bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dermorphin [D-Arg2, Lys4] (1-4) amide inhibits below-level heat hypersensitivity in mice after contusive thoracic spinal cord injury
Authors: Liu Shuguang , Huang Qian , He Shaoqiu , Chen Zhiyong , Gao Xinyan , Ma Danxu , Duan Wanru , Ford Neil , Yang Fei , Chen Xueming , Raja Srinivasa N. , Hao Dingjun , Guan Yun 
Published: July 2019

Abstract
Opioid use for chronic pain is limited by severe central adverse effects. We examined whether activating mu-opioid receptors (MORs) in the peripheral nervous system attenuates spinal cord injury (SCI) pain-like behavior in mice. We produced a contusive SCI at the T10 vertebral level and examined motor and sensory dysfunction for 6 weeks. At 6 weeks, we tested the effect of subcutaneous (s.c.) injection of dermorphin [D-Arg2, Lys4] (1-4) amide (DALDA), a peripherally acting MOR-preferring agonist, on mechanical and heat hypersensitivity. Basso mouse scale score was significantly decreased after SCI, and mice showed hypersensitivity to mechanical and heat stimulation at the hind paw beginning at 2 weeks, as indicated by increased paw withdrawal frequency to mechanical stimulation and decreased paw withdrawal latency to heat stimulation. In wild-type SCI mice, DALDA (1 mg/kg, s.c.) attenuated heat but not mechanical hypersensitivity. The effect was blocked by pretreatment with an intraperitoneal injection of methylnaltrexone (5 mg/kg), a peripherally restricted opioid receptor antagonist, and was also diminished in Pirt-MOR conditional knockout mice. DALDA did not adversely affect exploratory activity or induced preference to drug treatment in SCI mice. In vivo calcium imaging showed that DALDA (1, 10 mg/kg, s.c.) inhibited responses of small dorsal root ganglion neurons to noxious heat stimulation in Pirt-GCaMP6s mice after SCI. Western blot analysis showed upregulation of MOR in the lumbar spinal cord and sciatic nerves at 6 weeks after SCI. Our findings suggest that peripherally acting MOR agonist may inhibit heat hypersensitivity below the injury level with minimal adverse effects.
Comparing the Barriers and Facilitators of Heart Failure Management as Perceived by Patients, Caregivers, and Clinical Providers
Authors: Trivedi Ranak B. , Slightam Cindie , Nevedal Andrea , Guetterman Timothy C. , Fan Vincent S. , Nelson Karin M. , Rosland Ann-Marie , Heidenreich Paul A. , Timko Christine , Asch Steven M. , Piette John D. 
Published: July 2019

Background:
Heart failure (HF) management requires the participation of patients, their significant others, and clinical providers. Each group may face barriers to HF management that may be unique or may overlap.

Objective:
The aim of this study was to compare the barriers and facilitators of HF management as perceived by patients, significant others, and clinical providers.

Methods:
Participants were recruited from a Veterans Health Administration facility. Eligible patients had a diagnosis of HF (ICD9 code 428.XX), 1 or more HF-related visit in the previous year, and a significant other who was their primary caregiver. Significant others were adults with no history of cognitive impairments caring for patients with HF. Providers were eligible if they cared for patients with HF. All participants completed semistructured interviews designed to elicit barriers to managing HF and strategies that they used to overcome these barriers. Interviews were transcribed and analyzed using latent thematic analysis, and recruitment continued until thematic saturation was attained.

Results:
A total of 17 couples and 12 providers were recruited. All 3 groups identified poor communication as a key barrier to HF management, including communication between patients and their significant other, between couples and providers, and providers with each other. Significant others noted that the lack of direct communication with clinical providers hindered their efforts to care for the patient. All 3 groups emphasized the importance of family members in optimizing adherence to HF self-management recommendations.

Conclusions:
Providers, patients, and significant others all play important and distinct roles in the management of HF. Tools to enhance communication and collaboration for all 3 and supporting the needs of significant others are missing components of current HF care.
Factors Influencing Cardiovascular Risk Factors and Health Perception Among Kentuckians Living in Appalachia
Authors: Abraham Cilgy M. , Kelly Sarah , Wantland Dean , Chung Misook L. , Mudd-Martin Gia , Biddle Martha J. , Moser Debra K. 
Published: July 2019

Background:
Cardiovascular disease (CVD) and risk factors for CVD are prevalent among Appalachians from Kentucky. Appalachian men and women have high rates of engagement in unhealthy behaviors and poor physical health measures that increase their risk for CVD.

