bluuebunny/crossref_metadata_2025 huggingface dataset:
Characteristics of executive control network function based on a lateralized version of the ANT-R test in athletes from open skill sports: An fNIRS study
Authors: Yu Miao , Liu Yi B. , Yang Guang
Published: February 2019

The purpose of the study was to investigate the executive control network function characteristics of interceptive and strategic sports athletes from open skill sports. In order to do so, we used a revised lateralized attention network task to measure executive control efficiency and activation related to flanker interference changes on the right frontoparietal network using functional near-infrared spectroscopy in athletes from different sport sub-categories. Strategic athletes had higher accuracy and lower flanker conflict effects on accuracy, as well as longer reaction time and stronger conflict effects under the valid cue and invalid cue conditions. This was accompanied by higher activity in the right inferior frontal gyrus. These results extend the evidence suggesting that differences among interceptive sports and strategic sports athletes are due to the former using higher velocities to solve conflicts, and the latter using higher accuracy in the same tasks. These effects are attributed to differences in the right frontoparietal network.
PKA and HOG signaling contribute separable roles to anaerobic xylose fermentation in yeast engineered for biofuel production
Authors: Wagner Ellen R. , Myers Kevin S. , Riley Nicholas M. , Coon Joshua J. , Gasch Audrey P.
Published: February 2019

Lignocellulosic biomass offers a sustainable source for biofuel production that does not compete with food-based cropping systems. Importantly, two critical bottlenecks prevent economic adoption: many industrially relevant microorganisms cannot ferment pentose sugars prevalent in lignocellulosic medium, leaving a significant amount of carbon unutilized. Furthermore, chemical biomass pretreatment required to release fermentable sugars generates a variety of toxins, which inhibit microbial growth and metabolism, specifically limiting pentose utilization in engineered strains. Here we dissected genetic determinants of anaerobic xylose fermentation and stress tolerance in chemically pretreated corn stover biomass, called hydrolysate. We previously revealed that loss-of-function mutations in the stress-responsive MAP kinaseHOG1and negative regulator of the RAS/Protein Kinase A (PKA) pathway,IRA2, enhances anaerobic xylose fermentation. However, these mutations likely reduce cells’ ability to tolerate the toxins present in lignocellulosic hydrolysate, making the strain especially vulnerable to it. We tested the contributions of Hog1 and PKA signaling via IRA2 or PKA negative regulatory subunit BCY1 to metabolism, growth, and stress tolerance in corn stover hydrolysate and laboratory medium with mixed sugars. We found mutations causing upregulated PKA activity increase growth rate and glucose consumption in various media but do not have a specific impact on xylose fermentation. In contrast, mutation ofHOG1specifically increased xylose usage. We hypothesized improving stress tolerance would enhance the rate of xylose consumption in hydrolysate. Surprisingly, increasing stress tolerance did not augment xylose fermentation in lignocellulosic medium in this strain background, suggesting other mechanisms besides cellular stress limit this strain’s ability for anaerobic xylose fermentation in hydrolysate.
TIMP-1 attenuates the development of cutaneous inflammation-induced evoked and ongoing pain through receptor-mediated cell signaling
Authors: B.E. Knight , N. Kozlowski , J. Havelin , T. King , S.J. Crocker , E.E. Young , K.M. Baumbauer
Published: February 2019

Unresolved inflammation is a significant predictor for developing chronic pain, and targeting the mechanisms underlying inflammation offers opportunities for therapeutic intervention. During inflammation, matrix metalloproteinase (MMP) activity contributes to tissue remodeling and inflammatory signaling through proteolytic maturation of cytokines. MMP activity is regulated by tissue inhibitors of metalloproteinases (TIMPs) 1-4. TIMP-1 and −2 have known roles in pain, but only in the context of MMP inhibition. However, TIMP-1 also has receptor-mediated cell signaling functions that are not well understood. Here, we examined how TIMP-1-dependent cell signaling impacted inflammatory hypersensitivity and ongoing pain. We found that hindpaw injection of complete Freund’s adjuvant (CFA) increased keratinocyte-derived TIMP-1 that peaked 3 days following inflammation, when mechanical hypersensitivity began to emerge in WT mice. These data suggest that TIMP-1 expression inhibits the development of inflammatory hypersensitivity. To examine this possibility, we injected TIMP-1 knockout (T1KO) mice with a diluted CFA mixture to examine how subtle cutaneous inflammation affected behavioral hypersensitivity. T1KO mice exhibited rapid onset thermal and mechanical hypersensitivity at the site of inflammation that was absent or attenuated in WT controls. We also found that T1KO mice exhibited hypersensitivity in adjacent tissues innervated by different sets of afferents, and skin contralateral to the site of inflammation. Replacement of recombinant murine (rm)TIMP-1 alleviated hypersensitivity when administered at the site and time of inflammation. To examine the MMP-dependent and -independent mechanisms of rmTIMP-1, T1KO mice were administered full-length rmTIMP-1, the N-terminal region (TIMP-1(N)) with MMP-inhibitory properties, or the C-terminal region (TIMP-1(C)) that retains receptor signaling function. Each of the peptides prevented inflammatory hypersensitivity, suggesting that rmTIMP-1 acts through mechanisms that also include receptor-mediated cell signaling. We also found that hypersensitivity was neither due to genotype-specific differences in MMP-9 activity or expression, nor to differences in cytokine expression. Finally, to evaluate the potential clinical utility of TIMP-1, we administered rmTIMP-1 to WT mice and found that rmTIMP-1 prevented clonidine-induced conditioned place preference (e.g., ongoing pain) and inflammatory mechanical hypersensitivity. Collectively, our data suggest a novel role for TIMP-1 in the attenuation of inflammatory pain that occurs through previously uncharacterized cell signaling mechanisms.
Oligogenic effects of 16p11.2 copy number variation on craniofacial development
Authors: Qiu Yuqi , Arbogast Thomas , Lorenzo Sandra Martin , Li Honying , Tang Shih C. , Richardson Ellen , Hong Oanh , Cho Shawn , Shanta Omar , Pang Timothy , Corsello Christina , Deutsch Curtis K. , Chevalier Claire , Davis Erica E. , Iakoucheva Lilia M. , Herault Yann , Katsanis Nicholas , Messer Karen , Sebat Jonathan
Published: February 2019

