The Role of RAAS Inhibition by Aliskiren on Paracetamol-Induced Hepatotoxicity Model in Rats.
Paracetamol is one of the most popular and widely used analgesic and antipyretic agents, but an overdose can cause hepatotoxicity and lead to acute liver failure. Aliskiren directly inhibits renin which downregulates the renin-angiotensin-aldosterone system (RAAS). Recent findings suggest that RAAS system takes part in the pathogenesis of liver fibrosis. We aimed to reveal the relationship between hepatotoxicity and the RAAS by examining paracetamol induced hepatotoxicity. Rats were separated into five groups as follows: control, 100 mg/kg aliskiren (p.o.), 2 g/kg paracetamol (per os (p.o.)), 2 g/kg paracetamol + 50mg/kg aliskiren (p.o.), and 2 g/kg paracetamol + 100 mg/kg aliskiren(p.o.). Samples were analyzed at the biochemical, molecular, and histopathological levels. Paracetamol toxicity increased alanine aminotransferases (ALT), aspartate aminotransferases (AST), renin, and angiotensin II levels in the serum samples. In addition, the SOD activity and glutathione (GSH) levels decreased while Lipid Peroxidation (MDA) levels increased in the livers of the rats treated with paracetamol. Paracetamol toxicity caused a significant increase in TNF-α and TGF-β. Both aliskiren doses showed an improvement in ALT, AST, oxidative parameters, angiotensin II, and inflammatory cytokines. Only renin levels increased in aliskiren treatment groups due to its pharmacological effect. A histopathological examination of the liver showed that aliskiren administration ameliorated the paracetamol-induced liver damage. In immunohistochemical staining, the expression of TNF-α in the cytoplasm of the hepatocytes was increased in the paracetamol group but not in other treatment groups when compared to the control group. In light of these observations, we suggest that the therapeutic administration of aliskiren prevented oxidative stress and cytokine changes and also protected liver tissues during paracetamol toxicity by inhibiting the RAAS.


Crossmodal correspondences between basic tastes and visual design features: A narrative historical review.
People tend to associate abstract visual features with basic taste qualities. This narrative historical review critically evaluates the literature on these associations, often referred to as crossmodal correspondences, between basic tastes and visual design features such as color hue and shape curvilinearity. The patterns, discrepancies, and evolution in the development of the research are highlighted while the mappings that have been reported to date are summarized. The review also reflects on issues of cross-cultural validity and deviations in the matching patterns that are observed when correspondences are assessed with actual tastants versus with verbal stimuli. The various theories that have been proposed to account for different classes of crossmodal correspondence are discussed, among which the statistical and affective (or emotional-mediation) accounts currently appear most promising. Several critical research questions for the future are presented to address the gaps that have been identified in the literature and help validate the popular theories on the origin and operations of visual-taste correspondences.


Sum rule for the transmission cross section of apertures in thin opaque screens.
Extraordinary transmission through subwavelength apertures is usually observed in a narrow bandwidth range, and the transmission outside this range is low, in agreement with classical results. The analysis presented here is based on the Babinet's principle and hence scattering by the complementary structure, where the apertures are replaced by finite scatterers. It is shown that the transmission cross section of a set of apertures in an opaque screen satisfies a sum rule that relates the transmission cross section integrated over all wavelengths with the polarizability of the complementary structure as defined by Babinet's principle. The theoretical results are illustrated with numerical examples.


Regional brain volumes and cognition in childhood epilepsy: does size really matter?
Recent studies have correlated neurocognitive function and regional brain volumes in children with epilepsy. We tested whether brain volume differences between children with and without epilepsy explained differences in neurocognitive function. The study sample included 108 individuals with uncomplicated non-syndromic epilepsy (NSE) and 36 healthy age- and gender-matched controls. Participants received a standardized cognitive battery. Whole brain T1-weighted MRI was obtained and volumes analyzed with FreeSurfer (TM). Total brain volume (TBV) was significantly smaller in cases. After adjustment for TBV, cases had significantly larger regional grey matter volumes for total, frontal, parietal, and precentral cortex. Cases had poorer performance on neurocognitive indices of intelligence and variability of sustained attention. In cases, TBV showed small associations with intellectual indices of verbal and perceptual ability, working memory, and overall IQ. In controls, TBV showed medium associations with working memory and variability of sustained attention. In both groups, small associations were seen between some TBV-adjusted regional brain volumes and neurocognitive indices, but not in a consistent pattern. Brain volume differences did not account for cognitive differences between the groups. Patients with uncomplicated NSE have smaller brains than controls but areas of relative grey matter enlargement. That this relative regional enlargement occurs in the context of poorer overall neurocognitive functioning suggests that it is not adaptive. However, the lack of consistent associations between case-control differences in brain volumes and cognitive functioning suggests that brain volumes have limited explanatory value for cognitive functioning in childhood epilepsy.


Antibody-based profiling of cerebrospinal fluid within multiple sclerosis.
Antibody suspension bead arrays have proven to enable multiplexed and high-throughput protein profiling in unfractionated plasma and serum samples through a direct labeling approach. We here describe the development and application of an assay for protein profiling of cerebrospinal fluid (CSF). While setting up the assay, systematic intensity differences between sample groups were observed that reflected inherent sample specific total protein amounts. Supplementing the labeling reaction with BSA and IgG diminished these differences without impairing the apparent sensitivity of the assay. We also assessed the effects of heat treatment on the analysis of CSF proteins and applied the assay to profile 43 selected proteins by 101 antibodies in 339 CSF samples from a multiple sclerosis (MS) cohort. Two proteins, GAP43 and SERPINA3 were found to have a discriminating potential with altered intensity levels between sample groups. GAP43 was detected at significantly lower levels in secondary progressive MS compared to early stages of MS and the control group of other neurological diseases. SERPINA3 instead was detected at higher levels in all MS patients compared to controls. The developed assay procedure now offers new possibilities for broad-scale protein profiling of CSF within neurological disorders.


Anti-CCP antibody and rheumatoid factor concentrations predict greater disease activity in men with rheumatoid arthritis.
To examine associations of anti-cyclic citrullinated peptide (aCCP) antibody and rheumatoid factor (RF) concentrations with future disease activity in men with rheumatoid arthritis (RA). Outcome measures were examined in male US veterans with RA and included (1) proportion of observations in remission (disease activity score (DAS28) < or =2.6); (2) remission for > or =3 consecutive months; and (3) area under the curve (AUC) for DAS28. The associations of autoantibody concentration (per 100 unit increments) with outcomes were examined using multivariate regression. 826 men with RA were included in the analysis; the mean (SD) age was 65 (10.5) years and follow-up was for 2.6 (1.3) years. Most were aCCP (75%) and RF (80%) positive. After multivariate adjustment, aCCP (OR 0.93; 95% CI 0.89 to 0.96) and RF concentrations (OR 0.92; 95% CI 0.90 to 0.94) were associated with a lower odds of remission, a lower proportion of observation in remission (p=0.017 and p=0.002, respectively) and greater AUC DAS28 (p=0.092 and p=0.007, respectively). Among patients with discordant autoantibody status, higher concentrations of both aCCP and RF trended towards an inverse association with remission (OR 0.93; 95% CI 0.83 to 1.05 and OR 0.80; 95% CI 0.59 to 1.10, respectively). Higher aCCP concentrations (particularly in RF-positive patients) are associated with increased disease activity in US veterans with RA, indicating that aCCP concentration is predictive of future disease outcomes in men.


Preoperative prediction of small volume cancer (less than 0.5 ml) in radical prostatectomy specimens.
The detection of low volume and early stage prostate cancer has increased with the widespread use of prostate specific antigen screening for prostatic adenocarcinoma. This increased detection has led to efforts to stratify patient risk and the potential benefits of various treatments based on preoperative clinical and biopsy data. We examined various clinical parameters and prostate biopsy features to determine which variables are most predictive of small volume (less than 0.5 ml) cancer at prostatectomy. We studied 336 patients who underwent prostatectomy for prostate cancer. Radical prostatectomy specimens were completely embedded and whole mounted. Final tumor volume in the radical prostatectomy specimens was determined by the grid method. Clinical data were gathered by a review of patient charts. Various preoperative clinical and biopsy findings were analyzed to determine factors predictive of small volume cancer at prostatectomy. A total of 55 patients (16%) were found to have small volume cancer (less than 0.5 ml). On univariate logistic regression certain variables were significant predictors of small volume cancer, namely the highest Gleason score from all positive biopsy sites (p = 0.001), the Gleason score from the biopsy site with the highest percent of adenocarcinoma (p = 0.006), the highest percent of adenocarcinoma at any biopsy site (p <0.0001), the percent of adenocarcinoma at the biopsy site with the highest Gleason score (p <0.0001), the highest percent of cores positive for adenocarcinoma at any biopsy site (p = 0.001), the percent of cores with carcinoma at the site with the highest Gleason score (p = 0.002), the number of positive sites (p <0.0001) and tumor bilaterality (p <0.0001). None of the clinical parameters that we studied, including preoperative prostate specific antigen (p = 0.52), clinical stage (p = 0.62) or patient age (p = 0.94), was predictive of small volume cancer. On multivariate analysis the highest percent of adenocarcinoma at any site (adjusted OR 0.95, 95% CI 0.92 to 0.97, p <0.0001) and the number of positive biopsy sites (adjusted OR 0.97, 95% CI 0.96 to 0.99, p <0.0001) were significant predictors of small volume cancer. The number of positive biopsy sites and the highest percent of adenocarcinoma at any biopsy site are significant predictors of small volume cancer in radical prostatectomy specimens.


