bluuebunny/crossref_metadata_2025_split huggingface dataset:
Geographic Barriers to Achieving Universal Health Coverage in a rural district of Madagascar
Authors: Garchitorena Andres , Ihantamalala Felana A , Révillion Christophe , Cordier Laura F , Randriamihaja Mauricianot , Razafinjato Benedicte , Rafenoarivamalala Feno H , Finnegan Karen E. , Andrianirinarison Jean-Claude , Rakotonirina Julio , Herbreteau Vincent , Bonds Matthew H 
Published: July 2020

ABSTRACTPoor geographic access can persist even when affordable and well-functioning health systems are in place, limiting efforts for universal health coverage (UHC). It is unclear how health facilities and community health workers contribute to achieving UHC. Using geographic information from thousands of patients in a rural district of Madagascar we evaluate how a health system strengthening (HSS) intervention aimed towards UHC affects the geography of primary care access. We find that facility-based interventions (user-fee exemptions, improved readiness) achieved high utilization rates only among populations who lived in close proximity to supported facilities. Scaling only facility-based HSS programs across the district would result in large gaps in health care access for the majority of the population. Community health provided major improvements in service utilization for children regardless of their distance from facilities. Our results have implications for UHC policies and suggest that greater emphasis on professionalized community health programs is essential.
Age structuring and spatial heterogeneity in prion protein gene (PRNP) polymorphism in white-tailed deer
Authors: Chafin Tyler K. , Douglas Marlis R. , Martin Bradley T. , Zbinden Zachery D. , Middaugh Christopher R. , Ballard Jennifer R. , Gray M. Cory , White Don , Douglas Michael E. 
Published: July 2020

ABSTRACTChronic-wasting disease (CWD) is a prion-derived fatal neurodegenerative disease that has affected wild cervid populations on a global scale. Susceptibility has been linked unambiguously to several amino acid variants within the prion protein gene (PRNP). Quantifying their distribution across landscapes can provide critical information for agencies attempting to adaptively manage CWD. Here we attempt to further define management implications ofPRNPpolymorphism by quantifying the contemporary geographic distribution (i.e., phylogeography) ofPRNPvariants in hunter-harvested white-tailed deer (WTD;Odocoileus virginianus, N=1433) distributed across Arkansas (USA), including a focal spot for CWD since detection of the disease in February 2016. Of these,PRNPvariants associated with the well-characterized 96S non-synonymous substitution showed a significant increase in relative frequency among older CWD-positive cohorts. We interpreted this pattern as reflective of a longer life expectancy for 96S genotypes in a CWD-endemic region, suggesting either decreased probabilities of infection or reduced disease progression. Other variants showing statistical signatures of potential increased susceptibility, however, seemingly do so as an artefact of population structure. We also showed marked heterogeneity across the landscape in the prevalence of ‘reduced susceptibility’ genotypes. This may indicate, in turn, that differences in disease susceptibility among WTD in Arkansas are an innate, population-level characteristic that is detectable through phylogeographic analysis.
An offset ON-OFF receptive field is created by gap junctions between distinct types of retinal ganglion cells
Authors: Cooler Sam , Schwartz Gregory W. 
Published: July 2020

SummaryReceptive fields (RFs) are a foundational concept in sensory neuroscience. The RF of a sensory neuron is shaped by the properties of its synaptic inputs from connected neurons. In the early visual system, retinotopic maps define a strict relationship between the location of a cell’s dendrites and its RF location in visual space1–3. Retinal ganglion cells (RGCs), the output cells of the retina, form dendritic mosaics that tile retinal space and have corresponding RF mosaics that tile visual space1,2. The precise location of dendrites in some RGCs has been shown to predict their RF shape4. Previously described ON-OFF RGCs have aligned dendrites in ON and OFF synaptic layers, so the cells respond to increments and decrements of light at the same locations in visual space5–8. Here we report a systematic offset between the ON and OFF RFs of an RGC type. Surprisingly, this property does not come from offset ON and OFF dendrites but instead arises from electrical synapses with RGCs of a different type. This circuit represents a new channel for direct communication between ON and OFF RGCs. Using a multi-cell model, we find that offset ON-OFF RFs could improve the precision with which edge location is represented in an RGC population.
Ultradian Rhythms in Heart Rate Variability and Distal Body Temperature Anticipate the Luteinizing Hormone Surge Onset
Authors: Grant Azure D. , Newman Mark , Kriegsfeld Lance J. 
Published: July 2020