A copy number variant (CNV) of 16p11.2, which encompasses 30 genes, is associated with developmental and psychiatric disorders, head size and body mass. The genetic mechanisms that underlie these associations are not understood. To elucidate the effects of genes on development, we exploited the quantitative effects of CNV on craniofacial structure in humans and model organisms. We show that reciprocal deletion and duplication of 16p11.2 have characteristic “mirror” effects on craniofacial features that are conserved in human, rat and mouse. By testing gene dosage effects on the shape of the mandible in zebrafish, we show that the distribution of effects for all individual genes is consistent with that of the CNV, and some combinations have non-additive effects. Our results suggest that, at minimum, one third of genes within the 16p11.2 region influence craniofacial development, and the facial gestalt of each CNV represents a product of 30 dosage effects.

Highlights

Reciprocal CNVs of 16p11.2 have mirror effects on craniofacial structure. Copy number is associated with a positive effect on nasal and mandibular regions and a negative effect on frontal regions of the face.

Effects of CNV on craniofacial development in human are well conserved in rat and mouse models of 16p11.2 deletion and duplication.

7/30 genes each independently have significant effects on the shape of the mandible in zebrafish; these include SPN, C16orf54, SEZ6L2, ASPHD1, TAOK2, INO80E and FAM57B. Others (MAPK3, MVP, KCTD13) have detectable effects only in combination.

Overexpression of 30 genes individually showed a distribution of effects that was skewed in the same direction as that of the full duplication, suggesting that specific facial features represent the net of all individual effects combined.
Control ofϕC31 integrase-mediated site-specific recombination by protein trans splicing
Authors: Olorunniji Femi J. , Lawson-Williams Makeba , McPherson Arlene L. , Paget Jane E. , Marshall Stark W. , Rosser Susan J.
Published: February 2019

Serine integrases are emerging as core tools in synthetic biology and have applications in biotechnology and genome engineering. We have designed a split-intein serine integrase-based system for rapid regulation of site-specific recombination eventsin vivo.TheφC31integrase was split into two extein domains, and intein sequences(NpuDnaENandSspDnaEC) were attached to the two termini to be fused. Expression of these two components followed by post-translational proteintrans-splicinginE. coligenerated a fully functionalφC31integrase. Protein splicing is necessary for recombination activity; no activity was observed when theφC31 integrase N-and C-terminal extein domains without the intein sequences were co-expressed, nor when a key intein catalytic residue was mutated. As a proof of principle, we used a bistable switch based on an invertible promoter reporter system to demonstrate a potential application of the split intein-regulated site-specific recombination system. We usedaraCandtetinducible promoters to regulate the expression of the two parts of the split recombinase. Inversion of a DNA segment containing a constitutive promoter, catalyzed bytrans-spliced integrase, switches between RFP and GFP expression only when both inducible promoters are ON. We used the same split inteins to regulate the reconstitution of a split integrase-RDF fusion that efficiently catalyzed the reverseattRxattLrecombination, demonstrating that our split-intein regulated recombination system can function as a reversible AND gate in which the forward reaction is catalyzed by the integrase, and the reverse reaction by the integrase-RDF fusion. The split-intein integrase is a potentially versatile, regulatable component for building synthetic genetic circuits and devices.
Comparative analysis of commercially available single-cell RNA sequencing platforms for their performance in complex human tissues
Authors: Wang Yue J. , Schug Jonathan , Lin Jerome , Wang Zhiping , Kossenkov Andrew ,   the HPAP Consortium, Kaestner Klaus H.
Published: February 2019

The past five years have witnessed a tremendous growth of single-cell RNA-seq methodologies. Currently, there are three major commercial platforms for single-cell RNA-seq: Fluidigm C1, Clontech iCell8 (formerly Wafergen) and 10x Genomics Chromium. Here, we provide a systematic comparison of the throughput, sensitivity, cost and other performance statistics for these three platforms using single cells from primary human islets. The primary human islets represent a complex biological system where multiple cell types coexist, with varying cellular abundance, diverse transcriptomic profiles and differing total RNA contents. We apply standard pipelines optimized for each system to derive gene expression matrices. We further evaluate the performance of each system by benchmarking single-cell data with bulk RNA-seq data from sorted cell fractions. Our analyses can be generalized to a variety of complex biological systems and serve as a guide to newcomers to the field of single-cell RNA-seq when selecting platforms.
Graph-to-Signal Transformation Based Classification of Functional Connectivity Brain Networks
Authors: Munia Tamanna T. K. , Aviyente Selin
Published: February 2019