Effect of the 2011 Revisions to the Field Triage Guidelines on Under- and Over-Triage Rates for Pediatric Trauma Patients.
In 2011, revised Field Triage Guidelines were released jointly by the Centers for Disease Control and Prevention (CDC) and the American College of Surgeons - Committee on Trauma (ACS-COT). It is unknown how the modifications will affect the number of injured children identified by EMS providers as needing transport to a trauma center. To determine the change in under- and over-triage rates when the 2011 Field Triage Guidelines are compared to the 2006 and 1999 versions. EMS providers in charge of care for injured children (<15 years) transported to pediatric trauma centers in 3 mid-sized cities were interviewed immediately after completing transport. Patients were included regardless of injury severity. The interview included patient demographics and each criterion from the Field Triage Guidelines' physiologic status, anatomic injury, and mechanism of injury steps. Included patients were followed through hospital discharge. The 1999, 2006, and 2011 Guidelines were each retrospectively applied to the collected data. Children were considered to have needed a trauma center if they had non-orthopedic surgery within 24 hours, ICU admission, or died. Data were analyzed using descriptive statistics. EMS interviews were conducted for 5,610 children and outcome data was available for 5,594 (99.7%). Average age was 7.6 years; 5% of children were identified as needing a trauma center using the study outcome. Applying the 1999, 2006, or 2011 Guidelines to the EMS interview data the over-triage rate was 32.6%, 27.9%, and 28.0%, respectively. The under-triage rate was 26.5%, 35.1%, and 34.8%, respectively. The 2011 Guidelines resulted in an 8.2% (95% CI 0.6-15.9%) absolute increase in under-triage and a 4.6% (95% CI 2.8-6.3%) decrease in over-triage compared to 1999 Guidelines. Use of the Field Triage Guidelines for children resulted in an unacceptably high rate of under-triage regardless of the version used. Use of the 2011 Guidelines increased under-triage compared to the 1999 version. Research is needed to determine how to better assist EMS providers in identifying children who need the resources of a trauma center.


The development of candidate composite disease activity and responder indices for psoriatic arthritis (GRACE project).
To develop new composite disease activity indices for psoriatic arthritis (PsA). Data from routine clinic visits at multiple centres were collected in a systematic manner. Data included all domains identified as important in randomised controlled trials in PsA. Decisions to change treatment were used as surrogates for high disease activity. New indices were developed by multiple linear regression (psoriatic arthritis disease activity score: PASDAS) and empirically, utilising physician-defined cut-offs for disease activity (arithmetic mean of desirability functions: AMDF). These were compared with existing composite measures: Composite Psoriatic arthritis Disease Activity Index (CPDAI), Disease Activity for PSoriatic Arthritis (DAPSA), and Disease Activity Score for rheumatoid arthritis (DAS28). 161/503 (32%) subjects had treatment changes. Although all measures performed well, compared with existing indices, PASDAS was better able to discriminate between high and low disease activity (area under receiver operating curves (ROC)) curve with 95% CI: PASDAS 0.773 (0.723, 0.822); AMDF 0.730 (0.680, 0.780); CPDAI 0.719 (0.668, 0.770); DAPSA 0.710 (0.654, 0.766); DAS28 0.736 (0.680, 0.792). All measures were able to discriminate between disease activity states in patients with oligoarthritis, although area under the receiver operating curves (AUC) were generally smaller. In patients with severe skin disease (psoriasis area and severity index>10) both nonparametric and AUC curve statistics were nonsignificant for all measures. Two new composite measures to assess disease activity in PsA have been developed. Further testing in other datasets, including comparison with existing measures, is required to validate these instruments.


The ethical challenges of animal research.
In 1966, Henry K. Beecher published an article entitled "Ethics and Clinical Research" in the New England Journal of Medicine, which cited examples of ethically problematic human research. His influential paper drew attention to common moral problems such as inadequate attention to informed consent, risks, and efforts to provide ethical justification. Beecher's paper provoked significant advancements in human research policies and practices. In this paper, we use an approach modeled after Beecher's 1966 paper to show that moral problems with animal research are similar to the problems Beecher described for human research. We describe cases that illustrate ethical deficiencies in the conduct of animal research, including inattention to the issue of consent or assent, incomplete surveys of the harms caused by specific protocols, inequitable burdens on research subjects in the absence of benefits to them, and insufficient efforts to provide ethical justification. We provide a set of recommendations to begin to address these deficits.


Recent loss of self-incompatibility by degradation of the male component in allotetraploid Arabidopsis kamchatica.
The evolutionary transition from outcrossing to self-fertilization (selfing) through the loss of self-incompatibility (SI) is one of the most prevalent events in flowering plants, and its genetic basis has been a major focus in evolutionary biology. In the Brassicaceae, the SI system consists of male and female specificity genes at the S-locus and of genes involved in the female downstream signaling pathway. During recent decades, much attention has been paid in particular to clarifying the genes responsible for the loss of SI. Here, we investigated the pattern of polymorphism and functionality of the female specificity gene, the S-locus receptor kinase (SRK), in allotetraploid Arabidopsis kamchatica. While its parental species, A. lyrata and A. halleri, are reported to be diploid and mainly self-incompatible, A. kamchatica is self-compatible. We identified five highly diverged SRK haplogroups, found their disomic inheritance and, for the first time in a wild allotetraploid species, surveyed the geographic distribution of SRK at the two homeologous S-loci across the species range. We found intact full-length SRK sequences in many accessions. Through interspecific crosses with the self-incompatible and diploid congener A. halleri, we found that the female components of the SI system, including SRK and the female downstream signaling pathway, are still functional in these accessions. Given the tight linkage and very rare recombination of the male and female components on the S-locus, this result suggests that the degradation of male components was responsible for the loss of SI in A. kamchatica. Recent extensive studies in multiple Brassicaceae species demonstrate that the loss of SI is often derived from mutations in the male component in wild populations, in contrast to cultivated populations. This is consistent with theoretical predictions that mutations disabling male specificity are expected to be more strongly selected than mutations disabling female specificity, or the female downstream signaling pathway.


Budgeting for Environmental Health Services in Healthcare Facilities: A Ten-Step Model for Planning and Costing.
Environmental health services (EHS) in healthcare facilities (HCFs) are critical for safe care provision, yet their availability in low- and middle-income countries is low. A poor understanding of costs hinders progress towards adequate provision. Methods are inconsistent and poorly documented in costing literature, suggesting opportunities to improve evidence. The goal of this research was to develop a model to guide budgeting for EHS in HCFs. Based on 47 studies selected through a systematic review, we identified discrete budgeting steps, developed codes to define each step, and ordered steps into a model. We identified good practices based on a review of additional selected guidelines for costing EHS and HCFs. Our model comprises ten steps in three phases: planning, data collection, and synthesis. Costing-stakeholders define the costing purpose, relevant EHS, and cost scope; assess the EHS delivery context; develop a costing plan; and identify data sources (planning). Stakeholders then execute their costing plan and evaluate the data quality (data collection). Finally, stakeholders calculate costs and disseminate findings (synthesis). We present three hypothetical costing examples and discuss good practices, including using costing frameworks, selecting appropriate indicators to measure the quantity and quality of EHS, and iterating planning and data collection to select appropriate costing approaches and identify data gaps.


ADAM12 and ADAM17 are essential molecules for hypoxia-induced impairment of neural vascular barrier function.
Neural vascular barrier is essential for the life of multicellular organisms, and its impairment by tissue hypoxia is known to be a central of pathophysiology accelerating the progression of various intractable neural diseases. Therefore, the molecules involved in hypoxia-induced impairment of vascular barrier can be the targets to establish new therapies for intractable diseases. Here, we demonstrate that a disintegrin and metalloproteinases (ADAMs) 12 and 17 expressed in endothelial cells are the molecules responsible for the impairment of neural vascular barrier by hypoxia. Brain microvascular endothelial cells in vitro lost their barrier properties immediately after hypoxic stimulation through diminished localization of claudin-5, a tight junction molecule, on cell membranes. Hypoxic disappearance of claudin-5 from cell membranes and the consequent loss of barrier properties were completely suppressed by inhibition of the metalloproteinase activity which was found to be attributed to ADAM12 and ADAM17. Inhibition of either ADAM12 or ADAM17 was sufficient to rescue the in vivo neural vasculature under hypoxia from the loss of barrier function. This is the first report to specify the molecules which are responsible for hypoxia-induced impairment of neural vascular barrier and furthermore can be the targets of new therapeutic strategies for intractable neural diseases.


Association of cervical spondylosis with obstructive sleep apnea.
The study objective was to evaluate the association between cervical spondylosis (CS) and a subsequent diagnosis of obstructive sleep apnea (OSA) in light of the expected constricting impact of CS-associated cervical spine changes on the pharyngeal airway space, a key contributor to OSA. Data were retrieved from the Taiwan National Health Insurance Research Dataset. A total of 98,234 patients who newly received a diagnosis of OSA were identified. We identified four propensity score-matched controls per OSA patient (n = 392,936). Chi-square tests were used to compare cases and controls on sociodemographic characteristics, and multivariable logistic regression modelling to examine the association of OSA with prior CS. Of the 98,234 sampled patients, 18,070 (18.4%) patients had a prior CS diagnosis, significantly different among cases compared to controls, being 18.4% and12.1%, respectively, p < 0.001. Logistic regression analysis showed an adjusted odds ratio (OR) of prior CS of 1.778 (95% confident interval (CI): 1.744-1.814) relative to controls. The adjusted odds of prior CS without myelopathy was 1.764 for cases relative to controls (95% CI: 1.727-1.801), and for prior CS with myelopathy (adjusted OR: 1.778, 95% CI: 1.721-1.837). Analysis stratified by age showed that in the 45-64- and >64-year age groups, the adjusted ORs of CS were 1.803 (95% CI: 1.758-1.850) and 1.634 (95% CI: 1.568-1.703), respectively, for cases relative to controls. Our results suggest that OSA is associated with prior CS. The results call for professionals to be alert to the possibility of subsequent development of OSA among patients with CS.


Association of Enterobacter cloacae with Rhizome Rot of Edible Ginger in Hawaii.
Edible ginger is a popular spice crop that is grown in Hawaii primarily for the fresh market, and as such, rhizome quality is of paramount importance. In our studies, a Gram-negative, facultative anaerobic, rod-shaped bacterium was consistently isolated from decayed as well as symptomless ginger rhizomes. The bacterium was identified as Enterobacter cloacae by biochemical assays and 16S rDNA sequence analysis. Rot symptoms, which usually occurred in the central cylinder of the rhizome, were characterized by yellowish-brown to brown discolored tissue and firm to spongy texture. In inoculation experiments, ginger strains of E. cloacae produced basal stem and root rot, with foliar chlorosis and necrosis in tissue-cultured ginger plantlets, and discolored and spongy tissue in mature ginger rhizome slices and whole segments. In other hosts, ginger strains of E. cloacae caused internal yellowing of ripe papaya fruit and internal rot of onion bulbs. All strains that caused symptoms in inoculated plants were reisolated and identified as E. cloacae. Our studies suggest that E. cloacae can exist as an endophyte of ginger rhizomes, and under conditions that are favorable for bacterial growth, or host susceptibility, including maturity of tissues, rhizome rot may occur. Rhizome quality may be impacted by the presence of E. cloacae under conditions such as high temperature, high relative humidity, and low oxygen atmosphere that may affect the development of decay, and such conditions should be avoided during post-harvest handling and storage. The association of E. cloacae with a rhizome rot of ginger is a new finding.