Objective:
In this study, the relationship among gender, CVD risk factors, and health perception in Appalachians from Kentucky was explored.

Methods:
This cross-sectional secondary analysis is from a randomized controlled trial on CVD health in rural Kentucky. To assess gender differences in smoking history, χ
2 was used. Independent t tests compared the mean between participants 50 years or younger and those older than 50 years with differences in body mass index (BMI), waist circumference, systolic and diastolic blood pressure, hemoglobin A1C, total cholesterol, and physical activity. A multivariate linear regression analysis assessed variables predicting the outcome of health perception.

Results:
Most participants had a mean BMI of 33 kg/m2 and 94.3% of men used smokeless tobacco compared to 5.7% of the women. Differences existed between gender and current, ever, or never smoked (P < .001). Women had higher total cholesterol levels but men had higher waist circumference. Participants older than 50 years had higher engagement in physical activity than did those 50 years or younger. Higher BMI and hemoglobin A1C level were significant predictors of worse health perception (P ≤ .05). For every unit increase in the physical activity scale, there was a 0.2-unit improvement in health perception (P ≤ .001).

Conclusion:
Appalachians from Kentucky have many CVD risk factors. Minimal engagement in preventative measures against CVD can worsen patient outcomes.
Screening Versus Brief Domain-specific Tests to Assess Long-term Postoperative Cognitive Dysfunction After Concomitant Aortic Valve Replacement and Coronary Artery Bypass Grafting
Authors: Pérez-Belmonte Luis M. , Florido-Santiago Mercedes , Osuna-Sánchez Julio , Barbancho Miguel A. , Millán-Gómez Mercedes , Jímenez-Navarro Manuel F. , Bernal-López M. Rosa , Gómez-Huelgas Ricardo , Lara José P. 
Published: July 2019

Background
Although postoperative cognitive dysfunction is a relevant complication after surgery, assessment for the condition is not routine in clinical practice.

Objective
The aim of this study was to compare the use of screening versus brief domain-specific cognitive tests in assessing long-term cognitive dysfunction after concomitant aortic valve replacement and coronary artery bypass grafting.

Methods
In this observational prospective study, we evaluated 70 patients preoperatively and after 1, 6, and 12 months using 2 screening tests (Mini-Mental State Examination and Clock Drawing Test) and 2 brief domain-specific cognitive tests (Trail Making Test to evaluate attention and executive function, and Semantic and Phonological Tests to evaluate verbal fluency).

Results
The brief domain-specific cognitive tests detected significant postoperative worsening in performances (up to 19% on the Trail Making Test and 15.4% on verbal fluency tests at 6 months). Postoperative mild attention/executive dysfunction or inferior normal performance was detected with the maximums being seen at 6 months (44.6%, P < .001). Performances on screening tests did not significantly change during the study period.

Conclusions
A brief domain-specific cognitive evaluation could be routinely implemented in perioperative care practice to detect postoperative cognitive dysfunction.
Fox Insight Collects Online, Longitudinal Patient-Reported Outcomes and Genetic Data on Parkinson’s disease
Authors: Smolensky Luba , Amondikar Ninad , Crawford Karen , Neu Scott , Kopil Catherine M. , Daeschler Margaret , Riley Lindsey ,   23andMe Research Team, Brown Ethan , Toga Arthur W. , Tanner Caroline 
Published: July 2019

AbstractFox Insight is an online, longitudinal health study of people with and without Parkinson’s disease with targeted enrollment set to at least 125,000 individuals. Fox Insight data is a rich data set facilitating discovery, validation, and reproducibility in Parkinson’s disease research. The dataset is generated through routine longitudinal assessments (health and medical questionnaires evaluated at regular cycles), one-time questionnaires about environmental exposure and healthcare preferences, and genetic data collection.Qualified Researchers can explore, analyze, and download patient-reported outcomes (PROs) data and Parkinson’s disease-related genetic variants at https://foxden.michaeljfox.org. The full Fox Insight genetic data set, including approximately 600,000 single nucleotide polymorphisms (SNPs), can be requested separately with institutional review and are described outside of this data descriptor.Fox Insight is sponsored by The Michael J. Fox Foundation for Parkinson’s Research.
Super-resolution microscopy unveils FIP200-scaffolded, cup-shaped organization of mammalian autophagic initiation machinery
Authors: Kenny Samuel J , Chen Xuyan (Shirley) , Ge Liang , Xu Ke 
Published: July 2019