Complex network theory has been successful at unveiling the topology of the brain and showing alterations to the network structure due to brain disease, cognitive function and behavior. Functional connectivity networks (FCNs) represent different brain regions as the nodes and the connectivity between them as the edges of a graph. Graph theoretic measures provide a way to extract features from these networks enabling subsequent characterization and discrimination of networks across conditions. However, these measures are constrained mostly to binary networks and highly dependent on the network size. In this paper, we propose a novel graph-to-signal transform that overcomes these shortcomings to extract features from functional connectivity networks. The proposed transformation is based on classical multidimensional scaling (CMDS) theory and transforms a graph into signals such that the Euclidean distance between the nodes of the network is preserved. In this paper, we propose to use the resistance distance matrix for transforming weighted functional connectivity networks into signals. Our results illustrate how well-known network structures transform into distinct signals using the proposed graph-to-signal transformation. We then compute well-known signal features on the extracted graph signals to discriminate between FCNs constructed across different experimental conditions. Based on our results, the signals obtained from the graph-to-signal transformation allow for the characterization of functional connectivity networks, and the corresponding features are more discriminative compared to graph theoretic measures.
The seasonality of diarrheal pathogens: A retrospective study of seven sites over three years
Authors: Chao Dennis L. , Roose Anna , Roh Min , Kotloff Karen L. , Proctor Joshua L.
Published: February 2019

Background

Pediatric diarrhea can be caused by a wide variety of pathogens, from bacteria to viruses to protozoa. Pathogen prevalence is often described as seasonal, peaking annually and associated with specific weather conditions. Although many studies have described the seasonality of diarrheal disease, these studies have occurred predominantly in temperate regions. In tropical and resource-constrained settings, where nearly all diarrhea-associated mortality occurs, the seasonality of many diarrheal pathogens has not been well characterized. As a retrospective study, we analyze the seasonal prevalence of diarrheal pathogens among children with moderate-to-severe diarrhea (MSD) over three years from the seven sites of the Global Enteric Multicenter Study (GEMS), a case–control study. Using data from this expansive study on diarrheal disease, we characterize the seasonality of different pathogens, their association with site-specific weather patterns, and consistency across study sites.

Methodology/Principal Findings

Using traditional methodologies from signal processing, we found that certain pathogens peaked at the same time every year, but not at all sites. We also found associations between pathogen prevalence and weather or “seasons”, which are defined by applying modern machine-learning methodologies to site-specific weather data. In general, rotavirus was most prevalent during the drier “winter” months and out of phase with bacterial pathogens, which peaked during hotter and rainier times of year corresponding to “monsoon”, “rainy”, or “summer” seasons.

Conclusions/Significance

Identifying the seasonally-dependent prevalence for diarrheal pathogens helps characterize the local epidemiology and inform the clinical diagnosis of symptomatic children. Our multi-site, multi-continent study indicates a complex epidemiology of pathogens that does not reveal an easy generalization that is consistent across all sites. Instead, our study indicates the necessity of local data to characterizing the epidemiology of diarrheal disease. Recognition of the local associations between weather conditions and pathogen prevalence suggests transmission pathways and could inform control strategies in these settings.
Crystal structure of a host–guest complex of the tris-urea receptor, 3-(4-nitrophenyl)-1,1-bis{2-[3-(4-nitrophenyl)ureido]ethyl}urea, that encapsulates hydrogen-bonded chains of dihydrogen phosphate anions with separate tetra-n-butylammonium counter-ions
Authors: Wang Ruyu , Shu Xi , Fan Yu , Li Shoujian , Jin Yongdong , Xia Chuanqin , Huang Chao
Published: February 2019

The title compound, C25H25N9O9·C16H36N+·H2PO4
− (I) or (C25H25N9O9)·(n-Bu4N+)·(H2PO4
−) (systematic name: 3-(4-nitrophenyl)-1,1-bis{2-[3-(4-nitrophenyl)ureido]ethyl}urea tetrabutylammonium dihydrogen phosphate), comprises a tris-urea receptor (R), a dihydrogen phosphate anion and a tetra-n-butylammonium cation. It crystallizes with two independent formula units in the asymmetric unit. The conformations of the two tris-urea receptors are stabilized by N—H...O and C—H...O intramolecular hydrogen bonds. Each dihydrogen phosphate anion has two O—H...O intermolecular hydrogen-bonding interactions with the other dihydrogen phosphate anion. Inversion-related di-anion units are linked by further O—H...O hydrogen bonds, forming a chain propagating along the a-axis direction. Each dihydrogen phosphate anion makes a total of four N—H...O(H2PO4
−) hydrogen bonds with two ureido subunits from two different tris-urea receptors, hence each tris-urea receptor provides the two ureido subunits for the encapsulation of the H2PO4
− hydrogen-bonded chain. There are numerous intermolecular C—H...O hydrogen bonds present involving both receptor molecules and the tetra-n-butylammonium cations, so forming a supramolecular three-dimensional structure. One of the butyl groups and one of the nitro groups are disordered over two positions of equal occupancy.
Varied responses to and efficacies of hydroxychloroquine treatment according to cutaneous lupus erythematosus subtypes in Japanese patients
Authors: Ototake Yasushi , Yamaguchi Yukie , Kanaoka Miwa , Akita Asami , Ikeda Nobuaki , Aihara Michiko
Published: February 2019