Intrapleural Fibrinolytics and Deoxyribonuclease for Treatment of Indwelling Pleural Catheter-Related Pleural Infection: A Multi-Center Observational Study.
Indwelling pleural catheters (IPC) are increasingly used for management of recurrent (especially malignant) effusions. Pleural infection associated with IPC use remains a concern. Intrapleural therapy with tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) significantly reduces surgical referrals in non-IPC pleural infection, but data on its use in IPC-related pleural infection are scarce. To assess the safety and efficacy of intrapleural tPA and DNase in IPC-related pleural infection. Patients with IPC-related pleural infection who received intrapleural tPA/DNase in five Australian and UK centers were identified from prospective databases. Outcomes on feasibility of intrapleural tPA/DNase delivery, its efficacy and safety were recorded. Thirty-nine IPC-related pleural infections (predominantly Staphylococcus aureus and gram-negative organisms) were treated in 38 patients; 87% had malignant effusions. In total, 195 doses (median 6 [IQR = 3-6]/patient) of tPA (2.5 mg-10 mg) and DNase (5 mg) were instilled. Most (94%) doses were delivered via IPCs using local protocols for non-IPC pleural infections. The mean volume of pleural fluid drained during the first 72 h of treatment was 3,073 (SD = 1,685) mL. Most (82%) patients were successfully treated and survived to hospital discharge without surgery; 7 required additional chest tubes or therapeutic aspiration. Three patients required thoracoscopic surgery. Pleurodesis developed post-infection in 23/32 of successfully treated patients. No major morbidity/mortality was associated with tPA/DNase. Four patients received blood transfusions; none had systemic or significant pleural bleeding. Treatment of IPC-related pleural infection with intrapleural tPA/DNase instillations via the IPC appears feasible and safe, usually without additional drainage procedures or surgery. Pleurodesis post-infection is common.


Reduced prostate branching morphogenesis in stromal fibroblast, but not in epithelial, estrogen receptor α knockout mice.
Early studies suggested that estrogen receptor alpha (ERα) is involved in estrogen-mediated imprinting effects in prostate development. We recently reported a more complete ERα knockout (KO) mouse model via mating β-actin Cre transgenic mice with floxed ERα mice. These ACTB-ERαKO male mice showed defects in prostatic branching morphogenesis, which demonstrates that ERα is necessary to maintain proliferative events in the prostate. However, within which prostate cell type ERα exerts those important functions remains to be elucidated. To address this, we have bred floxed ERα mice with either fibroblast-specific protein (FSP)-Cre or probasin-Cre transgenic mice to generate a mouse model that has deleted ERα gene in either stromal fibroblast (FSP-ERαKO) or epithelial (pes-ERαKO) prostate cells. We found that circulating testosterone and fertility were not altered in FSP-ERαKO and pes-ERαKO male mice. Prostates of FSP-ERαKO mice have less branching morphogenesis compared to that of wild-type littermates. Further analyses indicated that loss of stromal ERα leads to increased stromal apoptosis, reduced expression of insulin-like growth factor-1 (IGF-1) and FGF10, and increased expression of BMP4. Collectively, we have established the first in vivo prostate stromal and epithelial selective ERαKO mouse models and the results from these mice indicated that stromal fibroblast ERα plays important roles in prostatic branching morphogenesis via a paracrine fashion. Selective deletion of the ERα gene in mouse prostate epithelial cells by probasin-Cre does not affect the regular prostate development and homeostasis.


Biological trade-offs underpin coral reef ecosystem functioning.
Human impact increasingly alters global ecosystems, often reducing biodiversity and disrupting the provision of essential ecosystem services to humanity. Therefore, preserving ecosystem functioning is a critical challenge of the twenty-first century. Coral reefs are declining worldwide due to the pervasive effects of climate change and intensive fishing, and although research on coral reef ecosystem functioning has gained momentum, most studies rely on simplified proxies, such as fish biomass. This lack of quantitative assessments of multiple process-based ecosystem functions hinders local and regional conservation efforts. Here we combine global coral reef fish community surveys and bioenergetic models to quantify five key ecosystem functions mediated by coral reef fishes. We show that functions exhibit critical trade-offs driven by varying community structures, such that no community can maximize all functions. Furthermore, functions are locally dominated by few species, but the identity of dominant species substantially varies at the global scale. In fact, half of the 1,110 species in our dataset are functionally dominant in at least one location. Our results reinforce the need for a nuanced, locally tailored approach to coral reef conservation that considers multiple ecological functions beyond the effect of standing stock biomass.


Determining the Number of Latent Factors in Statistical Multi-Relational Learning.
Statistical relational learning is primarily concerned with learning and inferring relationships between entities in large-scale knowledge graphs. Nickel et al. (2011) proposed a RESCAL tensor factorization model for statistical relational learning, which achieves better or at least comparable results on common benchmark data sets when compared to other state-of-the-art methods. Given a positive integer s, RESCAL computes an s-dimensional latent vector for each entity. The latent factors can be further used for solving relational learning tasks, such as collective classification, collective entity resolution and link-based clustering. The focus of this paper is to determine the number of latent factors in the RESCAL model. Due to the structure of the RESCAL model, its log-likelihood function is not concave. As a result, the corresponding maximum likelihood estimators (MLEs) may not be consistent. Nonetheless, we design a specific pseudometric, prove the consistency of the MLEs under this pseudometric and establish its rate of convergence. Based on these results, we propose a general class of information criteria and prove their model selection consistencies when the number of relations is either bounded or diverges at a proper rate of the number of entities. Simulations and real data examples show that our proposed information criteria have good finite sample properties.


Pancreatic Ductal Adenocarcinoma: Molecular Pathology and Predictive Biomarkers.
Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis due to the lack of methods or biomarkers for early diagnosis and its resistance to conventional treatment modalities, targeted therapies, and immunotherapies. PDACs are a heterogenous group of malignant epithelial neoplasms with various histomorphological patterns and complex, heterogenous genetic/molecular landscapes. The newly proposed molecular classifications of PDAC based on extensive genomic, transcriptomic, proteomic and epigenetic data have provided significant insights into the molecular heterogeneity and aggressive biology of this deadly disease. Recent studies characterizing the tumor microenvironment (TME) have shed light on the dynamic interplays between the tumor cells and the immunosuppressive TME of PDAC, which is essential to disease progression, as well as its resistance to chemotherapy, newly developed targeted therapy and immunotherapy. There is a critical need for the development of predictive markers that can be clinically utilized to select effective personalized therapies for PDAC patients. In this review, we provide an overview of the histological and molecular heterogeneity and subtypes of PDAC, as well as its precursor lesions, immunosuppressive TME, and currently available predictive molecular markers for patients.


K-252a, a potent protein kinase inhibitor, blocks nerve growth factor-induced neurite outgrowth and changes in the phosphorylation of proteins in PC12h cells.
Nerve growth factor (NGF) promotes neuronal differentiation of PC12 pheochromocytoma cells. One of the most prominent and distinguishing features of neuronal differentiation is neurite outgrowth. The mechanism by which NGF causes the cells to elaborate neurites is unknown. This study shows that K-252a, a potent protein kinase inhibitor, blocks NGF-induced neurite outgrowth and the changes in protein phosphorylation elicited by NGF. In the experiment with intact cells phosphorylated with 32P-orthophosphoric acid, an exposure of PC12h cells to NGF (50 ng/ml) caused an increase in the phosphorylation of tyrosine hydroxylase and a 35,000-D protein and a decrease in a 36,500-D protein. Pretreatment of PC12h cells with K-252a (100 nM) inhibited the effects of NGF on the phosphorylation of these three proteins. In the phosphorylation of cell-free extracts with [gamma-32P] ATP, treatment of PC12h cells with NGF (50 ng/ml) caused a decrease in the phosphorylation of Nsp100. Pretreatment of the cells with K-252a (30 nM) almost completely blocked the NGF effect on the phosphorylation of Nsp100 elicited by subsequent treatment of the cells with NGF. Treatment of PC12h cells with NGF promoted outgrowth of neurites. The addition of K-252a (100 nM) into the culture almost completely blocked the generation of neurites elicited by NGF. Earlier studies demonstrated that NGF-induced neurite outgrowth in PC12 cells involves at least two components: the first of these is transcription-dependent and the second is transcription-independent. To determine the component on which K-252a acts, experiments were carried out on NGF-induced priming or regeneration of neurites. When K-252a was present in the priming step, NGF induced only actinomycin D-sensitive neurites, showing that K-252a interferes with the transcription-dependent actions of NGF. When already primed cells were treated with NGF, actinomycin D-resistant neurites were formed and these were blocked by K-252a, showing that the inhibitor interferes with the transcription-independent actions of NGF as well. Although the exact mechanism of inhibition of NGF-promoted neurite formation by K-252a is unknown, the most probable explanation is that both transcription-dependent and -independent components are involved in at least one step of the activation of some specific protein kinase(s) that can be suppressed by K-252a.


Perioperative myocardial ischemic episodes are related to hematocrit level in patients undergoing radical prostatectomy.
The anemia associated with perioperative blood conservation has raised concerns regarding the safety of these strategies in patients with ischemic cardiovascular disease. Therefore the relationship between hematocrit level and myocardial ischemic episodes in a group of elderly patients undergoing elective noncardiac surgery was studied. One hundred ninety patients undergoing radical prostatectomy were randomly assigned to one of three blood conservation groups: preoperative autologous blood donation, acute normovolemic hemodilution, and preoperative erythropoietin therapy with acute normovolemic hemodilution. Patients underwent ambulatory electrocardiography monitoring to evaluate for myocardial ischemia at randomization (baseline), 7 days preoperatively, throughout surgery, and for 24 hours after surgery. Myocardial ischemic episodes occurred in 61 (34%) of 181 evaluable patients. Patients with hematocrit levels < 28 percent immediately after surgery were significantly (p = 0.05) more likely to have intraoperative and postoperative ECG ischemic episodes. Intraoperative ischemia and tachycardia correlated (r = 0.21, p = 0.008) with hematocrit levels. Hematocrit levels after surgery were associated with postoperative ischemia (r = 0.14, p = 0.03) and duration of myocardial ischemic episodes (r = 0.14, p = 0.04). After adjusting for other risk factors, intraoperative tachycardia episodes, hematocrit level < 28 percent immediately after surgery, and risk factors for coronary artery disease were independently associated with the likelihood of intraoperative ischemia (r = 0.36, p = 0.002, area under receiver operating characteristic curve = 0.73). Similarly, tachycardia episodes and hematocrit levels < 28 percent immediately after surgery were independently associated with ischemic episodes during the first postoperative day (r = 0.30, p = 0.004, area under receiver operating characteristic curve = 0.71). A hematocrit level < 28 percent is independently associated with risk for myocardial ischemia during and after noncardiac surgery. Avoidance of cardiac complications may require higher transfusion thresholds, closer attention to tachycardia, or better monitoring for ischemia.


