coagulation status of people receiving long-term vitamin K antagonist therapy, compared with standard UK practice: systematic review and economic evaluation.
Self-monitoring (self-testing and self-management) could be a valid option for oral anticoagulation therapy monitoring in the NHS, but current evidence on its clinical effectiveness or cost-effectiveness is limited. We investigated the clinical effectiveness and cost-effectiveness of point-of-care coagulometers for the self-monitoring of coagulation status in people receiving long-term vitamin K antagonist therapy, compared with standard clinic monitoring. We searched major electronic databases (e.g. MEDLINE, MEDLINE In Process & Other Non-Indexed Citations, EMBASE, Bioscience Information Service, Science Citation Index and Cochrane Central Register of Controlled Trials) from 2007 to May 2013. Reports published before 2007 were identified from the existing Cochrane review (major databases searched from inception to 2007). The economic model parameters were derived from the clinical effectiveness review, other relevant reviews, routine sources of cost data and clinical experts' advice. We assessed randomised controlled trials (RCTs) evaluating self-monitoring in people with atrial fibrillation or heart valve disease requiring long-term anticoagulation therapy. CoaguChek(®) XS and S models (Roche Diagnostics, Basel, Switzerland), INRatio2(®) PT/INR monitor (Alere Inc., San Diego, CA USA), and ProTime Microcoagulation system(®) (International Technidyne Corporation, Nexus Dx, Edison, NJ, USA) coagulometers were compared with standard monitoring. Where possible, we combined data from included trials using standard inverse variance methods. Risk of bias assessment was performed using the Cochrane risk of bias tool. A de novo economic model was developed to assess the cost-effectiveness over a 10-year period. We identified 26 RCTs (published in 45 papers) with a total of 8763 participants. CoaguChek was used in 85% of the trials. Primary analyses were based on data from 21 out of 26 trials. Only four trials were at low risk of bias. Major clinical events: self-monitoring was significantly better than standard monitoring in preventing thromboembolic events [relative risk (RR) 0.58, 95% confidence interval (CI) 0.40 to 0.84; p = 0.004]. In people with artificial heart valves (AHVs), self-monitoring almost halved the risk of thromboembolic events (RR 0.56, 95% CI 0.38 to 0.82; p = 0.003) and all-cause mortality (RR 0.54, 95% CI 0.32 to 0.92; p = 0.02). There was greater reduction in thromboembolic events and all-cause mortality through self-management but not through self-testing. Intermediate outcomes: self-testing, but not self-management, showed a modest but significantly higher percentage of time in therapeutic range, compared with standard care (weighted mean difference 4.44, 95% CI 1.71 to 7.18; p = 0.02). Patient-reported outcomes: improvements in patients' quality of life related to self-monitoring were observed in six out of nine trials. High preference rates were reported for self-monitoring (77% to 98% in four trials). Net health and social care costs over 10 years were £7295 (self-monitoring with INRatio2); £7324 (standard care monitoring); £7333 (self-monitoring with CoaguChek XS) and £8609 (self-monitoring with ProTime). The estimated quality-adjusted life-year (QALY) gain associated with self-monitoring was 0.03. Self-monitoring with INRatio2 or CoaguChek XS was found to have ≈ 80% chance of being cost-effective, compared with standard monitoring at a willingness-to-pay threshold of £20,000 per QALY gained. Compared with standard monitoring, self-monitoring appears to be safe and effective, especially for people with AHVs. Self-monitoring, and in particular self-management, of anticoagulation status appeared cost-effective when pooled estimates of clinical effectiveness were applied. However, if self-monitoring does not result in significant reductions in thromboembolic events, it is unlikely to be cost-effective, based on a comparison of annual monitoring costs alone. Trials investigating the longer-term outcomes of self-management are needed, as well as direct comparisons of the various point-of-care coagulometers. This study is registered as PROSPERO CRD42013004944. The National Institute for Health Research Health Technology Assessment programme.


Subjective and objective measures of physical activity in relationship to bone mineral content during late childhood: the Iowa Bone Development Study.
This study compared accelerometry to self-report for the assessment of physical activity (PA) in relation to bone mineral content (BMC). In addition, we compared the ability of these measures to assess PA in boys versus girls. Participants in this cross-sectional study included 449 children (mean age 11 years) from the Iowa Bone Development Study. PA was measured via 3-5 days of accelerometry using the Actigraph and 7 day self-report questionnaire using the Physical Activity Questionnaire for Children (PAQ-C). Hip, spine, and whole body BMC were measured via dual energy x ray absorptiometry (DXA). Partial correlation analysis (controlling for height, weight, and maturity) showed the Actigraph was significantly associated with hip (r = 0.40), spine (r = 0.20), and whole body (r = 0.33) BMC in boys, as was the PAQ-C (r = 0.28 hip, r = 0.19 spine, and r = 0.22 whole body). Among girls, only the Actigraph was significantly associated with hip (r = 0.18) and whole body (r = 0.16) BMC. Both the Actigraph and PAQ-C were significant in hip, spine, and whole body multivariable linear regression models (after controlling for body size and maturity) in boys. Only the Actigraph entered hip BMC regression model in girls. Our study supports previous work showing associations between everyday PA and BMC in older children. These associations are more likely to be detected with an objective versus subjective measure of PA, particularly in girls.


Short-Term High-Dose Vitamin C and E Supplementation Attenuates Muscle Damage and Inflammatory Responses to Repeated Taekwondo Competitions: A Randomized Placebo-Controlled Trial.
Background: Exercise-induced muscle damage during intensive sport events is a very common issue in sport medicine. Therefore, the purpose is to investigate the effects of short-term high-dose vitamin C and E supplementation on muscle damage, hemolysis, and inflammatory responses to simulated competitive Olympic Taekwondo (TKD) matches in elite athletes. Methods: Using a randomized placebo-controlled and double-blind study design, eighteen elite male TKD athletes were weight-matched and randomly assigned into either a vitamin C and E group (Vit C+E; N = 9) or placebo group (PLA; N = 9). Vit C+E or PLA supplements were taken daily (Vit C+E: 2000 mg/d vitamin C; 1400 U/d vitamin E) for 4 days (3 days before and on competition day) before taking part in 4 consecutive TKD matches on a single day. Plasma samples were obtained before each match and 24-hours after the first match for determination of markers of muscle damage, hemolysis, and systemic inflammatory state. Results: Myoglobin was lower in the Vit C+E group, compared to PLA, during the match day (area under curve, AUC -47.0% vs. PLA, p = 0.021). Plasma creatine kinase was lower in the Vit C+E group (AUC -57.5% vs. PLA, p = 0.017) and hemolysis was lower in the Vit C+E group (AUC -40.5% vs. PLA, p = 0.034). Conclusions: We demonstrated that short-term (4-days) vitamin C and E supplementation effectively attenuated exercise-induced tissue damage and inflammatory response during and after successive TKD matches.


Aligned platinum nanowire networks from surface-oriented lipid cubic phase templates.
Mesoporous metal structures featuring a bicontinuous cubic morphology have a wide range of potential applications and novel opto-electronic properties, often orientation-dependent. We describe the production of nanostructured metal films 1-2 microns thick featuring 3D-periodic 'single diamond' morphology that show high out-of-plane alignment, with the (111) plane oriented parallel to the substrate. These are produced by electrodeposition of platinum through a lipid cubic phase (Q(II)) template. Further investigation into the mechanism for the orientation revealed the surprising result that the Q(II) template, which is tens of microns thick, is polydomain with no overall orientation. When thicker platinum films are grown, they also show increased orientational disorder. These results suggest that polydomain Q(II) samples display a region of uniaxial orientation at the lipid/substrate interface up to approximately 2.8 ± 0.3 μm away from the solid surface. Our approach gives previously unavailable information on the arrangement of cubic phases at solid interfaces, which is important for many applications of Q(II) phases. Most significantly, we have produced a previously unreported class of oriented nanomaterial, with potential applications including metamaterials and lithographic masks.