Hydroxychloroquine is recommended as the first‐line systemic treatment for cutaneous lupus erythematosus (CLE) in Western countries, and it was approved in Japan in 2016. However, the efficacy of hydroxychloroquine in various cutaneous lupus erythematosus subtypes in Japanese patients has not been elucidated to date. Therefore, we investigated the efficacy of hydroxychloroquine for the treatment of cutaneous manifestations according to CLE subtypes in Japanese patients. We enrolled 35 patients (29 diagnosed with systemic lupus erythematosus and six with CLE) in this retrospective study. We analyzed the efficacy of hydroxychloroquine for the treatment of cutaneous manifestations according to cutaneous lupus erythematosus subtypes, time to the first skin improvement, as well as effects on laboratory data and reduction of concomitant immunosuppressive drug administration at 16 and 32 weeks of therapy. Complete improvement was observed at high rates for acute CLE (ACLE); however, partial or non‐improvement rates were higher for chronic CLE (CCLE) at 16 weeks. Several patients with alopecia without scarring achieved complete improvement at 32 weeks. CCLE tended to take more time to improve than ACLE. Overall, hydroxychloroquine was highly effective for skin: 87% of patients had at least some beneficial response at 16 weeks. Nevertheless, there were wide variations in complete improvement rates and duration for improvement among CLE subtypes. Our findings suggest that a therapeutic approach considering the subtypes of CLE will improve its management.
Methenamine's journey of 160 years: Repurposal of an old urinary antiseptic for treatment and hypoxic radiosensitization of cancers and glioblastoma
Authors: Altinoz Meric A. , Ozpinar Aysel , Ozpinar Alp , Perez Jennifer L. , Elmaci İlhan
Published: February 2019

Methenamine (hexamethylenetetramine, hexamine, urotropine) is a compound discovered in 1859, which is still currently being used as a urinary antiseptic. Methenamine is highly soluble in water and polar solvents, and its molecular constitution is similar to adamantane compounds with tetrahedral cage like structure. In acidic conditions, methenamine decomposes to formaldehyde and ammonia. Recently, methenamine has gained a renewal of interest due to antibiotic‐resistant bacteria urinary tract infections; interestingly, bacteria cannot gain resistance to formaldehyde. In 1968, David and Burkitt reported remarkable regression of four Burkitt Lymphoma patients in eight subjects who were treated with septicemine (a solution containing 6.3 g of methenamine iodomethylate and 1 g of methenamine sodium benzoate in 100 cc distilled water). Unfortunately, these striking observations did not gain interest in the medical community; despite experimental models that showed that methenamine synergized with hyperthermia, radiation, and chemotherapy to block cancer growth. As the hypoxic core of tumours have an acidic pH, it would be plausible to expect that methenamine would selectively target dormant, non‐proliferative, and treatment‐resistant cancer clones in large tumours. Moreover, previous data suggests that methenamine can be safely used intravenously and for treatment of infections of the central nervous system. It may therefore be an effective adjuvant in treatment of systemic cancers and glioblastoma.
Dim artificial light at night reduces the cellular immune response of the black field cricket, Teleogryllus commodus
Authors: Durrant Joanna , Green Mark P. , Jones Therésa M.
Published: February 2019

A functioning immune system is crucial for protection against disease and illness, yet increasing evidence suggests that species living in urban areas could be suffering from immune suppression, due to the presence of artificial light at night (ALAN). This study examined the effects of ecologically relevant levels of ALAN on three key measures of immune function (haemocyte concentration, lytic activity, and phenoloxidase activity) using a model invertebrate species, the Australian black field cricket, Teleogryllus commodus. We reared crickets under an ecologically relevant daily light‐cycle consisting of 12 hr bright daylight (2600 lx) followed by either 12 h darkness (0 lx) or dim environmentally relevant ALAN (1, 10, 100 lx), and then assessed immune function at multiple time points throughout adult life using haemolymph samples. We found that the presence of ALAN had a clear negative effect on haemocytes, while the effects on lytic activity and phenoloxidase activity were more complex or largely unaffected by ALAN. Furthermore, the effects of lifelong exposure to ALAN of 1 lx were comparable to those of 10 and 100 lx. Our data suggest that the effects of ALAN could be large and widespread, and such reductions in the core immune response of individuals will likely have greater consequences for fitness and survival under more malign conditions, such as those of the natural environment.
Contouring experiences amongst Australian, New Zealand and Singaporean radiation oncology trainees. Is it enough? What next?
Authors: Leung John , Lehman Margot
Published: February 2019

Introduction

This paper reports the key findings of the first survey of Australian, New Zealand (ANZ) and Singaporean radiation oncology trainees on contouring and planning.

Methods

The survey was conducted from May to July 2018 using a 35‐question instrument. It was emailed to all ANZ and Singaporean trainees on the Royal Australian and New Zealand College of Radiologists (RANZCR) database with at least 6 months experience. The questions related to demographics, time spent on contouring, most difficult sites to contour, most useful atlas, feedback on contouring, interaction with radiation therapists, plan reviews, stereotactic radiation therapy (SBRT), brachytherapy and suggested areas of improvement. Respondents were assured that their responses were anonymous.

