bluuebunny/crossref_metadata_2025_split huggingface dataset:
Variation at the TRIM11 locus modifies Progressive Supranuclear Palsy phenotype
Authors: Jabbari E , Woodside J , Tan MMX , Shoai M , Pittman A , Ferrari R , Mok KY , Zhang D , Reynolds RH , de Silva R , Grimm MJ , Respondek G , Müller U , Al-Sarraj S , Gentleman SM , Lees AJ , Warner TT , Hardy J , Revesz T ,   PROSPECT-UK consortium, Höglinger GU , Holton JL , Ryten M , Morris HR ,   PROSPECT-UK consortium
Published: May 2018

AbstractObjectiveThe basis for clinical variation related to underlying Progressive Supranuclear Palsy (PSP) pathology is unknown. We performed a genome wide association study (GWAS) to identify genetic determinants of PSP phenotype.MethodsTwo independent pathological and clinically diagnosed PSP cohorts were genotyped and phenotyped to create Richardson’s syndrome (RS) and non-RS groups. We carried out separate logistic regression GWAS to compare RS and non-RS groups and then combined datasets to carry out a whole cohort analysis (RS=367, non-RS=130). We validated our findings in a third cohort by referring to data from 100 deeply phenotyped cases from a recent GWAS. We assessed the expression/co-expression patterns of our identified genes and used our data to carry out gene-based association testing.ResultsOur lead single nucleotide polymorphism (SNP), rs564309, showed an association signal in both cohorts, reaching genome wide significance in our whole cohort analysis – OR 5.5 (3.2-10.0), p-value 1.7×10−9. rs564309 is an intronic variant of the tripartite motif-containing protein 11 (TRIM11) gene, a component of the ubiquitin proteasome system (UPS). In our third cohort, minor allele frequencies of surrogate SNPs in high linkage disequilibrium with rs564309 replicated our findings. Gene based association testing confirmed an association signal at TRIM11. We found that TRIM11 is predominantly expressed neuronally, in the cerebellum and basal ganglia.InterpretationOur study suggests that the TRIM11 locus is a genetic modifier of PSP phenotype and potentially adds further evidence for the UPS having a key role in tau pathology, therefore representing a target for disease modifying therapies.
The role of dendritic brain-derived neurotrophic factor transcripts on altered inhibitory circuitry in depression
Authors: Oh Hyunjung , Piantadosi Sean C. , Rocco Brad R. , Lewis David A. , Watkins Simon C. , Sibille Etienne 
Published: May 2018

ABSTRACTBackgroundA parallel downregulation of brain-derived neurotrophic factor (BDNF) and somatostatin (SST), a marker of inhibitory γ-amino-butyric acid (GABA) interneurons which target pyramidal cell dendrites, has been reported in several brain areas of subjects with major depressive disorder (MDD), and rodent genetic studies suggests they are linked and both contribute to the illness. However, the mechanism by which they contribute to the pathophysiology of the illness has remained elusive.MethodsWith qPCR, we determined the expression level of BDNF transcript variants and synaptic markers in the prefrontal cortex (PFC) of MDD patients and matched controls (n=19/group) and of C57BL/6J mice exposed to chronic stress or control conditions (n=12/group). We next suppressed BDNF transcripts with long 3’ untranslated region (L-3’-UTR) using small hairpin RNA (shRNA) and investigated changes in cell morphology, gene expression and behavior.ResultsL-3’-UTR containing BDNF mRNAs, which migrate to distal dendrites of pyramidal neurons, are selectively reduced and highly correlated with SST expression in the PFC of MDD subjects. A similar downregulation occurs in mice submitted to chronic stress. We next show that Bdnf L-3’-UTR knockdown is sufficient to induce (i) dendritic shrinkage in cortical neurons, (ii) cell-specific MDD-like gene changes (including Sst downregulation), and (iii) depressive-/anxiety-like behaviors. The translational validity of the Bdnf L-3’-UTR shRNA-treated mice was confirmed by significant cross-species correlation of changes in MDD-associated gene expression.ConclusionThese findings provide evidence for a novel MDD-related pathological mechanism linking local neurotrophic support, pyramidal cell structure, dendritic inhibition and mood regulation.
Extreme and rapid bursts of functional adaptations shape bite force in amniotes
Authors: Sakamoto Manabu , Ruta Marcello , Venditti Chris 
Published: May 2018