Polycystic ovary syndrome and the risk of gynaecological cancer: a systematic review.
The objective of this study was to perform a systematic review of the literature to determine whether there is an association between polycystic ovary syndrome (PCOS) and gynaecological malignancy. Medline and Embase databases (1968-2008) were searched to identify publications on the association between PCOS and gynaecological cancers including breast cancer. Studies were selected that examined the association between PCOS and all types of gynaecological malignancies. A total of 19 studies exploring the association between PCOS and breast, endometrial and ovarian cancer were identified. Of these, only eight could be included after review. The data showed variability in the definition of PCOS. A meta-analysis of the data suggests that women with PCOS are more likely to develop cancer of the endometrium (OR 2.70, 95% CI 1.00-7.29) and ovarian cancer (OR 2.52, 95% CI 1.08-5.89) but not breast cancer (OR 0.88, 95% CI 0.44-1.77). Women with PCOS appear to be three times more likely to develop endometrial cancer but are not at increased risk of breast cancer. There is insufficient evidence to implicate PCOS in the development of vaginal, vulval, cervical or ovarian cancers. The paucity of studies investigating the association between PCOS and gynaecological cancers is likely to affect the reliability of the conclusions.


Measurement of in vivo nitric oxide synthesis in humans using stable isotopic methods: a systematic review.
Stable isotopic methods are considered the "gold standard" for the measurement of rates of in vivo NO production. However, values reported for healthy human individuals differ by more than 1 order of magnitude. The reason for the apparent variability in NO production is unclear. The primary aim of this review was to evaluate and compare the rates of in vivo NO production in health and disease using stable isotope methods. Articles were retrieved using the PubMed electronic database. Information on concentrations, isotopic enrichments of fluxes, and conversion rates of molecules involved in the NO metabolic pathway was extracted from selected articles; 35 articles were included in the final analysis. Three protocols were identified, including the arginine-citrulline, the arginine-nitrate, and the oxygen-nitrate protocols. The arginine-citrulline protocol showed a wider variability compared to the arginine-nitrate and oxygen-nitrate protocols. The direction of the association between disease state and rate of NO production was essentially determined by the etiopathogenesis of the disorder (inflammatory, metabolic, vascular). Considerable variation in methodologies used to assess whole-body NO synthesis in humans exists. The precision of several aspects of the techniques and the validity of some assumptions made remain unknown, and there is a paucity of information about physiological rates of NO production from childhood over adolescence to old age.


Effect of LCZ696, a dual angiotensin receptor neprilysin inhibitor, on isoproterenol-induced cardiac hypertrophy, fibrosis, and hemodynamic change in rats.
Recent clinical studies have shown that treatment with LCZ696, a complex containing the angiotensin receptor blocker valsartan and neprilysin inhibitor sacubitril, improves the prognosis of heart failure patients with a reduced ejection fraction. This study evaluated whether LCZ696 affects left ventricular hypertrophy, fibrosis, and hemodynamics in isoproterenol (ISO)-treated rats compared with valsartan alone. Male Wistar rats received subcutaneous saline (n = 10), subcutaneous ISO (2.4 mg/kg/day; n = 10), subcutaneous ISO + oral LCZ696 (60 mg/kg/day; n = 20) (ISO-LCZ), or subcutaneous ISO + oral valsartan (30 mg/kg/day; n = 20) (ISO-VAL) for 7 days. LCZ696 and valsartan did not significantly reduce the increased heart weight/body weight ratio in rats treated with ISO. Echocardiography showed that the deceleration time shortened by ISO was restored by LCZ696 but not valsartan alone (p = 0.01 vs. the ISO group). Histological analysis showed that cardiac interstitial fibrosis increased by ISO was decreased significantly by LCZ696 but not valsartan alone (control: 0.10 ± 0.14%; ISO: 0.41 ± 0.32%; ISO-LCZ: 0.19 ± 0.23% [p < 0.01 vs. the ISO group]; ISO-VAL: 0.34 ± 0.23% [p = 0.34 vs. the ISO group]). Quantitative polymerase chain reaction showed that mRNA expression of Tgfb1, Col1a1, Ccl2, and Anp increased by ISO was significantly attenuated by LCZ696 but not valsartan alone (p < 0.05 vs. the ISO group). LCZ696 improves cardiac fibrosis, but not hypertrophy, caused by continuous exposure to ISO in rats.


MEG masked priming evidence for form-based decomposition of irregular verbs.
To what extent does morphological structure play a role in early processing of visually presented English past tense verbs? Previous masked priming studies have demonstrated effects of obligatory form-based decomposition for genuinely affixed words (teacher-TEACH) and pseudo-affixed words (corner-CORN), but not for orthographic controls (brothel-BROTH). Additionally, MEG single word reading studies have demonstrated that the transition probability from stem to affix (in genuinely affixed words) modulates an early evoked response known as the M170; parallel findings have been shown for the transition probability from stem to pseudo-affix (in pseudo-affixed words). Here, utilizing the M170 as a neural index of visual form-based morphological decomposition, we ask whether the M170 demonstrates masked morphological priming effects for irregular past tense verbs (following a previous study which obtained behavioral masked priming effects for irregulars). Dual mechanism theories of the English past tense predict a rule-based decomposition for regulars but not for irregulars, while certain single mechanism theories predict rule-based decomposition even for irregulars. MEG data was recorded for 16 subjects performing a visual masked priming lexical decision task. Using a functional region of interest (fROI) defined on the basis of repetition priming and regular morphological priming effects within the left fusiform and inferior temporal regions, we found that activity in this fROI was modulated by the masked priming manipulation for irregular verbs, during the time window of the M170. We also found effects of the scores generated by the learning model of Albright and Hayes (2003) on the degree of priming for irregular verbs. The results favor a single mechanism account of the English past tense, in which even irregulars are decomposed into stems and affixes prior to lexical access, as opposed to a dual mechanism model, in which irregulars are recognized as whole forms.


Nt-RhoGDI2 regulates Rac/Rop signaling and polar cell growth in tobacco pollen tubes.
Rac/Rop-type Rho-family small GTPases accumulate at the plasma membrane in the tip of pollen tubes and control the polar growth of these cells. Nt-RhoGDI2, a homolog of guanine nucleotide dissociation inhibitors (GDIs) regulating Rho signaling in animals and yeast, is co-expressed with the Rac/Rop GTPase Nt-Rac5 specifically in tobacco (Nicotiana tabacum) pollen tubes. The two proteins interact with each other in yeast two-hybrid assays, preferentially when Nt-Rac5 is prenylated. Transient over-expression of Nt-Rac5 and Nt-RhoGDI2 depolarized or inhibited tobacco pollen tube growth, respectively. Interestingly, pollen tubes over-expressing both proteins grew normally, demonstrating that the two proteins functionally interact in vivo. Nt-RhoGDI2 was localized to the pollen tube cytoplasm and effectively transferred co-over-expressed YFP-Nt-Rac5 fusion proteins from the plasma membrane to this compartment. A single amino acid exchange (R69A), which abolished binding to Nt-RhoGDI2, caused Nt-Rac5 to be mis-localized to the flanks of pollen tubes and strongly compromised its ability to depolarize pollen tube growth upon over-expression. Based on these observations, we propose that Nt-RhoGDI2-mediated recycling of Nt-Rac5 from the flanks of the tip to the apex has an essential function in the maintenance of polarized Rac/Rop signaling and cell expansion in pollen tubes. Similar mechanisms may generally play a role in the polarized accumulation of Rho GTPases in specific membrane domains, an important process whose regulation has not been well characterized in any cell type to date.


Cloning: A Review on Bioethics, Legal, Jurisprudence and Regenerative Issues in Iran.
In recent years, the cloning technology has remarkably developed in Iran, but unfortunately, the required legal framework has not been created to support and protect such developments yet. This legal gap may lead to abuse of scientific researches to obtain illegal benefits and to undermine the intellectual property rights of scientists and researchers. Thus to prevent such consequences, the attempts should be made to create an appropriate legal-ethical system and an approved comprehensive law. In this review we concluded that the right method is guiding and controlling the cloning technology and banning the technique is not always fruitful. Of course, it should be taken into accounts that all are possible if the religion orders human cloning in the view of jurisprudence and is considered as permission. In other words, although the religious order on human cloning can be an absolute permission based on the strong principle of permission, it is not unlikely that in the future, corruption is proved to be real for them, Jurists rule it as secondary sanctity and even as primary one. If it is proved, the phenomenon is considered as example of required affairs based on creation of ethical, social and medical disorders, religious and ethical rulings cannot be as permission for it, and it seems that it is a point that only one case can be a response to it and it needs nothing but time.