Results

The response rate was 50% (54/108). Most respondents were from New South Wales (31%) with nearly all working full time (96%) and a large majority in public practice (89%). All respondents had at least one other accredited trainee at their site. The large majority (75%) spent at least two hours per week contouring, but nearly 80% had to spend some time out of hours contouring with 10% performing all their contouring out of hours. Two‐thirds of respondents indicated there was insufficient time for contouring with over half having no allocated time for this activity. All respondents were allowed to independently contour by their consultants and were allowed to do radical and palliative cases. The most difficult cases to contour were head and neck and the upper gastrointestinal sites with the RTOG atlas the most useful guide. All trainee respondents received feedback on their contouring which was most often face to face. Interaction with radiation therapists was valuable and more interaction was desired. Two‐thirds (67%) of respondents had the opportunity to review treatment plans with consultants with one to two cases per week being the most common numbers reviewed, but this was usually not done (87%) on an allocated time in the roster. The large majority (90%) had the opportunity to be involved in brachytherapy, but this dropped to 60% for SBRT.

Three quarters (73%) of respondents felt that there was not enough time spent on contouring, planning and evaluation of plans.

Conclusions

This initial detailed survey of ANZ and Singaporean trainees on contouring and planning indicates that dedicated protected time without interruption is required for this integral activity with current hours spent on this activity inadequate. Optimisation and improvement in a number of areas is required. Feedback from this study should be adopted by sites and networks. Feedback could also be considered as the Faculty of Radiation Oncology transitions into programmatic assessment.
Community and Expert Wine Ratings and Prices
Authors: Oczkowski Edward , Pawsey Nicholas
Published: February 2019

This paper assesses the relative impact community consumer ratings and expert ratings have on Australian wine prices. Results suggest community ratings may better explain price variations than expert scores; however, the performance difference is not definitive. Expert scores are found to have some additional unique power beyond community ratings in explaining prices. These results hold for both models based on current quality and reputation ratings and a number of robustness checks. The results suggest that producers may need to monitor both expert and community assessments of wines based on numerous vintages to accurately assess wine prices.
Ultimate parent board reform and corporate overinvestment: a quasi‐natural experiment study
Authors: Xie Sujuan , Xu Yue , Zeng Yamin , Zhang Junsheng
Published: February 2019

Using government‐led board reform as a quasi‐natural experiment, we find that board reform at Chinese state controlling shareholders significantly alleviates overinvestment at their listed subsidiaries. The positive role of board reform in reducing overinvestment is stronger when state controlling shareholders have weak incentive to expropriate listed subsidiaries, or they can better monitor the listed subsidiaries through assigned top management. Furthermore, we find that board reform further reduces managerial cost at their listed subsidiaries. Overall, our findings suggest that government‐led board reform enhances internal governance at state controlling shareholders and has a positive effect on investment policy at their listed subsidiaries.
Traffic fatalities within US states that have legalized recreational cannabis sales and their neighbours
Authors: Lane Tyler J. , Hall Wayne
Published: February 2019

Background and aims

A growing body of evidence suggests that cannabis impairs driving ability. We used mortality data to investigate whether the commercial sale of cannabis for recreational use affected traffic fatality rates both in states that legalized it and in neighbouring jurisdictions.

Design

Interrupted time–series of traffic fatality rates adjusted for seasonality and autocorrelation. Changes are reported as step and trend effects against a comparator of states that had not implemented medicinal or recreational cannabis during the study period (2009–16). Sensitivity analyses added a 6‐month ‘phase‐in’ to account for lags in production. Meta‐analyses were used to derive pooled results.

Setting

Three states that legalized recreational cannabis sales [Colorado (January 2014), Washington State (June 2014) and Oregon (October 2015] and nine neighbouring jurisdictions [Kansas, Nebraska, New Mexico, Oklahoma and Utah (Colorado neighbours); British Columbia and Oregon (Washington neighbours); and California and Nevada (Oregon neighbours)].

Measurements

Monthly traffic fatalities rates per million residents using mortality data from CDC WONDER and RoadSafetyBC and census data.

Findings

There was a pooled step increase of 1.08 traffic fatalities per million residents followed by a trend reduction of −0.06 per month (both P < 0.001), although with significant heterogeneity between sites (step: I2 = 73.7%, P < 0.001; trend: I2 = 68.4%; P = 0.001). Effects were similar in both legalizing (step: 0.90, P < 0.001; trend: −0.05, P = 0.007) and neighbouring sites (step: 1.15, P = 0.005; trend: −0.06, P = 0.001). The 6‐month phase‐in produced similar if larger effects (step: 1.36, P = 0.006; trend: −0.07, P < 0.001).