Non-genetic Purification of Ventricular Cardiomyocytes from Differentiating Embryonic Stem Cells through Molecular Beacons Targeting IRX-4.
Isolation of ventricular cardiomyocytes (vCMs) has been challenging due to the lack of specific surface markers. Here we show that vCMs can be purified from differentiating mouse embryonic stem cells (mESCs) using molecular beacons (MBs) targeting specific intracellular mRNAs. We designed MBs (IRX4 MBs) to target mRNA encoding Iroquois homeobox protein 4 (Irx4), a transcription factor specific for vCMs. To purify mESC vCMs, IRX4 MBs were delivered into cardiomyogenically differentiating mESCs, and IRX4 MBs-positive cells were FACS-sorted. We found that, of the cells isolated, ~98% displayed vCM-like action potentials by electrophysiological analyses. These MB-purified vCMs continuously maintained their CM characteristics as verified by spontaneous beating, Ca(2+) transient, and expression of vCM-specific proteins. Our study shows the feasibility of isolating pure vCMs via cell sorting without modifying host genes. The homogeneous and functional ventricular CMs generated via the MB-based method can be useful for disease investigation, drug discovery, and cell-based therapies.


DGT as an in situ tool for measuring radiocesium in natural waters.
The application of diffusive gradients in thin-films (DGT) samplers for the measurement of cesium radionuclides in solution, using an ammonium molybdophosphate (AMP) binding agent, was tested under both laboratory and field conditions. In the former they proved able to reproduce known 134Cs concentrations (60 Bq L(-1)) with a high degree of accuracy and precision over periods up to approximately 1 d, in freshwaters over a wide range of pH and temperature, and in saline water. In field trials in a freshwater lake receiving nuclear power station discharges, mean concentrations of 137CS (47-61 mBq L(-1)) were measured over periods from 5 d to 1 month. These agreed, within error, with mean concentrations determined from grab samples but rigorous field validation of long-term (month) deployments of DGT devices proved impossible using conventional sampling procedures, due to loss of 137Cs to container walls. Identified limitations of the DGT technique included probable AMP degradation over longer periods and calibration problems if large changes in temperature and concentration occurred together. Potential limitations due to biofilm growth were considered not to be significant. Despite the limitations, the technique appears to measure concentrations accurately for deployment times of 1 month or less. It has several advantages over traditional sampling methods for monitoring radionuclides in the solution/dissolved phase, including its simplicity, provision of time-averaged mean concentrations, and automatic in-situ concentration onto a medium with ideal counting geometry for gamma spectrometry.


Functionalized micellar assemblies prepared via block copolymers synthesized by living free radical polymerization upon peptide-loaded resins.
Hybrid peptidic-synthetic amphiphilic block copolymers, synthesized by living free radical polymerization (LFRP) on solid support, have been utilized as precursors for nanoscale materials possessing bio-available peptides. LFRP initiators, coupled to the peptide terminus upon the resin, facilitated the growth of homo- and block copolymers via nitroxide mediated radical polymerization (NMRP) or atom transfer radical polymerization (ATRP). Herein, the versatile solid-support synthesis of the antimicrobial peptide tritrpticin, coupling of living free radical polymerization initiators to the peptide-loaded resin, and the controlled radical polymerization of various monomers to yield amphiphilic diblock copolymers are described. Assembly of the peptidic-synthetic block copolymers into micelles and a preliminary assessment of their in vitro biological properties are detailed.


Targeting the SPOCK1-snail/slug axis-mediated epithelial-to-mesenchymal transition by apigenin contributes to repression of prostate cancer metastasis.
Prostate cancer (PCa) is considered one of the most prevalent malignancy globally, and metastasis is a major cause of death. Apigenin (API) is a dietary flavonoid which exerts an antimetastatic effect in various cancer types. Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1) is a crucial modulator of tumor growth and metastasis in cancers. However, the role and underlying regulatory mechanisms of SPOCK1 in the API-mediated antimetastatic effects of PCa remain unclear. MTS, colony formation, wound-healing, and transwell assays were conducted to evaluate the effects of API on PCa cell proliferative, migratory, and invasive potentials. In vivo orthotopic bioluminescent xenograft model were employed to determine antitumor activity of API. PCa cells were transfected with either Snail-, Slug-, SPOCK1-overexpressing vector, or small hairpin (sh)SPOCK1 to determine the invasive abilities and expression levels of SPOCK1 and epithelial-to-mesenchymal transition (EMT) biomarkers in response to API treatment. Immunohistochemical (IHC) assays were carried out to evaluate the expression level of SPOCK1 in PCa xenografts and a PCa tissue array. Associations of SPOCK1 expression with clinicopathological features and prognoses of patients with PCa were analyzed by GEO or TCGA RNA-sequencing data. API significantly suppressed in vitro PCa cell proliferation, migration, and invasion and inhibited in vivo PCa tumor growth and metastasis. Moreover, survival times of animals were also prolonged after API treatment. Mechanistic studies revealed that API treatment resulted in downregulation of SPOCK1, which was accompanied by reduced expressions of mesenchymal markers and subsequent attenuation of invasive abilities of PCa cells. Overexpression of SPOCK1 in PCa xenografts resulted in significant promotion of tumor progression and relieved the anticancer activities induced by API, whereas knockdown of SPOCK1 had opposite effects. In clinical, SPOCK1 levels were higher in tumor tissues compared to non-tumor tissues, which was also significantly correlated with shorter disease-free survival in PCa patients. Levels of SPOCK1 increase with the progression of human PCa which suggests that SPOCK1 may act as a prognostic marker or therapeutic target for patients with PCa. Suppression of SPOCK1-mediated EMT signaling contributes to the antiproliferative and antimetastatic activities of API in vitro and in vivo.


How fast is too fast? a practice change in umbilical arterial catheter blood sampling using the Iowa Model for Evidence-Based Practice.
A multidisciplinary team at the University of Iowa Children's Hospital utilized the Iowa Model of Evidence-Based Practice to Promote Quality Care as a basis for changing practice related to the rate of drawing and flushing umbilical artery catheters in very low birth-weight infants. Research indicates that rapid withdrawal of blood or flushing of catheters that are placed in the aorta can affect cerebral blood flow velocity, volume, and oxygenation. Alteration of cerebral blood flow in premature infants has been correlated with the incidence of intraventricular hemorrhage and periventricular leukomalacia, which can be a significant cause of morbidity and mortality in this population. Using this research as a guide, along with expert opinion, scientific principles, and theories, a new standard of practice was written, and the staff educated.


Pain and swelling after periapical surgery related to the hemostatic agent used: anesthetic solution with vasoconstrictor or aluminum chloride.
To assess pain and swelling in the first 7 days after periapical surgery and their relationship with the agent used for bleeding control. A prospective study was conducted between October 2006 and March 2009. Patients subjected to root surgery, who completed the questionnaire and who consented to the postoperative instructions were included in the study. The subjects were divided into two groups according to the hemostatic agent used: A) gauze impregnated with anesthetic solution with vasoconstrictor; or B) aluminum chloride. The patients were administered a questionnaire, and were asked to record the severity of their pain and swelling on a plain horizontal visual analog scale (VAS). Data were recorded by the patients on the first 7 postoperative days. In addition, the patients were asked to record analgesic consumption. A total of 76 questionnaires (34 in group A and 42 in group B) were taken to be correctly completed. Pain was reported to be most intense two hours after surgery. At this point 52.6% of the patients had no pain. Seventy-five percent of the patients consumed analgesics in the first 24 hours. There were no significant differences between the two groups in terms of the intensity of pain or in the consumption of analgesics. Swelling reached its maximum peak on the second day; at this point, 60.6% of the patients suffered mild or moderate swelling. The Expasyl group showed significantly greater swelling than the gauzes group. The type of hemostatic agent used did not influence either the degree of pain or the need for analgesia among the patients in this study. However, the patients belonging to the Expasyl group suffered greater swelling than the patients treated with gauzes impregnated with anesthetic solution with vasoconstrictor.


The health of street youth: a Canadian perspective.
To review epidemiologic studies of the health of street youth in industrialized countries, with a special focus on Canadian youth. We identified 52 peer-reviewed studies from searches of the MEDLINE database and bibliographies of published papers, for data on blood-borne and sexually transmitted infections, mental health problems, pregnancy, violence and mortality. Rates of hepatitis B, hepatitis C, and HIV infection are much higher among street youth than among their non-street peers. Likewise, the prevalence of all mental health problems assessed in street youth is greater than that in non-street youth. Pregnancy is more frequent among street than household youth. Street youth also experience high levels of violence: a large proportion report physical abuse or assault. Finally, mortality is about 11 times the expected rate based on age and sex and is mainly caused by suicide and drug overdose. Current research results are useful to orient public health interventions for street youth, but further epidemiologic research is needed. The need for Canadian data is particularly acute in specific areas including mental health, violence, pregnancy, and sexually transmitted infections such as, for example, herpes infection and syphilis.