Orexin receptors exert a neuroprotective effect in Alzheimer's disease (AD) via heterodimerization with GPR103.
Orexins are neuropeptides that regulate the sleep-wake cycle and feeding behaviour. QRFP is a newly discovered neuropeptide which exerts similar orexigenic activity, thus playing an important role in energy homeostasis and regulation of appetite. The exact expression and signalling characteristics and physiological actions of QRFP and its receptor GPR103 are poorly understood. Alzheimer's disease (AD) patients experience increased nocturnal activity, excessive daytime sleepiness, and weight loss. We hypothesised therefore that orexins and QRFP might be implicated in the pathophysiology of AD. We report that the down-regulation of hippocampal orexin receptors (OXRs) and GPR103 particularly in the cornu ammonis (CA) subfield from AD patients suffering from early onset familial AD (EOFAD) and late onset familial AD (LOAD). Using an in vitro model we demonstrate that this downregulation is due to to Aβ-plaque formation and tau hyper-phosphorylation. Transcriptomics revealed a neuroprotective role for both orexins and QRFP. Finally we provide conclusive evidence using BRET and FRET that OXRs and GPR103 form functional hetero-dimers to exert their effects involving activation of ERK1/2. Pharmacological intervention directed at the orexigenic system may prove to be an attractive avenue towards the discovery of novel therapeutics for diseases such as AD and improving neuroprotective signalling pathways.


An empirical examination of the impacts of decentralized nursing unit design.
The objective of the study was to examine the impact of decentralization on operational efficiency, staff well-being, and teamwork on three inpatient units. Decentralized unit operations and the corresponding physical design solution were hypothesized to positively affect several concerns-productive use of nursing time, staff stress, walking distances, and teamwork, among others. With a wide adoption of the concept, empirical evidence on the impact of decentralization was warranted. A multimethod, before-and-after, quasi-experimental design was adopted for the study, focusing on five issues, namely, (1) how nurses spend their time, (2) walking distance, (3) acute stress, (4) productivity, and (5) teamwork. Data on all five issues were collected on three older units with centralized operational model (before move). The same set of data, with identical tools and measures, were collected on the same units after move in to new physical units with decentralized operational model. Data were collected during spring and fall of 2011. Documentation, nurse station use, medication room use, and supplies room use showed consistent change across the three units. Walking distance increased (statistically significant) on two of the three units. Self-reported level of collaboration decreased, although assessment of the physical facility for collaboration increased. Decentralized nursing and physical design models potentially result in quality of work improvements associated with documentation, medication, and supplies. However, there are unexpected consequences associated with walking, and staff collaboration and teamwork. The solution to the unexpected consequences may lie in operational interventions and greater emphasis on culture change.


Adverse subpopulation regression for multivariate outcomes with high-dimensional predictors.
Biomedical studies have a common interest in assessing relationships between multiple related health outcomes and high-dimensional predictors. For example, in reproductive epidemiology, one may collect pregnancy outcomes such as length of gestation and birth weight and predictors such as single nucleotide polymorphisms in multiple candidate genes and environmental exposures. In such settings, there is a need for simple yet flexible methods for selecting true predictors of adverse health responses from a high-dimensional set of candidate predictors. To address this problem, one may either consider linear regression models for the continuous outcomes or convert these outcomes into binary indicators of adverse responses using predefined cutoffs. The former strategy has the disadvantage of often leading to a poorly fitting model that does not predict risk well, whereas the latter approach can be very sensitive to the cutoff choice. As a simple yet flexible alternative, we propose a method for adverse subpopulation regression, which relies on a two-component latent class model, with the dominant component corresponding to (presumed) healthy individuals and the risk of falling in the minority component characterized via a logistic regression. The logistic regression model is designed to accommodate high-dimensional predictors, as occur in studies with a large number of gene by environment interactions, through the use of a flexible nonparametric multiple shrinkage approach. The Gibbs sampler is developed for posterior computation. We evaluate the methods with the use of simulation studies and apply these to a genetic epidemiology study of pregnancy outcomes.


Prevalence and risk factors of community-associated methicillin-resistant Staphylococcus aureus carriage in Asia-Pacific region from 2000 to 2016: a systematic review and meta-analysis.
Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is an emerging global public health threat. In response to a highlighted strategic priority of the World Health Organization Global Action Plan on Antimicrobial Resistance, to "strengthen the knowledge and evidence base through surveillance and research", we synthesized published articles to estimate CA-MRSA carriage prevalence in the Asia-Pacific region. A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO CRD:42017067399). We searched MEDLINE, EMBASE, and PubMed for articles published from 1 January 2000 to 19 May 2017, which reported CA-MRSA carriage (defined as either colonization or infection) in Asia-Pacific region from 2000 to 2016. Studies were stratified according to settings (community or hospital where CA-MRSA was isolated) and study populations (general public or subpopulations with specified characteristics). Ranges of CA-MRSA carriage prevalence were reported for study groups. In total, 152 studies were identified. Large diversity was observed among studies in most study groups. In community-level studies, the CA-MRSA carriage prevalence among the general public ranged from 0% to 23.5%, whereas that ranged from 0.7% to 10.4% in hospital settings. From community-level studies, countries with the highest prevalence were India (16.5%-23.5%), followed by Vietnam (7.9%) and Taiwan (3.5%-3.8%). Children aged ≤6 (range: 0.5%-40.3%) and household members of CA-MRSA carriers (range: 13.0%-26.4%) are subgroups without specific health conditions but with much higher CA-MRSA carriage when compared to the general population. Our CA-MRSA prevalence estimates serve as the baseline for future national and international surveillance. The ranges of prevalence and characteristics associated with CA-MRSA carriage can inform health authorities to formulate infection control policies for high-risk subgroups. Future studies should explore the heterogeneities in CA-MRSA carriage prevalence among subgroups and countries to clarify the predominant transmission mechanisms in Asia-Pacific and other regions.


Mind-Wandering and Mindfulness as Mediators of the Relationship Between Online Vigilance and Well-Being.
As mobile technology allows users to be online anywhere and at all times, a growing number of users report feeling constantly alert and preoccupied with online streams of online information and communication-a phenomenon that has recently been termed online vigilance. Despite its growing prevalence, consequences of this constant orientation toward online streams of information and communication for users' well-being are largely unclear. In the present study, we investigated whether being constantly vigilant is related to cognitive consequences in the form of increased mind-wandering and decreased mindfulness and examined the resulting implications for well-being. To test our assumptions, we estimated a path model based on survey data (N = 371). The model supported the majority of our preregistered hypotheses: online vigilance was indeed related to mind-wandering and mindfulness, but only mindfulness mediated the relationship with decreased well-being. Thus, those mentally preoccupied with online communication were overall less satisfied with their lives and reported less affective well-being when they also experienced reduced mindfulness.


Children's behavioral traits and risk of injury: analyses from a case-control study of agricultural households.
Children on family agricultural operations have high risk of injury. The association between children's behavioral traits and their risk of injury is not well understood. Data from the Regional Rural Injury Study-II were used to assess behavioral risk factors for injury to children ages six to <20 years. A total of 379 injury events (cases) and 1,562 randomly selected controls were identified. Adjusted odds ratios (OR) and 95% confidence intervals (CI), calculated using logistic regression, were used to estimate injury risk in reference to behavioral traits. Injury risks were greater for children with high levels of depressive symptoms (OR=1.9, CI=1.0-3.7) and aggression (OR=1.6, CI=0.9-2.7), and low levels of careful/cautious behavior (OR=1.8, CI=1.1-2.9). Children with low levels of self-regulation had reduced risks (OR=0.4, CI=0.2-0.8). Results suggest that children's behaviors affect their risk of agricultural injury. Additional research could elucidate mechanisms and inform interventions. The development of multifaceted, sustainable approaches for prevention is necessary for this unique population. These findings suggest a need for interventions that incorporate specific behavior-related risk factors in the context of family farms and ranches.