Conclusions

The combination of step increases and trend reductions suggests that in the year following implementation of recreational cannabis sales, traffic fatalities temporarily increased by an average of one additional traffic fatality per million residents in both legalizing US states of Colorado, Washington and Oregon and in their neighbouring jurisdictions.
Genetic variants at the EGLN1 locus associated with high‐altitude adaptation in Tibetans are absent or found at low frequency in highland Andeans
Authors: Heinrich Erica C. , Wu Lu , Lawrence Elijah S. , Cole Amy M. , Anza‐Ramirez Cecilia , Villafuerte Francisco C. , Simonson Tatum S.
Published: February 2019

EGLN1 encodes the hypoxia‐inducible factor (HIF) pathway prolyl hydroxylase 2 (PHD2) that serves as an oxygen‐sensitive regulator of HIF activity. The EGLN1 locus exhibits a signature of positive selection in Tibetan and Andean populations and is associated with hemoglobin concentration in Tibetans. Recent reports provide evidence for functional roles of protein‐coding variants within the first exon of EGLN1 (rs186996510, rs12097901) that are linked to an adaptive signal in Tibetans, yet whether these same variants are present and contribute to adaptation in Andean highlanders is unknown. We determined the frequencies of these adaptive Tibetan alleles in Quechua Andeans resident at high altitude (4,350 m) in addition to individuals of Nepali ancestry resident at sea level. The rs186996510 C (minor) allele previously found at high frequency in Tibetans is absent in Andean (G: 100%) and rare among Nepali (C: 11.8%, G: 88.2%) cohorts. The minor G allele of rs12097901 is found at similarly low frequencies in Andeans (G: 12.7%, C: 87.3%) and Nepalis (G: 23.5%, C: 76.5%) compared to Tibetans. These results suggest that adaptation involving EGLN1 in Andeans involves different mechanisms than those described in Tibetans. The precise Andean adaptive variants remain to be determined.
‘The public rely on me a lot’: Rural pharmacists’ perspectives on their roles in oral health care
Authors: Hoang Ha , Barnett Tony , Kirschbaum Mark , Dunbar Stephanie , Wong Rita
Published: February 2019

Objective

To examine rural pharmacists’ perspectives on their roles in oral health in rural communities and collaborations with dental practitioners.

Design

A qualitative research study using face‐to‐face, semistructured interviews. Interview data were thematically analysed with the assistance of Nvivo 10.

Setting

Eleven rural communities across rural Tasmania.

Participants

Twenty community pharmacists.

Results

Five major themes emerged: (i) barriers for patients to access dental services; (ii) oral health presentations to rural pharmacies; (iii) roles of pharmacists in oral health care (subthemes: advice; health promotion; and referrals); (iv) collaborations with dental practitioners; and (v) oral health education and training.

Conclusion

This study suggests that rural community pharmacists had advisory and referral roles in oral health and acknowledged that they could play a greater role in oral health promotion. It was suggested that oral health could be incorporated into existing pharmacy health promotion and surveillance activities. There was a lack of collaboration between pharmacists and dentists or dental services and limited oral health education and training provided to pharmacists. Stronger collaboration between pharmacists and dental practitioners and better oral health training for pharmacists may enhance their role in promoting oral health within rural communities.
Multi‐centre study found that strict adherence to guidelines led to computed tomography scans being overused in children with minor head injuries
Authors: Niele Nicky , van Houten Marlies A. , Boersma Bart , Biezeveld Maarten H. , Douma Matthijs , Heitink Katja , ten Tusscher Gavin W. , Tromp Ellen , van Goudoever Johannes B. , Plötz Frans B.
Published: February 2019

Aim

Our primary aim was to calculate the head computed tomography (CT) scan rate in children with a minor head injury (MHI) when the Dutch National guidelines were followed in clinical practice. The secondary aim was to determine the incidence of CT abnormalities and the guideline predictors associated with traumatic abnormalities.

Methods

We performed a multi‐centre, prospective observational cross‐sectional study in the emergency departments of six hospitals in The Netherlands between 1 April 2015 and 31 December 2016.

Results

Data on 1002 patients were studied and 69% of cases complied with the guidelines. The overall CT rate was 44% and the incidence of traumatic abnormal CT findings was 13%. CT scans were performed in 19% of children under two years of age, 48% of children between two and five years and 63% of children aged six years or more. Multivariate regression analysis for all age categories showed that CT abnormalities were predicted by a Glasgow Coma Scale of less than 15, suspicion of a basal skull fracture, vomiting and scalp haematomas or external lesions of the skull.

Conclusion

Strict adherence to the Dutch national guidelines resulted in CT overuse. New guidelines are needed to safely reduce CT scan indications.
Glutamate and GABA neurotransmission are increased in paraventricular nucleus of hypothalamus in rats induced to 6‐OHDA parkinsonism: Involvement of nNOS
Authors: Turossi Amorim Eric Diego , de Jager Lorena , Martins Andressa Busetti , Rodrigues Ananda Totti , Cruz Lucchetti Bruno Fernando , Ariza Deborah , Pinge‐Filho Phileno , Crestani Carlos Cesar , Uchoa Ernane Torres , Martins‐Pinge Marli Cardoso
Published: February 2019

Aim

Parkinson's disease (PD) is a progressive neurodegenerative disease that manifests itself clinically after reaching an advanced pathological stage. Besides motor signals, PD patients present cardiovascular and autonomic alterations. Recent data showed that rats induced to Parkinsonism by 6‐hydroxydopamine (6‐OHDA) administration in the substantia nigra pars compacta (SNpc) showed lower mean arterial pressure (MAP) and heart rate (HR), as reduction in sympathetic modulation. The paraventricular nucleus of the hypothalamus (PVN) is an important site for autonomic and cardiovascular control, and amino acid neurotransmission has a central role. We evaluate PVN amino acid neurotransmission in cardiovascular and autonomic effects of 6‐OHDA Parkinsonism.