Bilateral control of hindlimb scratching in the spinal turtle: contralateral spinal circuitry contributes to the normal ipsilateral motor pattern of fictive rostral scratching.
In a spinal turtle, unilateral stimulation in the rostral scratch receptive field elicited rhythmic fictive rostral scratching in ipsilateral hindlimb motor neurons; contralateral hip motor activity was also rhythmic and out-of-phase with ipsilateral hip motor activity. When left and right rostral scratch receptive fields were stimulated simultaneously, bilateral rhythmic fictive rostral scratching was produced; left hindlimb scratching was out-of-phase with right hindlimb scratching. Thus, spinal circuits coordinate interlimb phase during bilateral fictive scratching. We examined the contributions of contralateral spinal circuitry to the normal pattern of right hindlimb fictive rostral scratching by removing the left halves of the D7 segment and the hindlimb enlargement (D8-S2 segments). After left-hemicord removal, stimulation in the right rostral scratch receptive field usually elicited a variation of rostral scratching with rhythmic right hip flexor activity and no right hip extensor activity; thus, right hip flexor rhythm generation does not require left hindlimb enlargement circuitry. Normal right hindlimb rostral scratching with rhythmic alternation between hip flexor and extensor activities was rarely observed; thus, contralateral spinal circuitry contributes to the production of normal ipsilateral fictive rostral scratching. After left-hemicord removal, stimulation in the left rostral scratch receptive field elicited rhythmic right hip extensor activity; thus, contralateral spinal circuitry can generate a hip extensor rhythm during ipsilateral rostral scratch receptive field stimulation. Our observations and those of Berkowitz and Stein (1994a,b) support the concept that an ipsilateral hindlimb's normal rostral scratch motor pattern is generated by a modular central pattern generator that is bilaterally distributed in the spinal cord.


Polarization-sensitive surface plasmon Schottky detectors.
A polarization detector based on the excitation of surface plasmon polaritons on the periodically corrugated metal surface of Schottky structures is presented. The surface modes are only excited by light having the appropriate polarization; they are leaky at the metal-semiconductor interface and are thus radiated into the semiconductor, where they generate charge carriers. By this mechanism the photocurrent of the device is enhanced and depends strongly on the polarization angle of the incident light. By use of two detectors with different grating orientations the polarization of the light can be determined unambiguously.


COMPARATIVE ANALYSIS OF LATE RESULTS OF CERVICAL ESOPHAGOGASTRIC ANASTOMOSIS BY MANUAL AND MECHANICAL SUTURE IN PATIENTS SUBMITTED TO ESOPHAGEAL MUCOSECTOMY THROUGH ADVANCED MEGAESOPHAGUS.
Among the anastomoses of the gastrointestinal tract, those of the esophagus are of special interest due to several anatomical or even general peculiarities. Evaluate retrospectively the results comparing mechanical vs. manual suture at cervical esophagogastric anastomosis in megaesophagus treatment. Were included 92 patients diagnosed with advanced megaesophagus with clinical conditions to undergo the surgery. All underwent esophageal mucosectomy, performing anastomosis of the esophagus stump with the gastric tube at the cervical level. In order to make this anastomosis, the patients were divided into two groups: group A (n=53) with circular mechanical suture, lateral end; group B (n=39) with manual suture in two sides, lateral end. In the postoperative period, an early evaluation was performed, analyzing local and systemic complications and late (average 5.6 y) analyzing deglutition. Early evaluation: a) dehiscence of esophagogastric anastomosis n=5 (9.4%) in group A vs. n=9 (23.0%) in group B (p=0.0418); b) stenosis of esophagogastric anastomosis n=8 (15.1%) in group A vs. n=15 (38.4%) in group B (p=0.0105.); c) pulmonary infection n=5 (9.4%) in group A vs. n=3 (7.6%) in group B (p=1.0000.); d) pleural effusion n=5 (9.4%) in group A vs. n=6 (15.4%) in group B (p<0.518). Late evaluation showed that 86.4-96% of the patients presented the criteria 4 and 5 from SAEED, expressing effective swallowing mechanisms without showing significant differences among the groups. Cervical esophagogastric anastomosis by means of mechanical suture is more proper than the manual with lower incidence of local complications and, in the long-term evaluation, regular deglutition was acquired in both suture techniques in equal quality.


An engineered 800 kilobase deletion of Uchl3 and Lmo7 on mouse chromosome 14 causes defects in viability, postnatal growth and degeneration of muscle and retina.
The Acrg minimal region is a 1.5-1.7 Mb domain defined by genetic complementation among deletions generated around Ednrb on chromosome 14 in mice. Mice homozygous for one of the deletions, Ednrb(s-1Acrg), exhibit embryonic lethality with defects associated with mesoderm development. We predicted that the region contains a single cluster of four genes that encode a TBC domain-containing protein (KIAA0603), a novel protein AK000009, the ubiquitin C-terminal hydrolase L3 (UCHL3) and an F-box/PDZ/LIM domain protein LMO7. A targeted internal deletion of Uchl3 (Uchl3(Delta3-7)) produced viable mice, eliminating this gene as a candidate for the embryonic lethality. To dissect the Acrg minimal region further, we utilized Cre-loxP-mediated chromosome engineering to generate a targeted 800 kb deletion (Lmo7(Delta800)) that removes the distal portion of the region. The deletion includes Uchl3, Lmo7 and an additional 500 kb downstream of the 3' end of Lmo7 where no genes are thought to reside. We found that approximately 40% of mice homozygous for this deletion die between birth and weaning, and are severely runted. The remaining homozygotes are viable, thus ruling out Lmo7 as a single gene candidate for the Ednrb(s-1Acrg) embryonic lethality. Both Uchl3(Delta3-7) and Lmo7(Delta800) mutants displayed retinal degeneration, muscular degeneration and growth retardation, but the severity of the muscular degeneration and growth retardation were enhanced in Lmo7(Delta800) homozygotes. We suggest that the increase in severity may reflect an interaction between Uchl3 and Lmo7 in the ubiquitin-mediated protein degradation pathway.


A C-terminal PDZ binding domain modulates the function and localization of Kv1.3 channels.
The voltage-gated potassium channel, Kv1.3, plays an important role in regulating membrane excitability in diverse cell types ranging from T-lymphocytes to neurons. In the present study, we test the hypothesis that the C-terminal PDZ binding domain modulates the function and localization of Kv1.3. We created a mutant form of Kv1.3 that lacked the last three amino acids of the C-terminal PDZ-binding domain (Kv1.3ΔTDV). This form of Kv1.3 did not bind the PDZ domain containing protein, PSD95. We transfected wild type and mutant Kv1.3 into HEK293 cells and determined if the mutation affected current, Golgi localization, and surface expression of the channel. We found that cells transfected with Kv1.3ΔTDV had greater current and lower Golgi localization than those transfected with Kv1.3. Truncation of the C-terminal PDZ domain did not affect surface expression of Kv1.3. These findings suggest that PDZ-dependent interactions affect both Kv1.3 localization and function. The finding that current and Golgi localization changed without a corresponding change in surface expression suggests that PDZ interactions affect localization and function via independent mechanisms.


Temperature-dependent modification of muscle precursor cell behaviour is an underlying reason for lasting effects on muscle cellularity and body growth of teleost fish.
Temperature is an important factor influencing teleost muscle growth, including a lasting ('imprinted') influence of embryonic thermal experience throughout all further life. However, little is known about the cellular processes behind this phenomenon. The study reported here used digital morphometry and immunolabelling for Pax7, myogenin and H3P to quantitatively examine the effects of thermal history on muscle precursor cell (MPC) behaviour and muscle growth in pearlfish (Rutilus meidingeri) until the adult stage. Fish were reared at three different temperatures (8.5, 13 and 16°C) until hatching and subsequently kept under the same (ambient) thermal conditions. Cellularity data were combined with a quantitative analysis of Pax7+ MPCs including those that were mitotically active (Pax7+/H3P+) or had entered differentiation (Pax7+/myogenin+). The results demonstrate that at hatching, body lengths, fast and slow muscle cross-sectional areas and fast fibre numbers are lower in fish reared at 8.5 and 13°C than at 16°C. During the larval period, this situation changes in the 13°C-fish, so that these fish are finally the largest. The observed effects can be related to divergent cellular mechanisms at the MPC level that are initiated in the embryo during the imprinting period. Embryos of 16°C-fish have reduced MPC proliferation but increased differentiation, and thus give rise to larger hatchlings. However, their limited MPC reserves finally lead to smaller adults. By contrast, embryos of 13°C-fish and, to a lesser extent, 8.5°-fish, show enhanced MPC proliferation but reduced differentiation, thus leading to smaller hatchlings but allowing for a larger MPC pool that can be used for enhanced post-hatching growth, finally resulting in larger adults.


Identification of Genomic Regions Associated with Agronomic and Disease Resistance Traits in a Large Set of Multiple DH Populations.
Breeding maize lines with the improved level of desired agronomic traits under optimum and drought conditions as well as increased levels of resistance to several diseases such as maize lethal necrosis (MLN) is one of the most sustainable approaches for the sub-Saharan African region. In this study, 879 doubled haploid (DH) lines derived from 26 biparental populations were evaluated under artificial inoculation of MLN, as well as under well-watered (WW) and water-stressed (WS) conditions for grain yield and other agronomic traits. All DH lines were used for analyses of genotypic variability, association studies, and genomic predictions for the grain yield and other yield-related traits. Genome-wide association study (GWAS) using a mixed linear FarmCPU model identified SNPs associated with the studied traits i.e., about seven and eight SNPs for the grain yield; 16 and 12 for anthesis date; seven and eight for anthesis silking interval; 14 and 5 for both ear and plant height; and 15 and 5 for moisture under both WW and WS environments, respectively. Similarly, about 13 and 11 SNPs associated with gray leaf spot and turcicum leaf blight were identified. Eleven SNPs associated with senescence under WS management that had depicted drought-stress-tolerant QTLs were identified. Under MLN artificial inoculation, a total of 12 and 10 SNPs associated with MLN disease severity and AUDPC traits, respectively, were identified. Genomic prediction under WW, WS, and MLN disease artificial inoculation revealed moderate-to-high prediction accuracy. The findings of this study provide useful information on understanding the genetic basis for the MLN resistance, grain yield, and other agronomic traits under MLN artificial inoculation, WW, and WS conditions. Therefore, the obtained information can be used for further validation and developing functional molecular markers for marker-assisted selection and for implementing genomic prediction to develop superior elite lines.