On-line optical and X-ray spectroscopies with crystallography: an integrated approach for determining metalloprotein structures in functionally well defined states.
X-ray-induced redox changes can lead to incorrect assignments of the functional states of metals in metalloprotein crystals. The need for on-line monitoring of the status of metal ions (and other chromophores) during protein crystallography experiments is of growing importance with the use of intense synchrotron X-ray beams. Significant efforts are therefore being made worldwide to combine different spectroscopies in parallel with X-ray crystallographic data collection. Here the implementation and utilization of optical and X-ray absorption spectroscopies on the modern macromolecular crystallography (MX) beamline 10, at the SRS, Daresbury Laboratory, is described. This beamline is equipped with a dedicated monolithic energy-dispersive X-ray fluorescence detector, allowing X-ray absorption spectroscopy (XAS) measurements to be made in situ on the same crystal used to record the diffraction data. In addition, an optical microspectrophotometer has been incorporated on the beamline, thus facilitating combined MX, XAS and optical spectroscopic measurements. By uniting these techniques it is also possible to monitor the status of optically active and optically silent metal centres present in a crystal at the same time. This unique capability has been applied to observe the results of crystallographic data collection on crystals of nitrite reductase from Alcaligenes xylosoxidans, which contains both type-1 and type-2 Cu centres. It is found that the type-1 Cu centre photoreduces quickly, resulting in the loss of the 595 nm peak in the optical spectrum, while the type-2 Cu centre remains in the oxidized state over a much longer time period, for which independent confirmation is provided by XAS data as this centre has an optical spectrum which is barely detectable using microspectrophotometry. This example clearly demonstrates the importance of using two on-line methods, spectroscopy and XAS, for identifying well defined redox states of metalloproteins during crystallographic data collection.


Volume holographic phase-retardation elements.
The form birefringence of subwavelength period gratings can be applied to realize phase-retardation elements. Previous researchers used high-frequency surface relief structures or sinusoidal gratings formed in photoresist to fabricate phase-retardation elements. We present the performance of a volume holographic quarter-wave phase-retardation element formed in a dichromated gelatin emulsion for operation at 632.8 nm. To our knowledge this is the first demonstration of a retardation element exhibiting this magnitude of phase delay in a volume material. The phase properties of volume gratings are investigated by both effective medium theory and rigorous coupled-wave analysis.


Watching Aggressive, Attractive, Female Protagonists Shapes Gender Roles for Women Among Male and Female Undergraduate Viewers.
The impact of exposure to media representations of aggressive, attractive, female protagonists on audiences' gender role expectations for women was explored through a laboratory experiment with 122 undergraduates from a large university on the west coast of the United States. Participants viewed a segment of a major Hollywood motion picture that featured a female protagonist who was either highly attractive or less attractive and either highly aggressive or not aggressive. Viewing clips featuring a female protagonist who was both aggressive and stereotypically attractive led to greater endorsement of stereotypically feminine and stereotypically masculine gender role expectations for women. The effect on endorsement of stereotypically masculine expectations was partially mediated by the perception that the protagonist was a good role model for women. Although women endorsed both feminine and masculine gender role expectations for women more strongly than men, the effects of exposure to aggressive, attractive, female protagonists were similar for both male and female participants. Results are discussed in terms of gender stereotype activation and superwoman expectations for women.


Respiratory complications of the rheumatological diseases in childhood.
Pleuropulmonary manifestations of rheumatological diseases are rare in children but pose a significant risk to overall morbidity and mortality. We have reviewed the literature to provide an overview of the respiratory complications of the commonest rheumatological diseases to occur in children (juvenile systemic lupus erythematosus, scleroderma, juvenile dermatomyositis, mixed connective tissue disease, granulomatosis with polyangitis and juvenile idiopathic arthritis). Pulmonary function testing in these patients can be used to refine the differential diagnosis and establish disease severity, but also has a role in ongoing monitoring for respiratory complications. Early detection of pulmonary involvement allows for prompt and targeted therapies to achieve the best outcome for the child. This is best achieved with joint specialist paediatric rheumatology and respiratory reviews in a multidisciplinary setting.


Polymicrobial airway bacterial communities in adult bronchiectasis patients.
Chronic airway infection contributes to the underlying pathogenesis of non-cystic fibrosis bronchiectasis (NCFBr). In contrast to other chronic airway infections, associated with COPD and CF bronchiectasis, where polymicrobial communities have been implicated in lung damage due to the vicious circle of recurrent bacterial infections and inflammation, there is sparse information on the composition of bacterial communities in NCFBr. Seventy consecutive patients were recruited from an outpatient adult NCFBr clinic. Bacterial communities in sputum samples were analysed by culture and pyrosequencing approaches. Bacterial sequences were analysed using partial least square discrimination analyses to investigate trends in community composition and identify those taxa that contribute most to community variation. The lower airway in NCFBr is dominated by three bacterial taxa Pasteurellaceae, Streptococcaceae and Pseudomonadaceae. Moreover, the bacterial community is much more diverse than indicated by culture and contains significant numbers of other genera including anaerobic Prevotellaceae, Veillonellaceae and Actinomycetaceae. We found particular taxa are correlated with different clinical states, 27 taxa were associated with acute exacerbations, whereas 11 taxa correlated with stable clinical states. We were unable to demonstrate a significant effect of antibiotic therapy, gender, or lung function on the diversity of the bacterial community. However, presence of clinically significant culturable taxa; particularly Pseudomonas aeruginosa and Haemophilus influenzae correlated with a significant change in the diversity of the bacterial community in the lung. We have demonstrated that acute exacerbations, the frequency of exacerbation and episodes of clinical stability are correlated, in some patients, with a significantly different bacterial community structure, that are associated with a presence of particular taxa in the NCFBr lung. Moreover, there appears to be an inverse relationship between the abundance of P. aeruginosa and that of of H. influenzae within the NCFBr lung bacterial community. This interaction requires further exploration.


Clinical and immunologic results of a phase II trial of sequential imiquimod and photodynamic therapy for vulval intraepithelial neoplasia.
High-risk human papillomavirus (HPV)-associated vulval intraepithelial neoplasia (VIN) is difficult to treat by excision or ablation because of high recurrence rates. Small studies of photodynamic therapy (PDT) and imiquimod treatments have shown some success and function at least in part through stimulation of local immune responses. Indeed, there is evidence that immunosuppressed individuals have higher rates of VIN, suggesting immune control is relevant. In the study, 20 women with high-grade VIN were treated with topical imiquimod and the PDT sequentially. Vulval biopsy and blood were taken pretreatment and, after imiquimod and PDT, with follow up for 1 year. Clinical response was assessed by measuring lesion size. Biopsies were analyzed for HPV DNA and tumor-infiltrating lymphocytes including T regulatory cells. The treatment was well-tolerated. There was an overall response rate of 55% by intention treat and 64% per protocol. The 52-week symptom response was 65% asymptomatic, compared with 5% at baseline. The nonresponders showed a significantly higher level of T regulatory cells in the lesions after imiquimod treatment. The response rates are clinically relevant, and the treatment regimen was feasible for the majority. Initial nonresponders to imiquimod seem to be relatively refractory, and this may derive from their unfavorable local immune environment, in particular, the increased proportions of T regulatory cells, possibly the limiting action and/or development of any HPV T-cell immunity. The potential benefit of this treatment is its ability to treat multifocal disease.


Fecal water from ileostomic patients consuming oat beta-glucan enhances immune responses in enterocytes.
Yeast, fungal, and dietary beta-glucans have immune-modulating effects in vitro and in vivo, as thought, mainly by affecting leukocytes; however, effects of oat beta-glucan on enterocytes have never been studied. As recognized, supplying oat beta-glucans as such to cells in culture directly is difficult because of solubility problems. Therefore, six ileostomic patients consumed, in random order, a control diet or an oat beta-glucan enriched diet (5 g) and from the collected ileostomic content, fecal water was prepared and added to two small intestinal cell lines (INT407, Caco-2) and two colon cell lines (HT29, T84) together with a cytokine cocktail (IL-1beta + INFgamma + TNFalpha). Several parameters reflecting immune-modulation were measured. As compared to placebo fecal water, beta-glucan enriched fecal water significantly increased IL-8 production in HT29 (5.0%; p = 0.046) and INT407 cells (22.0%; p = 0.028). Intercellular adhesion molecule (ICAM)-1 expression increased in T84 (11.0%; p = 0.028) and Caco-2 cells (20.4%; p = 0.075). These immune-stimulating effects were confirmed by enhancement of inflammatory expression profiles, as determined with an antibody array. Our findings show immune enhancement by fecal water from ileostomic patients consuming oat beta-glucan both in small intestinal and colon cell lines after stimulation, which is in agreement with documented effects in leukocytes. Whether these immune-stimulating effects on enterocytes contribute to the enhanced protection of the host against invading pathogens as observed both in animals and in humans, as well as the underlying mechanism, needs further evaluation.