ABSTRACTAdaptation is the fundamental driver of functional and biomechanical evolution and can be linked to rates of phenotypic trait evolution. Significant shifts in evolutionary rates are seen as instances of exceptional adaptation. However, whether or not signatures of exceptional adaptations (elevated rates) can be distinguished from general adaptations (background rate) in biomechanical traits remains to be tested in a robust statistical framework. Here, we apply a recently developed phylogenetic statistical approach for detecting exceptional adaptations in bite force, in a large group of terrestrial vertebrates, the amniotes. Our results show that bite force in amniotes evolved through multiple bursts of exceptional changes, whereby whole groups – including Darwin′;s finches, maniraptoran dinosaurs (group of non-avian dinosaurs including birds), anthropoids and hominins (the group of species including modern humans) – experienced significant rate increases compared to the background rate. However, in most parts of the amniote tree of life we find no exceptional rate increases, indicating that coevolution with body size was primarily responsible for the patterns observed in bite force. Our approach represents a template for future studies in functional morphology and biomechanics, where exceptional functional adaptations can be quantified and potentially linked to specific ecological factors underpinning major evolutionary radiations.
TheNeurospora crassastandard Oak Ridge background exhibits an atypically efficient meiotic silencing by unpaired DNA
Authors: Giri Dev Ashish , Pankajam Ajith V. , Nishant Koodali T. , Kasbekar Durgadas P. 
Published: May 2018

AbstractMeiotic silencing by unpaired DNA (MSUD) was discovered in crosses made in the standard Oak Ridge (OR) genetic background ofNeurospora crassa. However, MSUD often was decidedly less efficient when the OR-derived MSUD tester strains were crossed with wild-isolated strains (W), which suggested either that sequence heterozygosity intesterx W crosses suppresses MSUD, or that OR represents the MSUD-conducive extreme in the range of genetic variation in MSUD efficiency. Our results support the latter model. MSUD was much less efficient in near-isogenic crosses made in a novelN. crassaB/S1 and theN. tetrasperma85 genetic backgrounds. Possibly, regulatory cues that in other genetic backgrounds calibrate the MSUD response are missing from OR. The OR versus B/S1 difference appears to be determined by loci on chromosomes 1, 2, and 5. OR crosses heterozygous for a duplicated chromosome segment (Dp) have for long been known to exhibit an MSUD-dependent barren phenotype. However, inefficient MSUD inN. tetrasperma85 madeDp-heterozygous crosses non-barren. This is germane to our earlier demonstration thatDps can act as dominant suppressors of repeat-induced point mutation (RIP). Occasionally, during ascospore partitioning rare asci contained >8 nuclei, and round ascospores dispersed less efficiently than spindle-shaped ones.General abstractIn crosses made in the standard OR genetic background ofNeurospora crassa, an RNAi-mediated process called MSUD efficiently silences any gene not properly paired with its homologue during meiosis. We found that MSUD was not as efficient in comparable crosses made in theN. crassaB/S1 andN. tetrasperma85 backgrounds, suggesting that efficient MSUD is not necessarily the norm in Neurospora. Indeed, using OR strains for genetic studies probably fortuitously facilitated the discovery of MSUD and its suppressors. As few as three unlinked loci appear to underlie the OR versus B/S1 difference in MSUD.
Development of Optically-Controlled “Living Electrodes” with Long-Projecting Axon Tracts for a Synaptic Brain-Machine Interface
Authors: Adewole Dayo O. , Struzyna Laura A. , Harris James P. , Nemes Ashley D. , Burrell Justin C. , Petrov Dmitriy , Kraft Reuben H. , Chen H. Isaac , Serruya Mijail D. , Wolf John A. , Cullen D. Kacy 
Published: May 2018