Hepatectomy: a critical analysis on expansion of the indications.
Hepatic resection has evolved to become safer, thereby making it possible to expand the indications. Aim : To assess the results from a group of patients presenting these expanded indications. Were prospectively studied all the hepatectomy procedures performed for hepatic tumor resection. Patients with benign and malignant primary and secondary tumors were included. Were included variables such as age, gender, preoperative diagnosis, preoperative treatment, type of operation performed, need for transfusion, final anatomopathological examination and postoperative evolution. The patients were divided into two groups: group A, with a traditional indication for hepatectomy; and group B, with an expanded indication (tumors in both hepatic lobes, extensive resection encompassing five or more segments, cirrhotic livers and postoperative chemotherapy using hepatotoxic drugs). Were operated 38 patients, and 40 hepatectomies were performed: 28 patients in group A and 10 in group B. The mean age was 57.7 years, and 25 patients were women. Three in group B were operated as two separate procedures. Groups A and B received means of 1.46 and 5.5 packed red blood cell units per operation, respectively. There were three cases with complications in group A (10.7%) and six in group B (60%). The mortality rate in group A was 3.5% (one patient) and in groups B, 40% (four patients). The imaging examinations were sensitive for the presence of tumors but not for defining the type of tumor. The blood and derivative transfusion rates, morbidity and mortality were greater in the group with expanded indications and more extensive surgery. The indications for liver biopsy and portal vein embolization or ligature can be expanded, with special need of cooperation of the anesthesiology department and the use of hepatic resection devices to diminish blood transfusion.


From Persian Gulf to Indonesia: interrelated phylogeographic distance and chemistry within the genus Peronia (Onchidiidae, Gastropoda, Mollusca).
The knowledge of relationships between taxa is essential to understand and explain the chemical diversity of the respective groups. Here, twelve individuals of the panpulmonate slug Peronia persiae from two localities in Persian Gulf, and one animal of P. verruculata from Bangka Island, Indonesia, were analyzed in a phylogenetic and chemotaxonomic framework. Based on the ABGD test and haplotype networking using COI gene sequences of Peronia specimens, nine well-supported clades were found. Haplotype network analysis highlighted a considerable distance between the specimens of P. persiae and other clades. Metabolomic analysis of both species using tandem mass spectrometry-based GNPS molecular networking revealed a large chemical diversity within Peronia of different clades and localities. While P. persiae from different localities showed a highly similar metabolome, only few identical chemical features were found across the clades. The main common metabolites in both Peronia species were assigned as polypropionate esters of onchitriols and ilikonapyrones, and osmoprotectant amino acid-betaine compounds. On the other hand, the isoflavonoids genistein and daidzein were exclusively detected in P. persiae, while cholesterol and conjugated chenodeoxycholic acids were only found in P. verruculata. Flavonoids, bile acids, and amino acid-betaine compounds were not reported before from Onchidiidae, some are even new for panpulmonates. Our chemical analyses indicate a close chemotaxonomic relation between phylogeographically distant Peronia species.


Do tax policies discriminate against female traders? A gender framework to study informal marketplaces in Nigeria.
Scholars have long debated formalizing the informal sector through taxation, but how do these processes affect gender inequalities? Our study in Nigerian markets contributes a gender framework to the equitable taxation literature on formalization. The study draws on a survey of 451 traders in 12 markets, key informant interviews, and ethnographic research in four markets of two states. We find that in at least two situations taxation policies discriminated against women implicitly: (1) male tax collectors had higher incidences of harassment on all traders and (2) taxing traders with flat taxes penalized women, as they earned less than men but were taxed the same.


Family Characteristics in Sex Communication and Social Support: Implications for Emerging Adult Men Who Have Sex with Men's PrEP Engagement.
While emerging adulthood (ages 18-25) is marked by increased independence from parents, parental support remains a strong correlate of positive sexual health outcomes for heterosexual youth. With the emergence of pre-exposure prophylaxis (PrEP), few studies have examined the potential for parent-child sex communication and PrEP adoption among emerging adult men who have sex with men (MSM). We aimed to describe the extent to which parents/family characteristics play supportive roles in emerging adult MSM's current PrEP use. PrEP-indicated participants (N = 222) were recruited via social media to complete an online survey. Multivariable logistic regression assessed associations between emerging adult MSM's current PrEP use and comfort with parent-child sex communication, family social support, family outness, and family prioritization, adjusted for sociodemographic variables. Thirty percent of participants reported current PrEP use. Only 20% reported moderate/high comfort with parent sex communication, 80% reported any family sexual identity disclosure, 70% reported moderate/high family social support, and 70% ranked family as a high/very high priority. Our multivariable model demonstrated an association between comfort with parent-child sex communication with current PrEP use only (AOR= 1.55, 95% CI 1.04-2.32). Our findings support that parents of emerging adult MSM possess a critical potential to reduce their sons' risk of HIV and promote PrEP uptake. Interventions that facilitate parents' efficacy to foster affirming, non-judgmental environments and discussions about their child's sexual behaviors, attractions/relationships, and health (e.g., PrEP) may be impactful in reducing the high HIV incidence rate that burdens emerging adult MSM.


Borderline personality disorder is equally trait-like and state-like over ten years in adult psychiatric patients.
Borderline personality disorder (PD) has historically been cast as an unabating condition. Longitudinal data, however, support a more variable time course marked by remission and relapse. In the present study, we tested the possibility that borderline PD has both stable (i.e., consistently present across time and situation, as modern diagnostic systems stipulate) and dynamic (i.e., episodic and situational) elements. Participants were 668 patients from the Collaborative Longitudinal Personality Disorders Study who were administered semistructured diagnostic interviews 5 times over a decade. Trait-state-occasion modeling dissected borderline pathology into time-invariant (i.e., trait) and time-varying (i.e., state) components. Contradicting traditional views of PD intransigence, less than half of borderline PD variability (approximately 45%) was time-invariant (i.e., perfectly stable) over the study timeframe. Furthermore, we found that the time-invariant component of borderline pathology, which we termed borderline proneness, was very closely related (r = .81) to a previously validated Five Factor Model trait composite of borderline features. Moreover, the trait versus state components showed a clear pattern of discriminant validity in relation to several putative causal agents for borderline PD (i.e., environmental pathogens, temperament dimensions). We conclude that borderline pathology contains a stable core and sizable situational components, and that both elements relate systematically to normative personality dimensions and known risk factors. These findings have key implications for etiological research, prognosis, and treatment for borderline PD. (PsycINFO Database Record


Human Sir2-related protein SIRT1 associates with the bHLH repressors HES1 and HEY2 and is involved in HES1- and HEY2-mediated transcriptional repression.
The Hairy-related bHLH proteins function as transcriptional repressors in most cases and play important roles in diverse aspects of metazoan development. Recently, it was shown that the Drosophila bHLH repressor proteins, Hairy and Deadpan, bind to and function with the NAD(+)-dependent histone deacetylase, Sir2. Here we demonstrate that the human Sir2 homologue, SIRT1, also physically associates with the human bHLH repressor proteins, hHES1 and hHEY2, both in vitro and in vivo. Moreover, using the reporter assay, we show that both SIRT1-dependent and -independent deacetylase pathways are involved in the transcriptional repressions mediated by these bHLH repressors. These results indicate that the molecular association between bHLH proteins and Sir2-related proteins is conserved among metazoans, from Drosophila to human, and suggest that the Sir2-bHLH interaction also plays important roles in human cells.


Network Receptive Field Modeling Reveals Extensive Integration and Multi-feature Selectivity in Auditory Cortical Neurons.
Cortical sensory neurons are commonly characterized using the receptive field, the linear dependence of their response on the stimulus. In primary auditory cortex neurons can be characterized by their spectrotemporal receptive fields, the spectral and temporal features of a sound that linearly drive a neuron. However, receptive fields do not capture the fact that the response of a cortical neuron results from the complex nonlinear network in which it is embedded. By fitting a nonlinear feedforward network model (a network receptive field) to cortical responses to natural sounds, we reveal that primary auditory cortical neurons are sensitive over a substantially larger spectrotemporal domain than is seen in their standard spectrotemporal receptive fields. Furthermore, the network receptive field, a parsimonious network consisting of 1-7 sub-receptive fields that interact nonlinearly, consistently better predicts neural responses to auditory stimuli than the standard receptive fields. The network receptive field reveals separate excitatory and inhibitory sub-fields with different nonlinear properties, and interaction of the sub-fields gives rise to important operations such as gain control and conjunctive feature detection. The conjunctive effects, where neurons respond only if several specific features are present together, enable increased selectivity for particular complex spectrotemporal structures, and may constitute an important stage in sound recognition. In conclusion, we demonstrate that fitting auditory cortical neural responses with feedforward network models expands on simple linear receptive field models in a manner that yields substantially improved predictive power and reveals key nonlinear aspects of cortical processing, while remaining easy to interpret in a physiological context.


Quantitative Methodologies to Dissect Immune Cell Mechanobiology.
Mechanobiology seeks to understand how cells integrate their biomechanics into their function and behavior. Unravelling the mechanisms underlying these mechanobiological processes is particularly important for immune cells in the context of the dynamic and complex tissue microenvironment. However, it remains largely unknown how cellular mechanical force generation and mechanical properties are regulated and integrated by immune cells, primarily due to a profound lack of technologies with sufficient sensitivity to quantify immune cell mechanics. In this review, we discuss the biological significance of mechanics for immune cells across length and time scales, and highlight several experimental methodologies for quantifying the mechanics of immune cells. Finally, we discuss the importance of quantifying the appropriate mechanical readout to accelerate insights into the mechanobiology of the immune response.


DRD1-Pol V-dependent self-silencing of an exogenous silencer restricts the non-cell autonomous silencing of an endogenous target gene.
In plants, the exogenous transgene transcribing inverted-repeat (exo-IR) sequences produces double-stranded RNAs that are processed by DCL4. The 21-nt small interfering RNAs generated function as mobile signals to trigger non-cell autonomous silencing of target endogenes in the neighboring 10-15 cells. The potential involvement of nuclear silencing pathway components in signal spreading or sensing in target cells is not clear. Here, we demonstrate that the exo-IR silencer (exo-Pdsi) is negatively autoregulated through methylation spreading, which acts in cis to reinforce the self-silencing of the silencer. Mutations affecting nuclear proteins DRD1 and Pol V (NRPE1 or NRPD2) relieved exo-Pdsi self-silencing, resulting in higher levels of Pdsi transcripts, which increased the non-cell autonomous silencing of endo-PDS. Our results suggest that in an experimental silencing pathway, methylation spreading on a silencer transgene may not have a direct endogenous plant counterpart when the protein-encoding gene is the target. DRD1-Pol V-dependent de novo methylation, by acting in cis to reinforce self-silencing of exo-IR, may play a role in restraining the inappropriate silencing of active protein-coding genes in plants.


