bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractA 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.HighlightsReciprocal 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

ABSTRACTSerine 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

ABSTRACTThe 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

AbstractComplex 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

AbstractBackgroundPediatric 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 FindingsUsing 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/SignificanceIdentifying 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.
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

AbstractHydroxychloroquine 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

SummaryMethenamine (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

AbstractA 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

AbstractIntroductionThis paper reports the key findings of the first survey of Australian, New Zealand (ANZ) and Singaporean radiation oncology trainees on contouring and planning.MethodsThe 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.ResultsThe 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.ConclusionsThis 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.
Ultimate parent board reform and corporate overinvestment: a quasi‐natural experiment study
Authors: Xie Sujuan , Xu Yue , Zeng Yamin , Zhang Junsheng 
Published: February 2019

AbstractUsing 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

AbstractBackground and aimsA 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.DesignInterrupted 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.SettingThree 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)].MeasurementsMonthly traffic fatalities rates per million residents using mortality data from CDC WONDER and RoadSafetyBC and census data.FindingsThere 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).ConclusionsThe 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

AbstractEGLN1 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.