AbstractThe human menstrual cycle is characterized by predictable patterns of physiological change across timescales, yet non-invasive anticipation of key events is not yet possible at individual resolution. Although patterns of reproductive hormones across the menstrual cycle have been well characterized, monitoring these measures repeatedly to anticipate the preovulatory luteinizing hormone (LH) surge is not practical for fertility awareness. In the present study, we explored whether non-invasive and high frequency measures of distal body temperature (DBT), sleeping heart rate (HR), sleeping heart rate variability (HRV), and sleep timing could be used to anticipate the preovulatory LH surge in women. To test this possibility, we used signal processing to examine these measures across the menstrual cycle. Cycles were examined from both pre- (n=45 cycles) and perimenopausal (n=10 cycles) women using days of supra-surge threshold LH and dates of menstruation for all cycles. For a subset of cycles, urinary estradiol and progesterone metabolites were measured daily around the time of the LH surge. Wavelet analysis revealed a consistent inflection point of ultradian rhythm (2-5 h) power of DBT and HRV that enabled anticipation of the LH surge at least 2 days prior to its onset in 100% of individuals. In contrast, the power of ultradian rhythms in heart rate, circadian rhythms in body temperature, and metrics of sleep duration and sleep timing were not predictive of the LH surge. Together, the present findings reveal fluctuations in distal body temperature and heart rate variability that consistently anticipate the LH surge and may aid in fertility awareness.Key PointsUltradian (2-5 h) rhythm power of distal body temperature and heart rate variability (RMSSD) exhibits a stereotyped inflection point and peak in the days leading up to the LH surge in premenopausal women.Circadian rhythms of distal body temperature and single time-point/day metrics do not permit anticipation of the LH surge.Measurement of continuous metabolic and autonomic outputs, enabling assessment of ultradian rhythms, may be of value to the fertility awareness method.
A spinoparabrachial circuit defined by Tacr1 expression drives pain
Authors: Barik Arnab , Sathyamurthy Anupama , Thompson James , Seltzer Mathew , Levine Ariel , Chesler Alexander 
Published: July 2020

AbstractPainful stimuli evoke a mixture of sensations, negative emotions and behaviors. These myriad effects are thought to be produced by parallel ascending circuits working in combination. Here we describe a pathway from spinal cord to brain for ongoing pain. Activation of a defined subset of spinal projection neurons expressing Tacr1 evokes a full repertoire of somatotopically-directed coping behaviors in the absence of noxious input. These cells project to a tiny cluster of Tacr1-positive neurons in the superior lateral parabrachial nucleus (PBN-SL) that themselves are responsive to sustained but not acute noxious stimuli. Activation of these PBN-SLTacr1neurons alone does not trigger pain responses but instead serves to dramatically heighten nocifensive behaviors and suppress itch. Remarkably, mice with silenced PBN-SLTacr1neurons ignore long-lasting noxious stimuli. These data reveal a spinoparabrachial pathway that plays a key role in the sensation of ongoing pain.
Pseudogene-mediated DNA demethylation leads to oncogene activation
Authors: Kwon Junsu , Liu Yanjing V. , Gao Chong , Bassal Mahmoud A. , Jones Adrianna I. , Yang Junyu , Chen Zhiyuan , Ying Li , Yang Henry , Chen Leilei , Di Ruscio Annalisa , Tay Yvonne , Chai Li , Tenen Daniel G. 
Published: July 2020

AbstractDespite being one of the leading causes of cancer-related deaths, there is an unmet clinical need for hepatocellular carcinoma (HCC) patients. The lack of effective treatment is, at least in part, due to our lack of understanding of the molecular pathogenesis of this disease. Oncofetal protein SALL4 is re-activated in patients with aggressive HCC along with other solid tumors and hematologic malignancies. This study identifies a previously unrecognized mechanism of SALL4 reactivation which is mediated by pseudogene-induced demethylation. Using a locus-specific demethylating technology, we identified the critical CpG region for SALL4 expression. We showed that SALL4 pseudogene 5 hypomethylates this region through interaction with DNMT1, resulting in SALL4 upregulation. Intriguingly, pseudogene 5 is significantly upregulated in a hepatitis B virus (HBV) model prior to SALL4 induction, and both are increased in HBV-HCC patients. Our results suggest that pseudogene-mediated demethylation represents a unique mechanism of oncogene activation in cancer.SignificanceOur study provides a mechanistic link between HBV infection, activation of the oncogene SALL4, and HCC. We reveal a previously undescribed capability of a pseudogene to epigenetically activate an oncogene by demethylation in a locus-specific manner.
Quantifying the monomer-dimer equilibrium of tubulin with mass photometry
Authors: Fineberg Adam , Surrey Thomas , Kukura Philipp 
Published: July 2020