Transplacental transmission and fetal parasitosis of Trypanosoma cruzi in outbred white Swiss mice.
Two strains of Trypanosoma cruzi, isolated from humans and assayed for their biological capacity to kill outbred white Swiss mice (HaM/CR-CD) following reticuloendothelial system blockade with thorium dioxide, were used in these experiments: the Maria Cristina strain, which killed all blocked mice at a rate following a rectangular dose-response curve, and the José Cardoso strain, which did not kill blocked mice at comparable dosages. When inoculated into pregnant HaM/CR-CD mice, the non-pathogenic José Cardoso strain did not cross the placental barrier, in either blocked or unblocked mice, to cause fetal parasitosis. The pathogenic Maria Cristina strain did not cross the barrier in non-blocked mice, but in thorium-dioxide blocked mice it produced an incidence of fetal parasitosis of 8.9% (7 of 79 fetuses). These results indicate that the transplacental transmission of T. cruzi was dependent on two restrictions: pathogenicity of the strain of T. cruzi, and blockade of phagocytic activity by thorium dioxide, suggesting that transplacental transmission of T. cruzi is related to interference with the phagocytic activity of the placenta.


In silico prediction of chemical subcellular localization via multi-classification methods.
Chemical subcellular localization is closely related to drug distribution in the body and hence important in drug discovery and design. Although many in vivo and in vitro methods have been developed, in silico methods play key roles in the prediction of chemical subcellular localization due to their low costs and high performance. For that purpose, machine learning-based methods were developed here. At first, 614 unique compounds localized in the lysosome, mitochondria, nucleus and plasma membrane were collected from the literature. 80% of the compounds were used to build the models and the rest as the external validation set. Both fingerprints and molecular descriptors were used to describe the molecules, and six machine learning methods were applied to build the multi-classification models. The performance of the models was measured by 5-fold cross-validation and external validation. We further detected key substructures for each localization and analyzed potential structure-localization relationships, which could be very helpful for molecular design and modification. The key substructures can also be used as features complementary to fingerprints to improve the performance of the models.


Nakahara memorial lecture. Non-receptor type protein-tyrosine kinases closely related to src and yes compose a multigene family.
We have determined the total coding sequence of human c-yes, a non-receptor type protein-tyrosine kinase gene, and found that the c-yes gene closely resembles the c-src gene. Recently, two new genes, syn and lyn, were found to encode proteins closely related to the yes product. In addition, we also determined the partial sequence of fgr. These genes together with lck reported by two American groups have very closely related structures and are thought to compose a closely related group of non-receptor type protein-tyrosine kinases. Partial analysis of the structures of these genes indicated that they have identical splicing junctions at all sites so far examined. On the other hand, the erbB-1/EGF (epidermal growth factor) receptor gene and the erbB-2/neu gene have completely different splicing junctions from those of the above gene group even in the kinase domain, although these genes also have protein kinase activity specific for tyrosine residues and the erbB-1 and -2 genes share splicing sites. These results suggest that the genes of the group of six non-receptor type kinases and those of the erbB-1 and erbB-2 gene group are descendants evolved by duplication of two distinct ancestor genes and are members of two distinct multi-gene families. The genes coding for protein kinases may be members of a super-family including multiple distinct gene families.


Clinical findings in 111 cases of influenza A (H7N9) virus infection.
During the spring of 2013, a novel avian-origin influenza A (H7N9) virus emerged and spread among humans in China. Data were lacking on the clinical characteristics of the infections caused by this virus. Using medical charts, we collected data on 111 patients with laboratory-confirmed avian-origin influenza A (H7N9) infection through May 10, 2013. Of the 111 patients we studied, 76.6% were admitted to an intensive care unit (ICU), and 27.0% died. The median age was 61 years, and 42.3% were 65 years of age or older; 31.5% were female. A total of 61.3% of the patients had at least one underlying medical condition. Fever and cough were the most common presenting symptoms. On admission, 108 patients (97.3%) had findings consistent with pneumonia. Bilateral ground-glass opacities and consolidation were the typical radiologic findings. Lymphocytopenia was observed in 88.3% of patients, and thrombocytopenia in 73.0%. Treatment with antiviral drugs was initiated in 108 patients (97.3%) at a median of 7 days after the onset of illness. The median times from the onset of illness and from the initiation of antiviral therapy to a negative viral test result on real-time reverse-transcriptase-polymerase-chain-reaction assay were 11 days (interquartile range, 9 to 16) and 6 days (interquartile range, 4 to 7), respectively. Multivariate analysis revealed that the presence of a coexisting medical condition was the only independent risk factor for the acute respiratory distress syndrome (ARDS) (odds ratio, 3.42; 95% confidence interval, 1.21 to 9.70; P=0.02). During the evaluation period, the novel H7N9 virus caused severe illness, including pneumonia and ARDS, with high rates of ICU admission and death. (Funded by the National Natural Science Foundation of China and others.).


Recurrent Risk of Preterm Birth in the Third Pregnancy in Korea.
Although preterm delivery is the most common cause of infant morbidity and mortality, an obvious cause cannot be found in most cases. Preterm delivery is known to be the most important risk factor for preterm birth in a subsequent pregnancy. We aimed to evaluate the recurrence rate of premature births for subsequent pregnancies in women with a history of a preterm birth. Study data were collected from the Korea National Health Insurance (KNHI) claims database and data from a national health-screening program for infants and children. We enrolled women who had their first delivery between January 1, 2007 and December 31, 2007 and a subsequent delivery before 2014. Preterm delivery had a significant higher risk of preterm birth in a subsequent singleton pregnancy. The risk of preterm birth at second pregnancy was 2.2% in women whose first delivery at ≥ 37 weeks and 18.6% in women whose first delivery at < 37 weeks (relative risks [RR], 8.64; 95% confidence interval [CI], 7.94-9.40). In the analysis of the third pregnancy, we compared women with an initial term birth followed by preterm birth and women with an initial preterm birth followed by a subsequent term birth. A history of a just preceding preterm birth at < 37 weeks was the most relevant factor for recurrence of preterm delivery in a subsequent pregnancy (26.6%, RR, 4.01; 95% CI, 2.45-6.58). We found that the prognosis of a third pregnancy was more closely related to the outcome of the second pregnancy to that of the first pregnancy.


Effects of injury to the suspensory apparatus, exercise, and horseshoe characteristics on the risk of lateral condylar fracture and suspensory apparatus failure in forelimbs of thoroughbred racehorses.
To assess concurrently the effects of moderate ligamentous suspensory apparatus injury (MLSAI), racing-speed exercise, and horseshoe characteristics on risk of catastrophic suspensory apparatus failure (SAF) or metacarpal condylar fracture (CDY) in forelimbs of racehorses. Cadavers of 301 Thoroughbred racehorses (108 with SAF, 33 with CDY and 160 control horses). A cross-sectional epidemiologic study was used to describe distributions and relationships between MLSAI, exercise, and horseshoe variables. Logistic regression was used to assess potential risk factors for developing SAF and CDY. Exercise variables were more highly associated with age than height of a steel bar affixed to the ground surface of the front of a horseshoe (ie, toe grab) or sex. Marginal associations were detected between MLSAI and age and height of toe grab. Higher risk for developing SAF was associated with MLSAI, use of a pad on a horseshoe, longer interval since last period of > or = 60 days without a race or timed workout (ie, layup), 2 to 5 career races, and higher intensity of recent exercise. Higher risk for developing CDY was associated with MLSAI, male horses, age between 2 and 5 years, higher intensity of recent exercise, and longer interval since layup. Recognition of MLSAI and rehabilitation of affected horses should reduce incidence of SAF and CDY. Horses in longterm continuous training with recent high-intensity exercise are at greater risk for injury. Use of pads in horseshoes was associated with SAF, although the relationship may not be causal.