AbstractAchievements in intracortical neural interfaces are compromised by limitations in specificity and long-term performance. A biological intermediary between devices and the brain may offer improved specificity and longevity through natural synaptic integration with deep neural circuitry, while being accessible on the brain surface for optical read-out/control. Accordingly, we have developed the first “living electrodes” comprised of implantable axonal tracts protected within soft hydrogel cylinders for the biologically-mediated monitoring/modulation of brain activity. Here we demonstrate the controlled fabrication, rapid axonal outgrowth, reproducible cytoarchitecture, and simultaneous optical stimulation and recording of neuronal activity within these engineered constructs in vitro. We also present their transplantation, survival, integration, and optical recording in rat cortex in vivo as a proof-of-concept for this neural interface paradigm. The creation and functional validation of these preformed, axon-based “living electrodes” is a critical step towards developing a new class of biohybrid neural interfaces to probe and modulate native circuitry.
An electrochemical biosensor for rapid detection of anti-dsDNA antibodies in absolute scale
Authors: Fagúndez Pablo , Brañas Gustavo , Laíz Justo , Tosar Juan Pablo 
Published: May 2018

AbstractAutoimmune diseases are chronic inflammatory pathologies that are characterized by the presence of antibodies against own epitopes in serum (autoantibodies). Systemic lupus erythematosus (SLE) is a common autoimmune pathology, characterized by the presence of antinuclear antibodies (ANAs). These include anti-dsDNA (α-dsDNA) antibodies, which are widely used for diagnosis and disease monitoring. Their determination is carried out by traditional techniques such as Indirect Immunofluorescence (IFI) or Enzyme Linked Immunosorbent Assay (ELISA), which are time consuming, require qualified technicians, and are not compatible with decentralized analysis outside a laboratory facility. Here, we show a sandwich-format electrochemical biosensor-based method for α-dsDNA determination in a rapid and simple manner. Total assay time is only 30 minutes and the sensor is capable of detecting 16 ng (8 μg / mL) of α-dsDNA antibodies. Using the current derived from the detection limit of the method as a cut-off, we could discriminate positive from negative serum samples with 90% sensitivity and 100% specificity. By using monoclonal antibodies for calibration curves, our results are presented in absolute scale (i.e., concentration instead of serum title) what will help to perform comparisons between methods and further improvements of this protocol. In an effort to render the sensor compatible with automation, we minimized manipulation steps without compromise of the analytical performance, even in complex samples such as serum.
Characterization of Oral Tactile Sensitivity and Chewing Efficiency Across Adulthood
Authors: Shupe Grace E. , Resmondo Zoe N. , Luckett Curtis R. 
Published: May 2018

AbstractTexture perception is one of the most important factors in food acceptance, yet population-wide differences in texture sensations are not well understood. The variation in texture perception across populations is thought to depend on oral tactile sensitivity and oral processing behaviors. To address this hypothesis, we aimed to measure tactile acuity with a battery of tests and quantitate the relationship to oral processing. The study was performed on 98 participants, in 3 age groups (20-25, 35-45, or over 62). Two main measures of oral sensitivity were performed: to assess bite force, subjects were asked to discriminate between foam samples of varying hardness. Secondly, to assess lingual sensitivity the subjects were asked to identify 3D printed shapes, ranging from 3mm to 8mm, using their tongue, as well as identify confectionary letters. Additionally, chewing efficiency was measured through assessing each participants ability to mix two-colored chewing gum. In general, we found that sensitivity and chewing efficiency in the younger age groups was superior to that of older adults (p<0.0001). We also found a positive linear trend between bite force sensitivity and chewing efficiency with younger participants, a trend not found in older participants. We found no significant relationship between age groups for bite force and chewing efficiency, suggesting that age-related declines in bite force sensitivity are not a significant cause of altered oral processing ability. These results help bolster evidence that sensitivity and oral processing are related, as well previously reported declines in both as people age.
GWAS meta-analysis highlights the hypothalamic-pituitary-gonadal axis (HPG axis) in the genetic regulation of menstrual cycle length
Authors: Laisk Triin , Kukuškina Viktorija , Palmer Duncan , Laber Samantha , Chen Chia-Yen , Ferreira Teresa , Rahmioglu Nilufer , Zondervan Krina , Becker Christian , Smoller Jordan W. , Lippincott Margaret , Salumets Andres , Granne Ingrid , Seminara Stephanie , Neale Benjamin , Mägi Reedik , Lindgren Cecilia M. 
Published: May 2018