AbstractTheαβ-tubulin heterodimer is the fundamental building block of microtubules, making it central to several cellular processes. Despite the apparent simplicity of heterodimerisation, the associated energetics and kinetics remain disputed, largely due to experimental challenges associated with quantifying affinities in the <μM range. We use mass photometry to observe tubulin monomers and heterodimers in solution simultaneously, thereby quantifying theαβ-tubulin dissociation constant (8.48±1.22 nM) and its tightening in the presence of GTP (3.69±0.65 nM), at a dissociation rate >10−2s−1. Our results demonstrate the capabilities of mass photometry for quantifying protein-protein interactions and clarify the energetics and kinetics of tubulin heterodimerisation.Abstract Figure
Undocumented migrants in the Netherlands: adverse life events, living conditions and mental health
Authors: Vollebregt Sandrine JC , Scholte Willem F , Hoogerbrugge Annette , Bolhuis Koen , Vermeulen Jentien 
Published: July 2020

AbstractBackgroundUndocumented migrants have worse health and living conditions and poor access to health care.Aims and objectivesTo examine the prevalence and determinants of mental health problems in undocumented migrants.DesignObservational study, integrating cross-sectional questionnaire data with retrospective electronic patient record data.MethodsUndocumented migrants attending medical and psychological consultation hours of a Netherlands-based non-governmental organization, completed the Self-Reporting Questionnaire (SRQ). We examined scores of the instrument’s 24 items version (SRQ-24) and its 20 items version (SRQ-20). Correlations with determinants were estimated using parametric tests.ResultsOn the SRQ-20, 85% of the sample (N=101) scored ≥8, the clinical cut-off value; mean=12.4 ± 4.6, range 0-20. Adverse life events like physical and sexual assault were reported in 37% of the medical records (N=99) and had a medium to large effect (Cohen’s d=0.76) on SRQ-24 scores.DiscussionMental health problems are common in undocumented migrants. Adverse life-events are critical determinants.
Clinical and molecular diagnostic study of 320 Chinese children with epilepsy by Genome Sequencing
Authors: Zou Dongfang , Wang Lin , Liao Jianxiang , Xiao Hongdou , Duan Jing , Zhang Tongda , Yin Zhenzhen , Zhou Jing , Yan Haisheng , Huang Yushan , Li Jianbiao , Zhan Nianji , Yang Ying , Ye Jingyu , Chen Fang , Zhu Shida , Wen Feiqiu , Guo Jian 
Published: July 2020

ABSTRACTPurposeTo evaluate the diagnostic value of Genome Sequencing(GS)in children with epilepsy.MethodsWe performed GS on 320 Chinese children with epilepsy and interpreted Single Nucleotide Variants (SNVs) and Copy Number Variant (CNVs) of all samples. The complete pedigree and clinical data of the probands were established and followed up. The clinical phenotypes, treatments, prognoses and genotypes of the patients were analyzed.ResultsPathogenic/likely pathogenic variants were found in 122 of 320 children (38.13%), of whom, 92 (28.8%) had SNVs, 27 (8.4%) had CNVs, and three had both SNVs and CNVs. Among these variants, there were 3 CNVs of <100K in length. The most frequently mutated gene was SCN1A(10.9%,10/92),which is related to Dravet Syndrome, followed by PRRT2(8.7%,8/92), which is relevant to benign familial infantile epilepsy, TSC2(7.6%,7/92), which is associated with Tuberous Sclerosis. The most common recurrent CNVs were 17p13.3 deletion (18.5%, 5/27), 16p11.2 deletion syndrome (14.8%, 4/27), 15q11.2 deletion (11.1%, 3/27), which are related to epilepsy, developmental retardation and congenital abnormalities.The diagnostic yield was higher as the age of seizure onset was smaller. The highest detection rate was 75% in whom developed seizures within one month after birth. 13.4% (43/320) cases were identified to be treatable based on GS. 1% (3/320) of epilepsy patients received direct therapeutic measures and demonstrated favorable prognosis.ConclusionGS can complete the genetic diagnosis, individualized treatment, and family reproductive guidance for patients. GS can replace Exome Sequencing and Chromosomal Microarray Analysis and is expected to be the first choice of genetic testing method for patients with epilepsy.
Analysis of 50,000 exome-sequenced UK Biobank subjects fails to identify genes influencing probability of psychiatric referral
Authors: Curtis David 
Published: July 2020