Advancing geriatrics education: evaluation of a new curricular initiative.
This study describes the development of a required 1-week curricular program in geriatric medicine for 3rd-year medical students and presents 3 years of evaluation data. Successful aging, heterogeneity of the aging population, and comprehensive geriatric assessment were emphasized. In addition to didactic sessions, students participated in panel discussions and small group case conferences, and performed history and physical examinations on older patients. Students' acquisition of knowledge about geriatric medicine was assessed with pre-and posttests; posttest scores showed statistically significant improvement. Because attitudes toward older patients can impact the care provided, students' completed pre- and postattitude assessment scales. Attitude measures were repeated for 2 student cohorts, 1 and 2 years after completion of the program. Independent t tests comparing mean pretest and posttest scores revealed significant improvement in students' attitudes, which were maintained when attitudes were retested. Standardized mean difference scores were computed to measure the relationship between the educational intervention and students' attitude measures. Time in the medical school curriculum is scarce, but these results indicate that significant improvements can be made in medical students' attitudes toward and knowledge of older patients in 1 week.


Advances in the diagnosis, treatment and prognosis of malignant pleural mesothelioma.
Malignant pleural mesothelioma (MPM) is a rare cancer originated from pleural mesothelial cells. MPM has been associated with long-term exposure to asbestos. The prognosis of MPM is poor due to the difficulty of making diagnosis in the early stage, the rapid progression, the high invasiveness and the lack of effective treatment. Although the incidence of MPM is low in China to date, it has a tendency to increase in the coming years. The variety of clinical features may cause the delay of diagnosis and high rate of misdiagnosis. The diagnosis of MPM is based on biopsy of the pleura and immunohistochemistry. As China has become the largest country in the consumption of asbestos, it would give rise to a new surge of MPM in the future. The current treatment of MPM is multimodality therapy including surgery, radiotherapy, chemotherapy and immunotherapy. Two surgical procedures are commonly applied: extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D). Three dimensional conformal radiotherapy is used to denote a spectrum of radiation planning and delivery techniques that rely on the 3D imaging to define the tumor. Cisplatin combined with pemetrexed (PEM) is the first-line chemotherapy for MPM. The principal targets in immunotherapy include T cells (Treg), CTLA-4 and PD-1. The diagnosis, treatment and prognosis still remain a major challenge for clinical research and will do so for years to come.


Simulative Minimization of Mass Transfer Limitations Within Hydrogel-Based 3D-Printed Enzyme Carriers.
In biotechnology, immobilization of functional reactants is often done as a surface immobilization on small particles. Examples are chromatography columns and fixed-bed reactors. However, the available surface for immobilization is directly linked to particle diameter and bed porosity for these systems, leading to high backpressure for small particle sizes. When larger molecules, such as enzymes are immobilized, physical entrapment within porous materials like hydrogels is an alternative. An emerging technique for the production of geometrically structured, three-dimensional and scalable hollow bodies is 3D-printing. Different bioprinting methods are available to produce structures of the desired size, resolution and solids content. However, in case of entrapped enzymes mass transfer limitations often determine the achievable reactivities. With increasing complexity of the system, for example a fixed-bed reactor, 3D-simulation is indispensable to understand the local reaction conditions to be able to highlight the optimization potential. Based on experimental data, this manuscript shows the application of the dimensionless numbers effectiveness factor and Thiele modulus for the design of a 3D-printed flow-through reactor. Within the reactor, enzymes are physically entrapped in 3D-printed hydrogel lattices. The local reaction rate of the enzymes is directly dependent on the provided substrate amount at the site of reaction which is limited by the diffusion properties of the hydrogel matrix and the diffusion distance. All three parameters can be summed up by one key figure, the Thiele modulus, which, in short, quantifies mass transfer limitations of a catalytic system. Depending on the rate of the enzymatic reaction in correlation to the diffusional transport, mass transfer limitations will shift the optimum of the system, favoring slow enzyme kinetics and small diffusion distances. Comparison with the enzymatic reaction rate in solution yields the effectiveness factor of the system. As a result, the optimization potential of varying the 3D-printed geometries or the reaction rate within the experimentally available design space can be estimated.


Helicobacter pylori serology in autoimmune diseases - fact or fiction?
The pathogenesis of autoimmunity is presumed to be a complex process including genetic predisposition, hormonal balance and environmental factors such as infectious agents. Helicobacter pylori, a common bacterial infectious agent has been associated with a variety of autoimmune disorders. However, this bacteria is also thought to play a protective role in the development of multiple sclerosis (MS), systemic lupus erythematosus (SLE) and inflammatory bowel disease (IBD). We tested various links between anti-H. pylori (anti-HP) antibodies and a wide profile of autoimmune diseases and autoantibodies. A total of 1290 patients diagnosed with 14 different autoimmune diseases from two geographical areas (Europe and Latin America) and two groups of healthy matching controls (n=385) were screened for the presence of H. pylori IgG antibodies by "pylori detect" kit. In parallel, a large profile belonging to three groups of autoantibodies was tested in all sera (anti-nuclear antibodies, autoantibodies associated with thrombophilia and gastrointestinal diseases). Our data demonstrate associations between anti-HP antibodies and anti-phospholipid syndrome, giant cell arteritis, systemic sclerosis and primary biliary cirrhosis. Our data also support a previously known negative association between the prevalence of anti-HP antibodies and IBD. Additionally, links were made between seropositivity to H. pylori and the presence of anti-nuclear antibodies, dsDNA, anti-Ro and some thrombophilia-associated antibodies, as well as negative associations with gastrointestinal-associated antibodies. Whether these links are epiphenomenal or H. pylori does play a causative role in the autoimmune diseases remains uncertain. The negative associations could possibly support the notion that in susceptible individuals infections may protect from the development of autoimmune diseases.


Modeling and estimating the feedback mechanisms among depression, rumination, and stressors in adolescents.
The systemic interactions among depressive symptoms, rumination, and stress are important to understanding depression but have not yet been quantified. In this article, we present a system dynamics simulation model of depression that captures the reciprocal relationships among stressors, rumination, and depression. Building on the response styles theory, this model formalizes three interdependent mechanisms: 1) Rumination contributes to 'keeping stressors alive'; 2) Rumination has a direct impact on depressive symptoms; and 3) Both 'stressors kept alive' and current depressive symptoms contribute to rumination. The strength of these mechanisms is estimated using data from 661 adolescents (353 girls and 308 boys) from two middle schools (grades 6-8). These estimates indicate that rumination contributes to depression by keeping stressors 'alive'-and the individual activated-even after the stressor has ended. This mechanism is stronger among girls than boys, increasing their vulnerability to a rumination reinforcing loop. Different profiles of depression emerge over time depending on initial levels of depressive symptoms, rumination, and stressors as well as the occurrence rate for stressors; levels of rumination and occurrence of stressors are stronger contributors to long-term depression. Our systems model is a steppingstone towards a more comprehensive understanding of depression in which reinforcing feedback mechanisms play a significant role. Future research is needed to expand this simulation model to incorporate other drivers of depression and provide a more holistic tool for studying depression.


Patients' perceptions on the impact of coffee consumption in inflammatory bowel disease: friend or foe?--a patient survey.
Environmental factors are an integral component in the pathogenesis of inflammatory bowel disease (IBD). There is an increasing interest in nutritive components. While the potential disease-modifying role of coffee has been intensively investigated in a variety of gastrointestinal diseases, the data on the potential impact on IBD is very limited. We aimed to determine the patients' perspective on coffee consumption in IBD. We conducted a questionnaire among IBD patients in Switzerland, assessing key questions regarding coffee consumption. Descriptive statistics including chi square testing were used for analysis of questionnaire data. Among a total of 442 patients 73% regularly consume coffee. 96% of patients attributing a positive and 91% of patients attributing no impact of coffee intake on IBD regularly drink coffee and surprisingly even 49% of those patients that assign a negative impact on disease symptoms. Among those patients refraining from regular coffee intake 62% are convinced that coffee adversely influences intestinal symptoms, significantly more in Crohn's disease (CD) than in ulcerative colitis (UC) (76% vs. 44%, p = 0.002). In total, 38% of all study subjects suppose that coffee has an effect on their symptoms of disease, significantly more in CD (54%) compared to UC patients (22%, p < 0.001). Moreover, while 45% of CD patients feel that coffee has a detrimental influence, only 20% of UC patients share this impression (p < 0.001). Two thirds of IBD patients regularly consume coffee. More than twice as many CD compared to UC patients attribute a symptom-modifying effect of coffee consumption, the majority a detrimental one. However, this negative perception does not result in abstinence from coffee consumption.