AbstractThe normal menstrual cycle requires a delicate interplay between the hypothalamus, pituitary, and ovary. Therefore, its length is an important indicator of female reproductive health. Menstrual cycle length has been shown to be partially controlled by genetic factors, especially in the follicle stimulating hormone beta-subunit (FSHB) locus. GWAS meta-analysis of menstrual cycle length in 44,871 women of European ancestry confirmed the previously observed association with the FSHB locus and identified four additional novel signals in, or near, the GNRH1, PGR, NR5A2 and INS-IGF2 genes. These findings confirm the role of the hypothalamic-pituitary-gonadal axis in the genetic regulation of menstrual cycle length, but also highlight potential novel local regulatory mechanisms, such as those mediated by IGF2.
WNT4 and WNT3A activate cell autonomous Wnt signaling independent of PORCN or secretion
Authors: Rao Deviyani M. , Bordeaux Evelyn K. , Yamamoto Tomomi M. , Bitler Benjamin G. , Sikora Matthew J. 
Published: May 2018

AbstractThe enzyme PORCN is considered essential for Wnt secretion and signaling, however, we observed PORCN inhibition did not phenocopy the effects of WNT4 knockdown in WNT4-dependent breast cancer cells. This suggests a unique relationship between PORCN and WNT4 signaling. To examine the role of PORCN in WNT4 signaling, WNT4 or WNT3A were over-expressed in breast and ovarian cancer, and fibrosarcoma cell lines. Conditioned medium from these lines, and co-culture systems, were used to assess the dependence of Wnt secretion and activity on critical Wnt secretion proteins PORCN and WLS. We observed that WLS was universally required for Wnt secretion and paracrine signaling. In contrast, the dependence of WNT3A secretion and activity on PORCN varied across cell lines, and WNT4 secretion was PORCN-independent in all models. Surprisingly, WNT4 did not present paracrine activity in any tested context. Absent the expected paracrine activity of secreted WNT4, we identified cell autonomous Wnt signaling activation by WNT4 and WNT3A, independent of PORCN or secretion. The PORCN-independent, cell-autonomous Wnt signaling demonstrated herein may be critical in WNT4-driven cellular contexts, or those that are otherwise considered to have dysfunctional Wnt signaling.Summary StatementWnt proteins can mediate an atypical mode of cell-autonomous signaling, distinct from paracrine signaling, that is independent of both palmitoylation by PORCN and Wnt secretion.
SciReader: A Cloud-based Recommender System for Biomedical Literature
Authors: Desai Priya , Telis Natalie , Lehmann Ben , Bettinger Keith , Pritchard Jonathan K. , Datta Somalee 
Published: May 2018

AbstractWith the growing number of biomedical papers published each year, keeping up with relevant literature has become increasingly important, and yet more challenging. SciReader (www.scireader.com) is a cloud-based personalized recommender system that specifically aims to assist biomedical researchers and clinicians identify publications of interest to them. SciReader uses topic modeling and other machine learning algorithms to provide users with recommendations that are recent, relevant, and of high quality1.
The hotspots in primate cortical brain evolution support supramodal cognitive flexibility
Authors: Sneve Markus H. , Grydeland Håkon , Rosa Marcello G. P. , Paus Tomáš , Chaplin Tristan , Walhovd Kristine , Fjell Anders M. 
Published: May 2018

AbstractPrimate cortical evolution has been characterized by massive and disproportionate expansion of a set of specific regions in the neocortex. The associated increase in neocortical neurons comes with a high metabolic cost, thus the functions served by these regions must have conferred significant evolutionary advantage. Here, across a series of experiments, we show that the evolutionary high-expanding ‘hotspots’ – as estimated from patterns of evolutionary expansion from several primate species – share functional connections with different brain networks in a context-dependent manner. This capacity of the hotspots to connect flexibly with various specialized brain networks depending on particular cognitive requirements suggests that their selective growth and sustainment in evolution has been linked to their involvement in supramodal cognition. In accordance with an evolutionary-developmental view, we find that this ability to flexibly modulate functional connections as a function of cognitive state emerges gradually through childhood, with a prolonged developmental trajectory plateauing in young adulthood.
Wealth-relative effects in cooperation games
Authors: Shuler Robert L. 
Published: May 2018