AbstractAutophagy is an essential physiological process by which eukaryotic cells degrade and recycle cellular materials. Although the biochemical hierarchies of the mammalian autophagy pathway have been identified, questions remain regarding the sequence, subcellular location, and structural requirements of autophagosome formation. Here, we characterize the structural organization of key components of the mammalian autophagic initiation machinery at ∼20 nm spatial resolution via three-color, three-dimensional super-resolution fluorescence microscopy. We thus show that upon cell starvation, FIP200, a large structural protein of the ULK1 complex with no direct yeast homolog, scaffolds the formation of cup-like structures located at SEC12-enriched remodeled ER-exit sites prior to LC3 lipidation. This cup scaffold, then, provides a structural asymmetry to enforce the directional recruitment of downstream components, including the Atg12-Atg5-Atg16 complex, WIPI2, and LC3, to the cup inside. Moreover, we provide evidence that the early autophagic machinery is recruited in its entirety to these cup structures prior to LC3 lipidation, and gradually disperses and dissociates on the outer face of the phagophore membrane during elongation. We thus shed new light on the physical process of mammalian autophagic initiation and development at the nanometer-scale.
Can Orthopaedics become the Gold Standard for Reproducibility? A Roadmap to Success
Authors: Fladie Ian A. , Evans Sheridan , Checketts Jake , Tritz Daniel , Norris Brent , Vassar Matt 
Published: July 2019

AbstractBackgroundScientific research is replete with poor accessibility to data, materials, and protocol, which limits the reproducibility of a study. Transparency with regard to materials, protocols, and raw data sets enhances reproducibility by providing the critical information necessary to verify, replicate, and resynthesize research findings. The extent to which transparency and reproducibility exist in the field of orthopaedics is unclear. In our study, we aimed to evaluate transparency and reproducibility-related characteristics of randomly sampled publications in orthopaedic journals.MethodsWe used the National Library of Medicine catalog to identify English language and MEDLINE-indexed orthopaedic journals. From the 74 journals meeting our inclusion criteria, we randomly sampled 300 publications using a refined PubMed search that were published between January 1, 2014, and December 31, 2018. Two investigators were trained for data extraction and analysis. Both investigators were blinded and independently extracted data from the 300 studies.ResultsOur initial search yielded 68,102 publications, from which we drew a random sample of 300 publications. Of these 300 publications, 286 were screened for empirical data and 14 were inaccessible. For analysis purposes, we excluded publications without empirical data. Of the 182 with empirical data, 13 studies (7.1%) included a data availability statement, 9 (4.9%) reported materials were available, none (0.0%) provided analysis scripts, 2 (1.1%) provided access to the protocol used, 5 (2.7%) were preregistered, and only 2 (1.1%) provided a statement about being a replicated study.ConclusionsComponents necessary for reproducibility are lacking in orthopaedic surgery journals. The vast majority of publications did not provide data or material availability statements, protocols, or analysis scripts, and had no preregistration statements. Intervention is needed to improve reproducibility in the field of orthopaedics. The current state of reproducibility in orthopaedic surgery could be improved by combined efforts from funding agencies, authors, peer reviewers, and journals alike.Level of EvidenceN/A
Induction of long-term allogeneic cell acceptance and formation of immune privileged tissue in immunocompetent hosts
Authors: Harding Jeffrey , Vintersten-Nagy Kristina , Shutova Maria , Yang Huijuan , Tang Jean Kit , Massumi Mohammad , Izaidfar Mohammad , Izadifar Zohreh , Zhang Puzheng , Li ChengJin , Nagy Andras 
Published: July 2019

ABSTRACTA vast number of diseases could be treated with therapeutic cells derived from pluripotent stem cells (PSCs). However, cell products that come from non-autologous sources can be immune rejected by the recipient’s immune system. Here, we show that forced expression of eight immunomodulatory transgenes, includingCcl21, Pdl1, Fasl, Serpinb9, H2-M3, Cd47, Cd200, andMfge8, allows mouse embryonic stem cells (mESCs) and their derivatives to escape immune rejection in fully immunocompetent, allogeneic recipients. Despite no genetic alterations to major histocompatibility complex (MHC) genes, immune-modified C57BL/6 mESCs could generate long-term, allogeneic tissues in inbred FVB/N, C3H, and BALB/c, as well as outbred CD-1 recipients. Due to the tandem incorporation of our safe-cell suicide system, which allows tight and drug-inducible control over proliferationin vivo, these allotolerated cells can generate safe and dormant ectopic tissues in the host. We show that these ectopic tissues maintain high expression of all eight immunomodulatory transgenes and are immune-privileged sites that can host and protect unmodified mouse and human cells from rejection in allogeneic and xenogeneic settings, respectively. If translated to human clinical settings, we envision the development of a single pluripotent cell line that can be used to generate allo-tolerated, off-the-shelf cell products to serve all humankind, as well as immune-privileged ectopic tissues to host and immune-protect any kind of therapeutic cell product.
The endoplasmic reticulum-associated mRNA-binding proteins ERBP1 and ERBP2 interact in bloodstream-formTrypanosoma brucei
Authors: Bajak Kathrin , Leiss Kevin , Clayton Christine , Erben Esteban 
Published: July 2019