Methods

Male Wistar rats were submitted to guide cannulas implantation into the PVN. 6‐OHDA or sterile saline (sham) was administered bilaterally in the SNpc. After 7 days, cardiovascular recordings in conscious state was performed.

Results

Bicuculline promoted an increase in MAP and HR in sham group and exacerbated those effects in 6‐OHDA group. NBQX (non‐NMDA inhibitor) did not promote changes in sham as in 6‐OHDA group. On the other hand, PVN microinjection of LY235959 (NMDA inhibitor) in sham group did not induced cardiovascular alterations, but decreased MAP and HR in 6‐OHDA group. Compared to Sham group, 6‐OHDA lesion increased the number of neuronal nitric oxide synthase (nNOS)‐immunoreactive neurons in the PVN and, nNOS inhibition promoted higher increases in MAP and HR.

Conclusion

Our data suggest that the decreased baseline blood pressure and heart rate in animals with Parkinsonism may be due to an increased GABAergic tone via nNOS in the PVN.
Effects of grazing regimes on the temporal dynamics of grassland communities
Authors: Boavista Lidiane da Rosa , Trindade José Pedro Pereira , Overbeck Gerhard Ernst , Müller Sandra Cristina
Published: February 2019

Questions

Grazing management influences grassland community dynamics, but few studies exist on the effects of specific management regimes in subtropical grasslands. Here, we ask how rotational and continuous grazing influences the composition, diversity, and biomass production of natural grasslands in southern Brazil.

Location

The study was conducted at four cattle farms within the south Brazilian grassland region (Campos Sulinos), in the upper area of the Camaquã river basin of Rio Grande do Sul, Brazil.

Methods

On each farm, grassland that had previously been subjected to continuous grazing (freely grazed by cattle) was divided into two experimental units; one managed by rotational grazing and the other maintained under continuous grazing. In each experimental unit, 14 permanent plots were monitored over six years for species composition and species biomass. Data were analyzed using linear mixed models to evaluate the effects of grazing management strategies on composition dissimilarity, diversity indices, and plant biomass.

Results

Grasslands under a rotational grazing regime changed steadily over the period of evaluation. Total biomass and species distribution patterns greatly differed from those in plots subjected to continuous grazing, leading to changes in species richness, dominance, and composition, as well as to an increase in overall plant biomass.

Conclusions

Community changes during the six‐year study period as a consequence of the distinct grazing treatments were evident. Grasslands under rotational grazing management benefitted from less selective grazing, enabling a more uniform growth of species within the communities, which in turn were richer at the end of the six‐year experiment. In contrast, the proportion of grazing‐resistant species or less‐consumed species was higher under continuous grazing, where foraging by cattle appears to be more selective. Rotational grazing thus not only leads to higher species richness and diversity, but also to higher primary and, in consequence, secondary productivity.
Prothymosin‐α enhances phosphatase and tensin homolog expression and binds with tripartite motif‐containing protein 21 to regulate Kelch‐like ECH‐associated protein 1/nuclear factor erythroid 2‐related factor 2 signaling in human bladder cancer
Authors: Tsai Yuh‐Shyan , Jou Yeong‐Chin , Tsai Hsin‐Tzu , Shiau Ai‐Li , Wu Chao‐Liang , Tzai Tzong‐Shin
Published: February 2019

Prothymosin‐α (PTMA) is a small, acidic protein that is usually transported into the nucleus and involves many cellular and immunological functions. Previous studies demonstrated that aberrant location of PTMA expression exists in human bladder cancer, but the role of PTMA protein expression remains elusive. In this study, we created ectopic nuclear or cytoplasmic PTMA expression in human bladder cancer cells by infecting lentiviruses carrying wild type or deleted nuclear localization signal of the PTMA gene. The in vivo tumorigenesis assay showed PTMA protein with deleted nuclear localization signal promotes J82 xenograft tumor growth in mice and shortens their survival more so than the wild type. Chromatin immunoprecipitation showed that wild‐type PTMA protein binds to the PTEN promoter and enhances phosphatase and tensin homolog (PTEN) expression. Through immunoblot proteomics and in vivo ubiquitination studies, PTMA protein can bind with tripartite motif‐containing protein 21 (TRIM21) and block its ubiquitination. Also, TRIM21 can downregulate both forms of PTMA protein. In human bladder tumors, loss of nuclear PTMA expression was an unfavorable prognostic indicator for shorter disease‐free survival (hazard ratio, 1.54; P = 0.009). Our data support that nuclear PTMA protein serves as a tumor suppressor in bladder cancer through upregulating PTEN and orchestrating TRIM21 for the regulation of Nrf2 signaling.
A high‐quality homology model for the human dopamine transporter validated for drug design purposes
Authors: Castellana Matthew C. , Castellar Montes Andrea , Sprague Jon E. , Mahfouz Tarek M.
Published: February 2019