AbstractThis paper investigates conditions under which game agents benefit from considering wealth relative to decision payoff, presents simulation analysis of these effects, and explains why they often do not show up but it is realistic that they should. We extend the known categories of games reported to exhibit wealth relative effects (chicken games) to many others (including Prisoner’s Dilemma) while clarifying that the poor must avoid survival risk, regardless of whether this is associated with cooperation or defection. A simulation of iterated Prisoner’s Dilemma with wealth accumulation and a survival threshold (which we call the Farmer’s Game) is used to evaluate tit-for-tat and four variants, including Subsist, Thief, Exploit and Middle (even lower risk than Subsist). Equilibrium payoffs are used to keep the game scaled to social relevance, with a fraction of all payoffs externalized as a turn cost parameter. Findings include poor performance of tit-for-tat near the survival threshold, superior performance of Subsist and Middle for both poor and wealthy players, dependence of survival of the poor near the threshold on tit-for-tat forgiveness, unexpected optimization of forgiveness without encountering a social dilemma, improved performance of a diverse mix of strategies, and a more abrupt threshold of social catastrophe for the better performing mix. Additionally we find that experimental results which appear to be at odds with conventional findings of cooperation vs. network size can be reconciled with theory and simulation via wealth-relative weighting, which opens the door to practical application of cooperation theory.Significance StatementEnabling comparison of theoretical and simulated game cooperation theory results to controlled experiments with live subjects and in-situ data from field surveys will enable application of scientifically verified results to societal and policy problems, and will generate new and unexpected insights through clearer interpretation of data. Extension of wealth-relative effects to a broader range of games also allows analysis of real life situations with greater confidence.
Adiposity-Independent Effects of Aging on Insulin Sensitivity and Clearance in Humans and Mice
Authors: Ehrhardt Nicole , Cui Jinrui , Dagdeviren Sezin , Saengnipanthkul Suchaorn , Goodridge Helen S. , Kim Jason K. , Lantier Louise , Guo Xiuqing , Chen Yii-Der I. , Raffel Leslie J. , Buchanan Thomas A. , Hsueh Willa A. , Rotter Jerome I. , Goodarzi Mark O. , Péterfy Miklós 
Published: May 2018

ABSTRACTAims/hypothesisAging is associated with impaired insulin sensitivity and increased prevalence of type 2 diabetes. However, it remains unclear whether aging-related insulin resistance is due to age per se, or increased adiposity associated with advanced age. In the present study, we investigate the impact of aging on insulin sensitivity independent of changes in body composition.MethodsCohorts of C57BL/6J male mice at 4-8 months of age (‘young’) and 18-27 mo (‘aged’) exhibiting similar body composition were characterized with static (plasma glucose and insulin levels) and dynamic (glucose and insulin tolerance tests) measures of glucose metabolism on chow and high-fat diets. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp analysis. The relationship between aging and insulin resistance in humans was investigated in 1,250 non-diabetic Mexican-American individuals who underwent hyperinsulinemic-euglycemic clamps.ResultsIn mice with similar body composition, age had no detrimental effect on plasma glucose and insulin levels. However, aged mice demonstrated mildly, but reproducibly, improved glucose tolerance on both chow and high-fat diets due to increased glucose-stimulated insulin secretion. Moreover, hyperinsulinemic-euglycemic clamps revealed impaired insulin sensitivity and reduced insulin clearance in aged mice on both diets. Consistent with results in the mouse, age remained an independent determinant of insulin resistance after adjustment for body composition in Mexican-Americn males. Advanced age was also associated with diminished insulin clearance, but this effect was dependent on increased BMI.Conclusions/interpretationThis study demonstrates for the first time that aging per se impairs insulin sensitivity independent of adiposity in mice and humans. These results raise the possibility that the pathogenetic mechanisms of age-related and obesity-associated insulin resistance are distinct.AbbreviationsBAIbody adiposity indexGEEgeneralized estimating equations HF high-fatIQRinterquartile rangeMCRImetabolic clearance rate of insulinT2Dtype 2 diabetes