Association of exposure to polycyclic aromatic hydrocarbons (estimated from job category) with concentration of 1-hydroxypyrene glucuronide in urine from workers at a steel plant.
Increased risk of lung cancer has been associated with employment in the steel industry. This association is thought to be due in part to increased concentrations of polycyclic aromatic hydrocarbons (PAHs) in air found in this work environment. Measurement of PAH metabolites in human urine provides a means of assessing individual internal dose of PAHs. This study examined the relative contribution of occupation and smoking to urinary concentration of 1-hydroxypyrene glucuronide (1-OHPG) among a group of workers at a steel plant. Concentrations of 1-OHPG in urine from 44 workers with jobs associated with increased air concentrations of PAHs and 40 workers with jobs with low or no exposure to PAHs were measured. 20 workers in each group were not current smokers. Urinary 1-OHPG was measured by synchronous fluorescence spectroscopy after immunoaffinity chromatography specific for PAH metabolites. Mean (SEM) urinary 1-OHPG concentration was 2.16 (0.42) pmol/ml urine among the 44 occupationally exposed workers compared with 0.38 (0.05) among the 40 workers with no or low exposure (P < 0.0001). Mean urinary 1-OHPG concentration was 1.82 (0.41) pmol/ml urine among the 44 current smokers compared with 0.75 (0.20) among the 40 non-smokers (P < 0.005). Mean 1-OHPG concentrations in non-smokers were 0.26 (n = 20), 0.70 (n = 15), and 2.84 pmol/ml urine (n = 5) for strata of exposure to PAHs (no or low, mid, and high) based on job category; the corresponding values in smokers were 0.55 (n = 20), 0.94 (n = 12), and 4.91 pmol/ml (n = 12), respectively. Multiple linear regression showed significant differences between subjects in different PAH exposure with increased concentrations of 1-OHPG in urine. Amounts of foods containing PAHs ingested by this group of workers were relatively low and did not contribute significantly to urinary 1-OHPG concentrations. These results indicate that 1-OHPG is a common urinary metabolite in people with recent occupational exposure to PAHs and is associated with both job category and estimated stratum of PAH exposure.


Differential transcriptional response following glucocorticoid activation in cultured blood immune cells: a novel approach to PTSD biomarker development.
Post-traumatic stress disorder (PTSD) is a condition of stress reactivity, whose clinical manifestations are evident when patients are triggered following exposure to a traumatic event. While baseline differences in gene expression of glucocorticoid signaling and inflammatory cytokines in peripheral blood mononuclear cells (PBMCs) have been associated with PTSD, these alterations do not fully recapitulate the molecular response to physiological triggers, such as stress hormones. Therefore, it is critical to develop new techniques that will capture the dynamic transcriptional response associated with stress-activated conditions relative to baseline conditions. To achieve this goal, cultured PBMCs from combat-exposed veterans with PTSD(+) (n = 10) and without PTSD(-) (n = 10) were incubated with increasing concentrations (vehicle, 2.5 nM, 5 nM, 50 nM) of dexamethasone (DEX). Across diagnosis and dosage, several genes and gene networks were reliable markers of glucocorticoid stimulation (FDR < 5%), including enhanced expression of FKPB5, VIPR1, NR1I3, and apoptosis-related pathways, and reduced expression of NR3C1, STAT1, IRF1, and related inflammatory and cellular stress-responsive pathways. Dose-dependent differential transcriptional changes in several genes were also identified between PTSD+ and PTSD-. Robust changes in expression were observed at 2.5 nM DEX in PTSD- but not PTSD+ participants; whereas, with increasing concentrations (5 nM and 50 nM), several genes were identified to be uniquely up-regulated in PTSD+ but not PTSD- participants. Collectively, these preliminary findings suggest that genome-wide gene expression profiling of DEX-stimulated PBMCs is a promising method for the exploration of the dynamic differential molecular responses to stress hormones in PTSD, and may identify novel markers of altered glucocorticoid signaling and responsivity in PTSD.


The role of immunohistochemistry in the differential diagnosis of papillary lesions of the breast.
Papillary lesions of the breast represent a heterogeneous group with differing biological behaviour. Correct diagnosis is crucial but may be difficult, as many benign and malignant papillary lesions have similar appearances. Immunohistochemistry plays a useful role in their differentiation. Myoepithelial markers can help in differentiating papilloma from papillary carcinoma, as the former usually shows a continuous layer of myoepithelial cells. In intracystic papillary carcinoma, there is controversy as to the presence of a complete myoepithelial cell layer around these lesions. p63 is the marker of choice as the staining is nuclear, cross-reactivity is minimal, and sensitivity is high. Papilloma may frequently be complicated by superimposed different types of epithelial hyperplasia, which range from usual to atypical or even ductal carcinoma in situ, and they many be morphologically similar. Basal cytokeratins (CKs) are useful to differentiate these entities; as usual hyperplasia is positive for basal CKs with a mosaic staining pattern. CK5/6 is probably the best marker. Neuroendocrine markers (chromogranin A and synaptophysin) may be positive in papillary carcinoma, particularly in the solid type, and there may be some overlap with the ductal carcinoma in situ with spindle cells or endocrine ductal carcinoma in situ. A panel of CK5/6, p63 and neuroendocrine markers can be useful in the diagnostic investigation of problematic papillary lesions of the breast. As the experience with these markers remains rather limited, it is too early to recommend basing treatment choices on these marker studies alone. Complete removal of lesion is probably still the treatment of choice.


DRUG-INDUCED CHANGES IN THE LIVER ENDOPLASMIC RETICULUM: ASSOCIATION WITH DRUG-METABOLIZING ENZYMES.
The cellular changes which lead to the increase of drug-metabolizing enzymes following drug administration are explained by correlating new biochemical data with previously reported electron microscopic and pharmacologic observations. Repeated administration of phenobarbital and several other drugs results in a quantitative increase of the smooth endoplasmic reticulum of the liver cell. The marked increase in drug-metabolizing enzymes is found to occur in this enlarged smooth membrane fraction of the endoplasmic reticulum.


Law, ethics, and the patient preference predictor.
The Patient Preference Predictor (PPP) is intended to improve treatment decision making for incapacitated patients. The PPP would collect information about the treatment preferences of people with different demographic and other characteristics. It could be used to indicate which treatment option an individual patient would be most likely to prefer, based on data about the preferences of people who resemble the patient. The PPP could be incorporated into existing US law governing treatment for incapacitated patients, although it is unclear whether it would be classified as evidence of a specific patient's preferences or those of a reasonable person sharing certain characteristics with the patient. Ethical concerns about the quality and significance of PPP choices could influence legal decision makers' views of the PPP.


Collective stresses drive competition between monolayers of normal and Ras-transformed cells.
We study the competition for space between two cell lines that differ only in the expression of the Ras oncogene. The two cell populations are initially separated and set to migrate antagonistically towards an in-between stripe of free substrate. After contact, their interface moves towards the population of normal cells. We interpret the velocity and traction force data taken before and after contact thanks to a hydrodynamic description of collectively migrating cohesive cell sheets. The kinematics of cells, before and after contact, allows us to estimate the relative material parameters for both cell lines. As predicted by the model, the transformed cell population with larger collective stresses pushes the wild type cell population.


Indoor air pollution and lung function growth among children in four Chinese cities.
Ambient air pollution has been associated with decreased growth in lung function among children; but little is known about the impact of indoor air pollution. We examined relationships between indoor air pollution metrics and lung function growth, among children (n = 3273) aged 6-13 years living in four Chinese cities. Lung function parameters (FVC and FEV(1) ) were measured twice a year. Questionnaires were used to determine home coal burning and ventilation practices. Generalized estimating equations were used to examine associations. Use of coal as a household fuel was associated with 16.5 ml/year lower (33%, P < 0.001) and 20.5 ml/year lower (39%, P < 0.001) growth in children's FEV(1) and FVC, respectively. FEV(1) growth was 10.2 ml/year higher (20%, P = 0.009), and FVC growth was 17.0 ml/year higher (33%, P < 0.001) among children who lived in houses with the presence of a ventilation device. Among children living in houses where coal was used as a fuel and no ventilation devices were present, adjusted FVC and FEV(1) growth, respectively, were 37% and 61% that of the average growth per year in the full cohort. This suggests that household coal use may cause deficits in lung function growth, while using ventilation devices may be protective of lung development. Nearly 3.4 billion people use solid fuels in homes for cooking and/or heating. We report the following findings from a longitudinal study: (i) household coal use is significantly associated with reduction in children's lung function growth and (ii) the use of household ventilation devices is significantly associated with higher lung function growth, particularly among children living in households where coal is used as a fuel. These findings not only provide evidence that indoor coal use impairs children's lung development but also point to the importance of improving ventilation conditions in reducing harmful effects of indoor air pollution sources.


Spontaneous Bacterial Peritonitis and Anasarca in a Female Patient with Ovarian Hyperstimulation Syndrome Complicated by Respiratory and Kidney Failure.
Ovarian hyperstimulation syndrome (OHSS) was first described in 1960. It may occur as a complication of gonadotropin hormone therapy during assisted pregnancy or for primary infertility. A 26-year-old female patient with polycystic ovarian syndrome and primary infertility was treated to conceive. She received intravenous gonadotropin-releasing hormone (GnRH) along with follicle-stimulating hormone in an outside private clinic. She presented to the emergency department with abdominal and chest pain, loose stool, vomiting, shortness of breath and decreasing urine output. She was found to have edema, ascites, effusion and acute kidney injury (AKI). Considering the symptoms preceding the drug history and anasarca, a diagnosis of severe OHSS was made. Ascites was further complicated by spontaneous bacterial peritonitis (SBP), which had already been reported before. We speculate that low immunity due to decreased immunoglobulin in patients with OHSS makes them prone to SBP. In our case, septicemia secondary to SBP and fluid loss due to capillary leakage from OHSS resulted in AKI and respiratory failure. This critically ill patient was treated in a special care unit, and she fully recovered with supportive measures. Severe OHSS may present as anasarca including ascites which can develop SBP leading to sepsis and multiorgan failure.