AbstractBackgroundDepression is moderately heritable but there is no common genetic variant which has a major effect on susceptibility. It is possible that some very rare variants could have substantial effect sizes and these could be identified from exome sequence data.MethodsData from 50,000 exome-sequenced UK Biobank participants was analysed. Subjects were treated as cases if they had reported having seen a psychiatrist for “nerves, anxiety, tension or depression”. Gene-wise weighted burden analysis was performed to see if there were any genes or sets of genes for which there was an excess of rare, functional variants in cases.ResultsThere were 5,872 cases and 43,862 controls. There were 22,028 informative genes but none produced a statistically significant result after correction for multiple testing. Of the 25 genes individually significant at p<0.001 none appeared to be a biologically plausible candidate. No set of genes achieved statistical significance after correction for multiple testing and those with the lowest p values again did not appear to be biologically plausible candidates.LimitationsThe phenotype is based on self-report and the cases are likely to somewhat heterogeneous. The number of cases is on the low side for a study of exome sequence data.ConclusionsThe results conform exactly with the expectation under the null hypothesis. It seems unlikely that depression genetics research will produce findings that might have a substantial clinical impact until far larger samples become available.
Towards middle-up analysis of polyclonal antibodies: subclass-specificN-glycosylation profiling of murine immunoglobulin G (IgG) by means of HPLC-MS
Authors: Blöchl Constantin , Regl Christof , Huber Christian G. , Winter Petra , Weiss Richard , Wohlschlager Therese 
Published: July 2020

AbstractAdvanced analytical strategies including top-down and middle-up HPLC-MS approaches have become powerful alternatives to classical bottom-up analysis for the characterization of therapeutic monoclonal antibodies. Here, we assess feasibility of middle-up analysis of polyclonal IgGs posing additional challenges due to extensive sequence variability. The presented workflow is based on Fc/2 portions as conserved subunits of IgGs and enables global profiling of subclasses and their glycosylation patterns, both of which influence IgG effector functions. To obtain subunits of murine IgGs, we established digestion with the bacterial protease SpeB. The resulting Fc/2 portions characteristic of different subclasses were subsequently analysed by ion-pair reversed-phase HPLC hyphenated to high-resolution mass spectrometry allowing relative quantification of IgG subclasses and theirN-glycosylation variants. In order to assess method capabilities in an immunological context, we applied the analytical workflow to polyclonal antibodies obtained from BALB/c mice immunized with the grass pollen allergen Phl p 6. This analysis simultaneously revealed a shift in IgG subclasses and Fc-glycosylation patterns in total and antigen-specific IgGs from different mouse cohorts. Eventually, Fc/2 characterization may reveal other protein modifications including oxidation, amino acid exchanges, and C-terminal lysine as demonstrated for monoclonal IgGs, which may be implemented for quality control of functional antibodies.
Drone-derived canopy height predicts biomass across non-forest ecosystems globally
Authors: Cunliffe A.M. , Anderson K. , Boschetti F. , Brazier R.E. , Graham H.A. , Myers-Smith I.H. , Astor T. , Boer M.M. , Calvo L. , Clark P.E. , Cramer M.D. , Encinas-Lara M.S. , Escarzaga S.M. , Fernández-Guisuraga J.M. , Fisher A.G. , Gdulová K. , Gillespie B.M. , Griebel A. , Hanan N.P. , Hanggito M.S. , Haselberger S. , Havrilla C.A. , Heilman P. , Ji W. , Karl J.W. , Kirchhoff M. , Kraushaar S. , Lyons M.B. , Marzolff I. , Mauritz M.E. , McIntire C.D. , Metzen D. , Méndez-Barroso L.A. , Power S.C. , Prošek J. , Sanz-Ablanedo E. , Sauer K.J. , Schulze-Brüninghoff D. , Šímová P. , Sitch S. , Smit J.L. , Steele C.M. , Suárez-Seoane S. , Vargas S.A. , Villarreal M.L. , Visser F. , Wachendorf M. , Wirnsberger H. , Wojcikiewicz R. 
Published: July 2020