AbstractKinetoplastids rely heavily on post-transcriptional mechanisms for control of gene expression, and on RNA-binding proteins that regulate mRNA splicing, translation and decay.Trypanosoma bruceiERBP1 (Tb927.10.14150) and ERBP2 (Tb927.9.9550) were previously identified as mRNA binding proteins that lack canonical RNA-binding domains. We here show that ERBP1 is associated with the endoplasmic reticulum, like ERBP2, and that the two proteins interactin vivo. Loss of ERBP1 from bloodstream-formT. bruceiinitially resulted in a growth defect but proliferation was restored after more prolonged cultivation. Results from a pull-down of tagged ERBP1 suggest that it preferentially binds to ribosomal protein mRNAs. The ERBP1 sequence resembles that ofSaccharomyces cerevisiaeBfr1, which also localises to the endoplasmic reticulum and binds to ribosomal protein mRNAs. However, unlike Bfr1, ERBP1 does not bind to mRNAs encoding secreted proteins, and it is also not recruited to stress granules after starvation.
Developmental Genome-Wide DNA Methylation Asymmetry Between Mouse Placenta and Embryo
Authors: Legault LM , Doiron K , Lemieux A , Caron M , Chan D , Lopes FL , Bourque G , Sinnett D , McGraw S 
Published: July 2019

ABSTRACTIn early embryos, DNA methylation is remodelled to initiate the developmental program but for mostly unknown reasons, methylation marks are acquired unequally between embryonic and placental cells. To better understand this, we generated high-resolution DNA methylation maps of mouse mid-gestation (E10.5) embryo and placenta. We uncovered specific subtypes of differentially methylated regions (DMRs) that contribute directly to the developmental asymmetry existing between mid-gestation embryonic and placental DNA methylation patterns. We show that the asymmetry occurs rapidly during the acquisition of marks in the post-implanted conceptus (E3.5-E6.5), and that these patterns are long-lasting across subtypes of DMRs throughout prenatal development and in somatic tissues. We reveal that at the peri-implantation stages, thede novomethyltransferase activity of DNMT3B is the main driver of methylation marks on asymmetric DMRs, and that DNMT3B can largely compensate for lack of DNMT3A in the epiblast and extraembryonic ectoderm, whereas DNMT3A can only partially compensate in the absence of DNMT3B. However, as development progresses and as DNMT3A becomes the principalde novomethyltransferase, the compensatory DNA methylation mechanism of DNMT3B on DMRs becomes less effective.
Rapid resistance to pesticide control is predicted to evolve in an invasive fish
Authors: Christie Mark R. , Sepúlveda Maria S. , Dunlop Erin S. 
Published: July 2019

AbstractXenobiotic resistance is commonly found in species with short generation times such as bacteria, annual plants, and insects. Nevertheless, the fundamental evolutionary principles that govern the spread of resistance alleles hold true for species with longer generation times. One such example could occur with sea lamprey (Petromyzon marinus), a parasitic invasive species in the Laurentian Great Lakes that decimated native fish populations prior to its control with the pesticide 3-trifluoromethyl-4-nitrophenol (TFM). Since the 1950s, tributaries have been treated annually with TFM, where treatments effectively remove most, but not all, larval sea lamprey. We developed an eco-genetic model of sea lamprey to examine factors affecting the evolution of resistance and found that resistance alleles rapidly rise to fixation after 40-80 years of treatment, despite the species’ relatively long generation time (4-7 years). The absence of natal homing allows resistant individuals to spread quickly throughout the entire system, but also makes the early detection of resistance challenging. High costs of resistance and density independent reproduction can delay, but not prevent, the onset of resistance. These results illustrate that sea lamprey have the potential to evolve resistance to their primary control agent in the near future, highlighting the urgent need for alternative controls.
Probabilistic index models for testing differential expression in single cell RNA sequencing data
Authors: Assefa Alemu Takele , Vandesompele Jo , Thas Olivier 
Published: July 2019