The human dopamine transporter (hDAT) plays many vital functions within the central nervous system and is thus targeted by many pharmaceutical agents. Dopamine‐related therapies are in current development for individuals with dopamine‐related disorders including depression, Parkinson's disease, and psychostimulant addictions such as cocaine abuse. Yet, most efforts to develop new dopamine therapies are within costly structure–activity relationship studies. Through structure‐based drug design techniques, the binding site of hDAT can be utilized to develop novel selective and potent dopamine therapies at reduced costs. However, no structural models of hDAT specifically validated for rational drug design purposes currently exist. Here, using the Drosophila dopamine transporter as a template, a homology model for the hDAT was developed and validated. The model was able to reproduce experimental binding modes with great accuracy, was able to rank inhibitors in the correct order of increasing potency with an R2 value of 0.81 for the test set, and it also outperformed other published hDAT models. Thus, the model can be used reliably in structure‐based drug design projects.
Confirmatory tests for the diagnosis of primary aldosteronism: A systematic review and meta‐analysis
Authors: Wu Sicen , Yang Jun , Hu Jinbo , Song Ying , He Wenwen , Yang Shumin , Luo Rong , Li Qifu
Published: February 2019

Objective

Saline infusion test (SIT), captopril challenge test (CCT), fludrocortisone suppression test (FST) and oral sodium loading test (SLT) are recommended by the Endocrine Society's Clinical Practice Guidelines to diagnose primary aldosteronism, but which one is the best remains controversial. We aimed to summarize the available comparative data and evaluate the diagnostic accuracy of these four tests.

Design

We searched PubMed, Embase and the Cochrane Library for relevant studies published between January 1980 and January 2018.

Patients

Eligible studies reported on the accuracy of one or more of the four confirmatory tests in patients suspected of PA.

Measurements

Two reviewers independently conducted the data extraction of all selected studies, which consisted of study characteristics and data to estimate the summary receiver operating characteristic (SROC) curve and the corresponding summary area under the curve (SAUC), pooled sensitivity and specificity, diagnostic odds ratios (DOR) with 95% confidence interval (CI).

Results

We identified 26 articles including 3686 patients. Fifteen articles evaluated the diagnostic accuracy of CCT, 10 of SIT, 1 of FST and none of SLT. For CCT, the SAUC was 0.9207, and the pooled sensitivity and specificity were 0.87 (95% CI: 0.84‐0.89) and 0.84 (95% CI: 0.81‐0.86), respectively. For SIT, the SAUC was 0.9232, and the pooled sensitivity and specificity were 0.85 (95% CI: 0.82‐0.87) and 0.87 (95% CI: 0.85‐0.89), respectively. For FST, the pooled sensitivity and specificity were 0.87 (95% CI: 0.66‐0.97) and 0.95 (95% CI: 0.82‐0.99), respectively. Overall, we found no significant differences in the diagnostic accuracy of CCT and SIT.

Conclusions

CCT and SIT exhibit high and comparable accuracy for diagnosing PA. CCT may be a more feasible alternative as it is safe and much easier to perform.
Optical coherence tomography and optical coherence tomography angiography in uveitis: A review
Authors: Invernizzi Alessandro , Cozzi Mariano , Staurenghi Giovanni
Published: February 2019

Optical coherence tomography (OCT) has dramatically changed the understanding and management of uveitis and other ocular conditions. Currently, OCT angiography (OCTA) combines structural information with the visualization of blood flow within the imaged area. The aim of this review is to present the basic principles of OCT and OCTA interpretation and to investigate the role of these imaging techniques in the diagnosis and management of uveitis. Common complications of intraocular inflammation such as macular oedema and inflammatory choroidal neovascularization are often diagnosed and followed with OCT/OCTA scans. However, uveitis specialists can obtain much more information from tomographic scans. This review provides a comprehensive description of typical OCT/OCTA findings characterizing different ocular structures in uveitis, proceeding from the cornea to the choroid. A careful interpretation of OCT/OCTA images can help in the differential diagnosis, the prediction of clinical outcomes, and the follow‐up of patients with uveitis.
Evaluating the predicted impact of changes to the AJCC/TMN staging system for differentiated thyroid cancer (DTC): A prospective observational study of patients in South East Scotland
Authors: Hulse Kate , Williamson Adam , Gibb Fraser W. , Conn Brendan , Nixon Iain J.
Published: February 2019

Objectives

To assess the impact of the eighth edition AJCC/TMN staging system on patients with new diagnoses of differentiated thyroid cancers presenting to our regional multidisciplinary team meetings.

Design

We analysed Endocrine Cancer MDT meeting records from 2009 to 2015 to identify all patients in the region presenting with a new diagnosis of differentiated thyroid cancer. We re‐staged patients according to the eighth edition AJCC/TNM staging classification and analysed the survival outcomes of patients in each stage under the seventh and eighth systems.

Setting

Tertiary referral centre in South East Scotland (NHS Lothian).

Participants

Three hundred and sixty‐one patients were newly diagnosed with DTC within South East Scotland during the study period and met our inclusion criteria. Main outcome measures: Disease‐specific mortality at any time during follow‐up.

Results

In total, 119 of 361 (33%) patients were re‐staged when the eighth edition AJCC/TMN system was applied. The number of patients classified as having advanced stage (III/IV) disease fell from 76 (21%) to 8 (2%). The most common reason for down‐staging was re‐classification of tumour size, a factor in 96 (80.7%) down‐staged patients. The five‐year disease‐specific survival of the cohort overall was 98%. Overall, 7 (1.9%) thyroid cancer–related deaths occurred during follow‐up, three of whom were down‐staged.

Conclusions

On implementation of the eighth edition of the AJCC/TMN staging system, we expect many patients who would previously have been considered to have advanced thyroid cancer will now be classified as early stage. This will accurately reflect their excellent survival outcomes.