Hypotension and adverse neurodevelopmental outcomes among children with multiple exposures to general anesthesia: Subanalysis of the Mayo Anesthesia Safety in Kids (MASK) Study.
The potential adverse effects of exposures to general anesthesia on the developing human brain remain controversial. It has been hypothesized that hypotension accompanying anesthesia could be contributory. We hypothesized that among children exposed to multiple anesthetics prior to age 3, children developing adverse neurodevelopmental outcomes would be more likely to have intraoperative hypotension. Two previously published study cohorts were utilized for analysis: the retrospective and prospective Mayo Anesthesia Safety in Kids cohorts. The two lowest consecutive systolic blood pressure measurements were abstracted and standardized by calculating a z-score for noninvasive blood pressure reference ranges for children. The lowest systolic blood pressure z-score (continuous variable) and intraoperative hypotension (lowest systolic blood pressure z-score <-1.0) were used to assess the association of intraoperative hypotension with the incidence of learning disabilities or attention-deficit/hyperactivity disorder(retrospective cohort) and factor scores/cluster membership (prospective cohort). One hunderd and sixteen and 206 children with multiple exposures to general anesthesia were analyzed in the retrospective and prospective cohorts with mean lowest systolic blood pressure z-scores -0.26 (SD 1.02) and -0.62 (SD 1.10), respectively. There was no overall association of the lowest z-score or hypotension with learning disabilities or attention-deficit/hyperactivity disorder in the retrospective cohort. In the prospective cohort, there was no overall association of the lowest systolic blood pressure or hypotension with factor scores or cluster membership. We did not find evidence to support the hypothesis that, among children exposed to multiple anesthetics prior to age 3, children developing adverse neurodevelopmental outcomes would be more likely to have intraoperative hypotension compared with those who did not.


Spatial clustering of all-cause and HIV-related mortality in a rural South African population (2000-2006).
Sub-Saharan Africa bears a disproportionate burden of HIV infection. Knowledge of the spatial distribution of HIV outcomes is vital so that appropriate public health interventions can be directed at locations most in need. In this regard, spatial clustering analysis of HIV-related mortality events has not been performed in a rural sub-Saharan African setting. Kulldorff's spatial scan statistic was used to identify HIV-related and all-cause mortality clusters (p<0.05) in a population-based demographic surveillance survey in rural KwaZulu Natal, South Africa (2000-2006). The analysis was split pre (2000-2003) and post (2004-2006) rollout of antiretroviral therapy, respectively. Between 2000-2006 a total of 86,175 resident individuals ≥15 years of age were under surveillance and 5,875 deaths were recorded (of which 2,938 were HIV-related) over 343,060 person-years of observation (crude all-cause mortality rate 17.1/1000). During both time periods a cluster of high HIV-related (RR = 1.46/1.51, p = 0.001) and high all-cause mortality (RR = 1.35/1.38, p = 0.001) was identified in peri-urban communities near the National Road. A consistent low-risk cluster was detected in the urban township in both time periods (RR = 0.60/0.39, p = 0.003/0.005) and in the first time period (2000-2003) a large cluster of low HIV-related and all-cause mortality in a remote rural area was identified. HIV-related and all-cause mortality exhibit strong spatial clustering tendencies in this population. Highest HIV-related mortality and all-cause mortality occurred in the peri-urban communities along the National Road and was lowest in the urban township and remote rural communities. The geography of HIV-related mortality corresponded closely to the geography of HIV prevalence, with the notable exception of the urban township where high HIV-related mortality would have been expected on the basis of the high HIV prevalence. Our results suggest that HIV treatment and care programmes should be strengthened in easy-to-reach high density, peri-urban populations near National Roads where both HIV-related and all-cause mortality are highest.


Lower bumblebee colony reproductive success in agricultural compared with urban environments.
Urbanization represents a rapidly growing driver of land-use change. While it is clear that urbanization impacts species abundance and diversity, direct effects of urban land use on animal reproductive success are rarely documented. Here, we show that urban land use is linked to long-term colony reproductive output in a key pollinator. We reared colonies from wild-caught bumblebee (Bombus terrestris) queens, placed them at sites characterized by varying degrees of urbanization from inner city to rural farmland and monitored the production of sexual offspring across the entire colony cycle. Our land-use cluster analysis identified three site categories, and this categorization was a strong predictor of colony performance. Crucially, colonies in the two clusters characterized by urban development produced more sexual offspring than those in the cluster dominated by agricultural land. These colonies also reached higher peak size, had more food stores, encountered fewer parasite invasions and survived for longer. Our results show a link between urbanization and bumblebee colony reproductive success, supporting the theory that urban areas provide a refuge for pollinator populations in an otherwise barren agricultural landscape.


Tuning resonant optical transmission of metallic nanoslit arrays with embedded microcavities.
We numerically study the characteristics of optical transmission of metallic nanoslit arrays (MNSAs) with embedded microcavities (MC-MNSAs) and demonstrate that passbands of the transmission spectra can be monotonously tuned by adjusting the dimensions of the microcavities. The study discloses that spectra of conventional MNSAs and MC-MNSAs are determined mainly by cavity resonances of the slits or embedded microcavities, modified by in-plane surface-plasmon wave resonances. It is also found that coupling of cavity resonances between neighboring slits or microcavities has considerable effects on the passbands. The MC-MNSA structure is shown to have potentials in applications of tunable filter arrays.


Microorganism-Based Larval Diets Affect Mosquito Development, Size and Nutritional Reserves in the Yellow Fever Mosquito Aedes aegypti (Diptera: Culicidae).
Mosquito larvae feed on organic detritus from the environment, particularly microorganisms comprising bacteria, protozoa, and algae as well as crustaceans, plant debris, and insect exuviae. Little attention has been paid to nutritional studies in Aedes aegypti larvae. We investigated the effects of yeast, bacteria and microalgae diets on larval development, pupation time, adult size, emergence, survivorship, lifespan, and wing morphology. Microorganisms (or Tetramin® as control) were offered as the only source of food to recently hatched first instar larvae and their development was followed until the adult stage. Protein, carbohydrate, glycogen, and lipid were analyzed in single larvae to correlate energetic reserve accumulation by larva with the developmental rates and nutritional content observed. FITC-labeled microorganisms were offered to fourth instar larvae, and its ingestion was recorded by fluorescence microscopy and quantitation. Immature stages developed in all diets, however, larvae fed with bacteria and microalgae showed a severe delay in development rates, pupation time, adult emergence and low survivorship. Adult males emerged earlier as expected and had longer survival than females. Diets with better nutritional quality resulted in adults with bigger wings. Asaia sp. and Escherichia coli resulted in better nutrition and developmental parameters and seemed to be the best bacterial candidates to future studies using symbiont-based control. The diet quality was measured and presented different protein and carbohydrate amounts. Bacteria had the lowest protein and carbohydrate rates, yeasts had the highest carbohydrate amount and microalgae showed the highest protein content. Larvae fed with microalgae seem not to be able to process and store these diets properly. Larvae were shown to be able to process yeast cells and store their energetic components efficiently. Together, our results point that Ae. aegypti larvae show high plasticity to feed, being able to develop under different microorganism-based diets. The important role of Ae. aegypti in the spread of infectious diseases requires further biological studies in order to understand the vector physiology and thus to manage the larval natural breeding sites aiming a better mosquito control.


Genome of Rhodnius prolixus, an insect vector of Chagas disease, reveals unique adaptations to hematophagy and parasite infection.
Rhodnius prolixus not only has served as a model organism for the study of insect physiology, but also is a major vector of Chagas disease, an illness that affects approximately seven million people worldwide. We sequenced the genome of R. prolixus, generated assembled sequences covering 95% of the genome (∼ 702 Mb), including 15,456 putative protein-coding genes, and completed comprehensive genomic analyses of this obligate blood-feeding insect. Although immune-deficiency (IMD)-mediated immune responses were observed, R. prolixus putatively lacks key components of the IMD pathway, suggesting a reorganization of the canonical immune signaling network. Although both Toll and IMD effectors controlled intestinal microbiota, neither affected Trypanosoma cruzi, the causal agent of Chagas disease, implying the existence of evasion or tolerance mechanisms. R. prolixus has experienced an extensive loss of selenoprotein genes, with its repertoire reduced to only two proteins, one of which is a selenocysteine-based glutathione peroxidase, the first found in insects. The genome contained actively transcribed, horizontally transferred genes from Wolbachia sp., which showed evidence of codon use evolution toward the insect use pattern. Comparative protein analyses revealed many lineage-specific expansions and putative gene absences in R. prolixus, including tandem expansions of genes related to chemoreception, feeding, and digestion that possibly contributed to the evolution of a blood-feeding lifestyle. The genome assembly and these associated analyses provide critical information on the physiology and evolution of this important vector species and should be instrumental for the development of innovative disease control methods.