Targeting the underserved for breast and cervical cancer screening: the utility of ecological analysis using the National Health Interview Survey.
This study tested the utility of ecological variables created from the National Health Interview Survey (NHIS) for strategic targeting of health services for the underserved. Ecological variables were created using the 1989-1991 survey years of the NHIS public use data files. Segments, the NHIS secondary sampling units, permit computation of secondary sampling characteristics by percentage Black, percentage Hispanic, percentage below poverty, percentage unemployed, median education, median income, median age, and percentage residing in the United States for 5 years or less. These variables were analyzed with the NHIS Health Promotion and Disease Prevention 1990 supplement reporting mammogram, clinical breast examination, and Pap test use. Median education of areas was inversely related to never having mammograms. Areas with a high proportion (70%-100%) of Hispanic respondents also were more likely not to have mammograms. Women residing in areas with moderate or high proportions of Hispanic respondents were more likely never to have clinical breast examinations and Pap tests, as were those in areas with low income, poverty, and respondents who had resided in the United States 5 years or less. The new methodology of constructing ecological variables using the NHIS demonstrates an application that may help identify underserved areas or areas with underutilized services. More studies using this methodology are warranted.


A noise-reduction GWAS analysis implicates altered regulation of neurite outgrowth and guidance in autism.
Genome-wide Association Studies (GWAS) have proved invaluable for the identification of disease susceptibility genes. However, the prioritization of candidate genes and regions for follow-up studies often proves difficult due to false-positive associations caused by statistical noise and multiple-testing. In order to address this issue, we propose the novel GWAS noise reduction (GWAS-NR) method as a way to increase the power to detect true associations in GWAS, particularly in complex diseases such as autism. GWAS-NR utilizes a linear filter to identify genomic regions demonstrating correlation among association signals in multiple datasets. We used computer simulations to assess the ability of GWAS-NR to detect association against the commonly used joint analysis and Fisher's methods. Furthermore, we applied GWAS-NR to a family-based autism GWAS of 597 families and a second existing autism GWAS of 696 families from the Autism Genetic Resource Exchange (AGRE) to arrive at a compendium of autism candidate genes. These genes were manually annotated and classified by a literature review and functional grouping in order to reveal biological pathways which might contribute to autism aetiology. Computer simulations indicate that GWAS-NR achieves a significantly higher classification rate for true positive association signals than either the joint analysis or Fisher's methods and that it can also achieve this when there is imperfect marker overlap across datasets or when the closest disease-related polymorphism is not directly typed. In two autism datasets, GWAS-NR analysis resulted in 1535 significant linkage disequilibrium (LD) blocks overlapping 431 unique reference sequencing (RefSeq) genes. Moreover, we identified the nearest RefSeq gene to the non-gene overlapping LD blocks, producing a final candidate set of 860 genes. Functional categorization of these implicated genes indicates that a significant proportion of them cooperate in a coherent pathway that regulates the directional protrusion of axons and dendrites to their appropriate synaptic targets. As statistical noise is likely to particularly affect studies of complex disorders, where genetic heterogeneity or interaction between genes may confound the ability to detect association, GWAS-NR offers a powerful method for prioritizing regions for follow-up studies. Applying this method to autism datasets, GWAS-NR analysis indicates that a large subset of genes involved in the outgrowth and guidance of axons and dendrites is implicated in the aetiology of autism.


Improved Microassays Used to Test Natural Product-Based and Conventional Fungicides on Plant Pathogenic Fungi.
Seven important plant pathogenic fungi (Botrytis cinerea, Colletotrichum acutatum, C. fragariae, C. gloeosporioides, Fusarium oxysporum, Phomopsis obscurans, and P. viticola) valuable in screening fungicides were tested. Our procedure included washing conidia to reduce germination times, incorporating Roswell Park Memorial Institute 1640 as a medium of known composition, and using coverslips in the 24-well cell culture clusters to document the effect of fungicides on fungal morphology. The natural product-based fungicide, sampangine, a sampangine analog, 4-bromosampangine, plus seven conventional fungicides (benomyl, captan, cyprodinil, fenbuconazole, fenhexamid, iprodione, and kresoxim-methyl) were tested in vitro for their ability to inhibit germination and growth of the seven fungal species. Sampangine inhibited germination in all fungi except C. acutatum. Comparison of results of germination and morphology microbioassays with results of microtiter assays suggests that some fungicides stop fungal germination, whereas others only slow down fungal growth. We hypothesize that sampangine, except against C. acutatum, has the same physical mode of action, germination inhibition, as the conventional fungicides captan, iprodione, and kresoxim-methyl. 4-Bromosampangine caused morphological anomalies including excessive branching of germ tubes of C. fragariae and splaying and branching of germ tubes of B. cinerea.


Switchable Catalysis Improves the Properties of CO2-Derived Polymers: Poly(cyclohexene carbonate-b-ε-decalactone-b-cyclohexene carbonate) Adhesives, Elastomers, and Toughened Plastics.
Carbon dioxide/epoxide copolymerization is an efficient way to add value to waste CO2 and to reduce pollution in polymer manufacturing. Using this process to make low molar mass polycarbonate polyols is a commercially relevant route to new thermosets and polyurethanes. In contrast, high molar mass polycarbonates, produced from CO2, generally under-deliver in terms of properties, and one of the most widely investigated, poly(cyclohexene carbonate), is limited by its low elongation at break and high brittleness. Here, a new catalytic polymerization process is reported that selectively and efficiently yields degradable ABA-block polymers, incorporating 6-23 wt % CO2. The polymers are synthesized using a new, highly active organometallic heterodinuclear Zn(II)/Mg(II) catalyst applied in a one-pot procedure together with biobased ε-decalactone, cyclohexene oxide, and carbon dioxide to make a series of poly(cyclohexene carbonate-b-decalactone-b-cyclohexene carbonate) [PCHC-PDL-PCHC]. The process is highly selective (CO2 selectivity >99% of theoretical value), allows for high monomer conversions (>90%), and yields polymers with predictable compositions, molar mass (from 38-71 kg mol-1), and forms dihydroxyl telechelic chains. These new materials improve upon the properties of poly(cyclohexene carbonate) and, specifically, they show good thermal stability (Td,5 ∼ 280 °C), high toughness (112 MJ m-3), and very high elongation at break (>900%). Materials properties are improved by precisely controlling both the quantity and location of carbon dioxide in the polymer chain. Preliminary studies show that polymers are stable in aqueous environments at room temperature over months, but they are rapidly degraded upon gentle heating in an acidic environment (60 °C, toluene, p-toluene sulfonic acid). The process is likely generally applicable to many other lactones, lactides, anhydrides, epoxides, and heterocumulenes and sets the scene for a host of new applications for CO2-derived polymers.


A scoping review of home-produced heroin and amphetamine-type stimulant substitutes: implications for prevention, treatment, and policy.
Several home-produced substances such as krokodil and boltushka are prevalent in many Eastern European countries. Anecdotal reports of its use have been circulating in Germany and Norway; however, this has not been confirmed. Its use has also been reported by the media in the USA, although only one confirmed report of its use exists. Home-produced drugs are associated with high levels of morbidity and a number of complex health issues such as the spread of blood borne viruses, gangrene, and internal organ damage. The high incidence of HIV rates amongst people who inject home-produced substances is a public health concern. The resulting physical health consequences of injecting these crude substances are very severe in comparison to heroin or amphetamine acquired in black markets. Due to this fact and the increased mortality associated with these substances, professionals in the area of prevention, treatment, and policy development need to be cognisant of the presentation, harms, and the dangers associated with home-produced substances globally. This scoping review aimed to examine existing literature on the subject of home-produced heroin and amphetamine-type stimulant substitutes. The review discussed the many implications such research may have in the areas of policy and practice. Data were gathered through the use of qualitative secondary resources such as journal articles, reports, reviews, case studies, and media reports. The home production of these substances relies on the utilisation of precursor drugs such as less potent stimulants, tranquillizers, analgesics, and sedatives or natural plant ingredients. The Internet underpins the facilitation of this practice as recipes, and diverted pharmaceutical sales are available widely online, and currently, ease of access to the Internet is evident worldwide. This review highlights the necessity of prevention, education, and also harm reduction related to home-produced drugs and also recommends consistent monitoring of online drug fora, online drug marketplaces, and unregulated pharmacies.


glbase: a framework for combining, analyzing and displaying heterogeneous genomic and high-throughput sequencing data.
Genomic datasets and the tools to analyze them have proliferated at an astonishing rate. However, such tools are often poorly integrated with each other: each program typically produces its own custom output in a variety of non-standard file formats. Here we present glbase, a framework that uses a flexible set of descriptors that can quickly parse non-binary data files. glbase includes many functions to intersect two lists of data, including operations on genomic interval data and support for the efficient random access to huge genomic data files. Many glbase functions can produce graphical outputs, including scatter plots, heatmaps, boxplots and other common analytical displays of high-throughput data such as RNA-seq, ChIP-seq and microarray expression data. glbase is designed to rapidly bring biological data into a Python-based analytical environment to facilitate analysis and data processing. In summary, glbase is a flexible and multifunctional toolkit that allows the combination and analysis of high-throughput data (especially next-generation sequencing and genome-wide data), and which has been instrumental in the analysis of complex data sets. glbase is freely available at http://bitbucket.org/oaxiom/glbase/.


Monitoring enzyme replacement therapy in Fabry disease--role of urine globotriaosylceramide.
Anderson-Fabry disease (referred to as Fabry disease) is an X-linked disorder characterized by a deficiency of the lysosomal enzyme alpha-galactosidase A and the subsequent accumulation in various tissues of globotriaosylceramide (Gb(3)), the main substrate of the defective enzyme. Enzyme replacement therapy (ERT) offers a specific treatment for patients with Fabry disease, though monitoring of treatment is hampered by a lack of surrogate markers of response. In this study, the efficacy of long-term ERT in six Fabry hemizygotes and two symptomatic heterozygotes has been evaluated. Patients were administered recombinant alpha-galactosidase A every 2 weeks for up to a year. The efficacy of ERT was assessed by monitoring symptomatology and renal function. Urinary glycolipid concentration was estimated by a novel tandem mass spectrometric method. Urine glycolipid (Gb(3)) was elevated at baseline and fell impressively on ERT where patients were hemizygotes and in the absence of renal transplantation. In heterozygotes and in a recipient of a renal allograft, elevations and changes in urine glycolipids were less pronounced. In one patient, after several months of ERT, there was a transient increase in Gb(3) concentrations to baseline (pre-ERT) levels, associated with the presence of antibodies to the recombinant alpha-galactosidase A. The marked decline in urine Gb(3) on ERT, and its subsequent increase in association with an inhibitory antibody response, suggest that this analyte deserves further investigation as a potential marker of disease severity and response to treatment.