AbstractSingle-cell RNA sequencing (scRNA-seq) technologies profile gene expression patterns in individual cells. It is often of interest to test for differential expression (DE) between conditions, e.g. treatment vs control or between cell types. Simulation studies have shown that non-parametric tests, such as the Wilcoxon-rank sum test, can robustly detect significant DE, with better performance than many parametric tools specifically developed for scRNA-seq data analysis. However, these rank tests cannot be used for complex experimental designs involving multiple groups, multiple factors and confounding variables. Further, rank based tests do not provide an interpretable measure of the effect size. We propose a semi-parametric approach based on probabilistic index models (PIM) that form a flexible class of models that generalize classical rank tests. Our method does not rely on strong distributional assumptions and it allows accounting for confounding factors. Moreover, it allows for the estimation of the effect size in terms of a probabilistic index. Real data analysis demonstrate that PIM is capable of identifying biologically meaningful DE. Our simulation studies also show that DE tests succeed well in controlling the false discovery rate at its nominal level, while maintaining good sensitivity as compared to competing methods.
Evaluating the burstlet theory of inspiratory rhythm and pattern generation
Authors: Kallurkar Prajkta S. , Grover Cameron , Picardo Maria Cristina D. , Del Negro Christopher A. 
Published: July 2019

ABSTRACTThe preBötzinger complex (preBötC) generates the rhythm and rudimentary motor pattern for inspiratory breathing movements. Here, we test ‘burstlet’ theory (Kam, Worrell, Janczewski, et al. 2013), which posits that low amplitude burstlets, subthreshold from the standpoint of inspiratory bursts, reflect the fundamental oscillator of the preBötC. In turn, a discrete suprathreshold process transforms burstlets into full amplitude inspiratory bursts that drive motor output, measurable via hypoglossal nerve (XII) dischargein vitro. We recap observations by Kam & Feldman: field recordings from preBötC demonstrate bursts and concurrent XII motor output intermingled with lower amplitude burstlets that do not produce XII motor output. Manipulations of excitability affect the relative prevalence of bursts and burstlets and modulate their frequency. Whole-cell and photonic recordings of preBötC neurons suggest that burstlets involve inconstant subsets of rhythmogenic interneurons. We conclude that discrete rhythm- and pattern-generating mechanisms coexist in the preBötC and that burstlets reflect its fundamental rhythmogenic nature.
Low-dose Perampanel rescues cortical gamma dysregulation associated with parvalbumin interneuron GluA2 upregulation in epileptic Syngap1+/- mice
Authors: Sullivan Brennan J. , Ammanuel Simon , Kipnis Pavel A. , Araki Yoichi , Huganir Richard L. , Kadam Shilpa D. 
Published: July 2019

AbstractLoss-of-function SYNGAP1 mutations cause a neurodevelopmental disorder characterized by intellectual disability and epilepsy. SYNGAP1 is a Ras-GTPase-activating protein that underlies the formation and experience-dependent regulation of postsynaptic densities. The mechanisms that contribute to this proposed monogenic cause of intellectual disability and epilepsy remain unresolved. Here, we establish the phenotype of the epileptogenesis in a Syngap1+/- mouse model using 24h video electroencephalogram/electromyogram (vEEG/EMG) recordings at advancing ages. A progressive worsening of clinically-similar seizure phenotypes, interictal spike frequency, sleep dysfunction, and hyperactivity was identified in Syngap1+/- mice. Interictal spikes emerged predominantly during NREM in 24h vEEG of Syngap1+/- mice. Myoclonic seizures occurred at behavioral-state transitions both in Syngap1+/- mice and during an overnight EEG from a child with SYNGAP1 haploinsufficiency. In Syngap1+/- mice, EEG spectral power analyses identified a significant loss of cortical gamma homeostasis during behavioral-state transitions from NREM to Wake and NREM to REM. The loss of gamma homeostasis was associated with a region- and location-specific significant increase of GluA2 AMPA receptor subunit expression in the somas of parvalbumin-positive (PV+) interneurons. Acute dosing with Perampanel, an FDA approved AMPA antagonist significantly rescued cortical gamma homeostasis, identifying a novel mechanism implicating Ca2+ impermeable AMPARs on PV+ interneurons underlying circuit dysfunction in SYNGAP1 haploinsufficiency.