AbstractNon-forest ecosystems, dominated by shrubs, grasses and herbaceous plants, provide ecosystem services including carbon sequestration and forage for grazing, yet are highly sensitive to climatic changes. Yet these ecosystems are poorly represented in remotely-sensed biomass products and are undersampled byin-situmonitoring. Current global change threats emphasise the need for new tools to capture biomass change in non-forest ecosystems at appropriate scales. Here we assess whether canopy height inferred from drone photogrammetry allows the estimation of aboveground biomass (AGB) across low-stature plant species sampled through a global site network. We found mean canopy height is strongly predictive of AGB across species, demonstrating standardised photogrammetric approaches are generalisable across growth forms and environmental settings. Biomass per-unit-of-height was similarwithin, but differentamong, plant functional types. We find drone-based photogrammetry allows for monitoring of AGB across large spatial extents and can advance understanding of understudied and vulnerable non-forested ecosystems across the globe.
Financial strain and stressful social environment drive depressive symptoms, whileFKBP5variant intensifies the effect, in African Americans living in Tallahassee
Authors: Fuller Kia , Gravlee Clarence C. , McCarty Chris , Mitchell Miaisha M. , Mulligan Connie J. 
Published: July 2020

AbstractThe World Health Organization estimates that almost 300 million people suffer from depression worldwide. Depression is the most common mental health disorder and shows racial disparities in disease prevalence, age of onset, severity of symptoms, frequency of diagnosis, and treatment utilization across the United States. Since depression has both social and genetic risk factors, we propose a conceptual model wherein social stressors are primary risk factors for depression, but genetic variants increase or decrease individual susceptibility to the effects of the social stressors. Our research strategy incorporates both social and genetic data to investigate variation in symptoms of depression (CES-D scores). We collected data on financial strain (difficulty paying bills) and personal social networks (a model of an individual’s social environment), and we genotyped genetic variants in five genes involved in stress reactivity (HTR1a, BDNF, GNB3, SLC6A4, andFKBP5) in 135 African Americans residing in Tallahassee, Florida. We found that high financial strain and a high percentage of people in one’s social network who are a source of stress or worry were significantly associated with higher CES-D scores and explained more variation in CES-D scores than did genetic factors. Only one genetic variant (rs1360780 inFKBP5) was significantly associated with CES-D scores and only when the social stressors were included in the model. Interestingly, the effect ofFKPB5appeared to be strongest in individuals with high financial strain such that participants with a T allele at rs1360780 inFKBP5and high financial strain had the highest mean CES-D scores in our study population. These results suggest that material disadvantage and a stressful social environment increases the risk of depression, but that individual-level genetic variation may increase susceptibility to the adverse health consequences of social stressors.
Insights from the reanalysis of high-throughput chemical genomics data forEscherichia coliK-12
Authors: Wu Peter I-Fan , Ross Curtis , Siegele Deborah A. , Hu James C. 
Published: July 2020

ABSTRACTDespite the demonstrated success of genome-wide genetic screens and chemical genomics studies at predicting functions for genes of unknown function or predicting new functions for well-characterized genes, their potential to provide insights into gene function hasn’t been fully explored. We systematically reanalyzed a published high-throughput phenotypic dataset for the model Gram-negative bacteriumEscherichia coliK-12. The availability of high-quality annotation sets allowed us to compare the power of different metrics for measuring phenotypic profile similarity to correctly infer gene function. We conclude that there is no single best method; the three metrics tested gave comparable results for most gene pairs. We also assessed how converting qualitative phenotypes to discrete, qualitative phenotypes affected the association between phenotype and function. Our results indicate that this approach may allow phenotypic data from different studies to be combined to produce a larger dataset that may reveal functional connections between genes not detected in individual studies.