Fenofibrate metabolism in the cynomolgus monkey using ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry-based metabolomics.
Fenofibrate, widely used for the treatment of dyslipidemia, activates the nuclear receptor, peroxisome proliferator-activated receptor alpha. However, liver toxicity, including liver cancer, occurs in rodents treated with fibrate drugs. Marked species differences occur in response to fibrate drugs, especially between rodents and humans, the latter of which are resistant to fibrate-induced cancer. Fenofibrate metabolism, which also shows species differences, has not been fully determined in humans and surrogate primates. In the present study, the metabolism of fenofibrate was investigated in cynomolgus monkeys by ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOFMS)-based metabolomics. Urine samples were collected before and after oral doses of fenofibrate. The samples were analyzed in both positive-ion and negative-ion modes by UPLC-QTOFMS, and after data deconvolution, the resulting data matrices were subjected to multivariate data analysis. Pattern recognition was performed on the retention time, mass/charge ratio, and other metabolite-related variables. Synthesized or purchased authentic compounds were used for metabolite identification and structure elucidation by liquid chromatographytandem mass spectrometry. Several metabolites were identified, including fenofibric acid, reduced fenofibric acid, fenofibric acid ester glucuronide, reduced fenofibric acid ester glucuronide, and compound X. Another two metabolites (compound B and compound AR), not previously reported in other species, were characterized in cynomolgus monkeys. More importantly, previously unknown metabolites, fenofibric acid taurine conjugate and reduced fenofibric acid taurine conjugate were identified, revealing a previously unrecognized conjugation pathway for fenofibrate.


Induction of proliferative kidney disease (PKD) in rainbow trout Oncorhynchus mykiss via the bryozoan Fredericella sultana infected with Tetracapsula bryosalmonae.
Proliferative kidney disease (PKD) is a serious infection of wild and farmed salmonids, affecting mainly the kidney and spleen but becoming systemic in most susceptible fish hosts. This report deals with the transmission of Tetracapsula bryosalmonae Canning, Curry, Feist, Longshaw & Okamura 1999 from naturally infected bryozoans Fredericella sultana Blumenbach 1779 to naive rainbow trout Oncorhynchus mykiss Walbaum 1792, thereby confirming the recent conclusion based on partial 18S rDNA sequence data that bryozoans are hosts of the myxozoan parasite T. bryosalmonae (formerly PKX organism) that causes the disease. Parasite transmission using T. bryosalmonae spores was successful by short-term exposure to disrupted bryozoans known to contain T. bryosalmonae spores and T bryosalmonae sacs liberated from the bryozoans, and by long-term cohabitation with infected bryozoan colonies. Infection was confirmed by examination of kidney imprints, detection of the parasite in stained tissue sections, PCR using T. bryosalmonae-specific primers, and comparison of amplified 18S rDNA sequences from the bryozoans and experimentally infected fish. Transmission was not apparent, nor was PKD induced, in fish challenged by intraperitoneal injection of spores isolated from F. sultana.


A Kernel Theory of Modern Data Augmentation.
Data augmentation, a technique in which a training set is expanded with class-preserving transformations, is ubiquitous in modern machine learning pipelines. In this paper, we seek to establish a theoretical framework for understanding data augmentation. We approach this from two directions: First, we provide a general model of augmentation as a Markov process, and show that kernels appear naturally with respect to this model, even when we do not employ kernel classification. Next, we analyze more directly the effect of augmentation on kernel classifiers, showing that data augmentation can be approximated by first-order feature averaging and second-order variance regularization components. These frameworks both serve to illustrate the ways in which data augmentation affects the downstream learning model, and the resulting analyses provide novel connections between prior work in invariant kernels, tangent propagation, and robust optimization. Finally, we provide several proof-of-concept applications showing that our theory can be useful for accelerating machine learning workflows, such as reducing the amount of computation needed to train using augmented data, and predicting the utility of a transformation prior to training.


Using Data From the Microsoft Kinect 2 to Quantify Upper Limb Behavior: A Feasibility Study.
The objective of this study was to assess whether the novel application of a machine learning approach to data collected from the Microsoft Kinect 2 (MK2) could be used to classify differing levels of upper limb impairment. Twenty-four healthy subjects completed items of the Wolf Motor Function Test (WMFT), which is a clinically validated metric of upper limb function for stroke survivors. Subjects completed the WMFT three times: 1) as a healthy individual; 2) emulating mild impairment; and 3) emulating moderate impairment. A MK2 was positioned in front of participants, and collected kinematic data as they completed the WMFT. A classification framework, based on Riemannian geometry and the use of covariance matrices as feature representation of the MK2 data, was developed for these data, and its ability to successfully classify subjects as either "healthy," "mildly impaired," or "moderately impaired" was assessed. Mean accuracy for our classifier was 91.7%, with a specific accuracy breakdown of 100%, 83.3%, and 91.7% for the "healthy," "mildly impaired," and "moderately impaired" conditions, respectively. We conclude that data from the MK2 is of sufficient quality to perform objective motor behavior classification in individuals with upper limb impairment. The data collection and analysis framework that we have developed has the potential to disrupt the field of clinical assessment. Future studies will focus on validating this protocol on large populations of individuals with actual upper limb impairments in order to create a toolkit that is clinically validated and available to the clinical community.


Validation of distal radius failure load predictions by homogenized- and micro-finite element analyses based on second-generation high-resolution peripheral quantitative CT images.
This study developed a well-standardized and reproducible approach for micro-finite element (mFE) and homogenized-FE (hFE) analyses that can accurately predict the distal radius failure load using either mFE or hFE models when using the approaches and parameters developed in this study. Micro-FE analyses based on high-resolution peripheral quantitative CT (HR-pQCT) images are frequently used to predict distal radius failure load. With the introduction of a second-generation HR-pQCT device, however, the default modelling approach no longer provides accurate results. The aim of this study was to develop a well-standardized and reproducible approach for mFE and hFE analyses that can provide precise and accurate results for distal radius failure load predictions based on second-generation HR-pQCT images. Second-generation HR-pQCT was used to scan the distal 20-mm section of 22 cadaver radii. The sections were excised and mechanically tested afterwards. For these sections, mFE and hFE models were made that were used to identify required material parameters by comparing predicted and measured results. Using these parameters, the models were cropped to represent the 10-mm region recommended for clinical studies to test their performance for failure load prediction. After identification of material parameters, the measured failure load of the 20-mm segments was in good agreement with the results of mFE models (R2 = 0.969, slope = 1.035) and hFE models (R2 = 0.966, slope = 0.890). When the models were restricted to the clinical region, mFE still accurately predicted the measured failure load (R2 = 0.955, slope = 1.021), while hFE predictions were precise but tended to overpredict the failure load (R2 = 0.952, slope = 0.780). It was concluded that it is possible to accurately predict the distal radius failure load using either mFE or hFE models when using the approaches and parameters developed in this study.


New and known mutations associated with inborn errors of metabolism in a heterogeneous Middle Eastern population.
To identify the mutations underlying a number of inborn errors of metabolism (IEM) disorders among United Arab Emirates (UAE) residents. Molecular diagnostic and bioinformatics tools were used to identify the causative mutations of IEM disorders from multi-ethnic patients residing in UAE. The study was conducted in Al-Ain, UAE, between April 2009 and September 2010. This is a case series retrospective study where patients attending the metabolic clinic at Tawam Hospital were recruited. Thirty patients and 26 parents were included. We present evidence in the UAE of 7 new mutations and 19 mutations that have previously been reported in other populations, all causing a number of common IEM disorders, including phenylketonuria, maple syrup urine disease, glycogen storage diseases, beta-ketothiolase deficiency, and Zellweger syndrome among many others. Reflecting the diverse ethnic groups residing in the UAE, we found mutations in several different population groups. However, consanguinity is evident in most cases. This report is of utmost importance for taking the necessary steps toward the prevention of inherited disorders, not just in the UAE, but anywhere in the world where these Arab and Asian populations reside, or where consanguinity is a cultural norm.