bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glial Synaptobrevin mediates peripheral nerve insulation, neural metabolic supply, and is required for motor function
Authors: Böhme Mathias A. , McCarthy Anthony W. , Blaum Natalie , Berezeckaja Monika , Ponimaskine Kristina , Schwefel David , Walter Alexander M. 
Published: April 2021

AbstractPeripheral nerves contain sensory and motor neuron axons coated by glial cells whose interplay ensures function, but molecular details are lacking. SNARE‐proteins mediate the exchange and secretion of cargo by fusing vesicles with target organelles, but how glial SNAREs contribute to peripheral nerve function is largely unknown. We, here, identify non‐neuronal Synaptobrevin (Syb) as the essential vesicular SNARE in Drosophila peripheral glia to insulate and metabolically supply neurons. We show that tetanus neurotoxin light chain (TeNT‐LC), which potently inhibits SNARE‐mediated exocytosis from neurons, also impairs peripheral nerve function when selectively expressed in glia, causing nerve disintegration, defective axonal transport, tetanic muscle hyperactivity, impaired locomotion, and lethality. While TeNT‐LC disrupts neural function by cleaving neuronal Synaptobrevin (nSyb), it targets non‐neuronal Synaptobrevin (Syb) in glia, which it cleaves at low rates: Glial knockdown of Syb (but not nSyb) phenocopied glial TeNT‐LC expression whose effects were reverted by a TeNT‐LC‐insensitive Syb mutant. We link Syb‐necessity to two distinct glial subtypes: Impairing Syb function in subperineurial glia disrupted nerve morphology, axonal transport, and locomotion, likely, because nerve‐isolating septate junctions (SJs) could not form as essential SJ components (like the cell adhesion protein Neurexin‐IV) were mistargeted. Interference with Syb in axon‐encircling wrapping glia left nerve morphology and locomotion intact but impaired axonal transport, likely because neural metabolic supply was disrupted due to the mistargeting of metabolite shuffling monocarboxylate transporters. Our study identifies crucial roles of Syb in various glial subtypes to ensure glial‐glial and glial‐neural interplay needed for proper nerve function, animal motility, and survival.
Co‐culture of exogenous oligodendrocytes with unmyelinated cerebella: Revisiting ex vivo models and new tools to study myelination
Authors: Baudouin Lucas , Adès Noémie , Kanté Kadia , Czarnecki Antonny , Bachelin Corinne , Baskaran Asha , Langui Dominique , Millécamps Aymeric , Gurchenkov Basile , Velut Yoan , Duarte Kévin , Barnier Jean‐Vianney , Nait Oumesmar Brahim , Bouslama‐Oueghlani Lamia 
Published: April 2021

AbstractCommon in vitro models used to study the mechanisms regulating myelination rely on co‐cultures of oligodendrocyte precursor cells (OPCs) and neurons. In such models, myelination occurs in an environment that does not fully reflect cell–cell interactions and environmental cues present in vivo. To avoid these limitations while specifically manipulating oligodendroglial cells, we developed a reliable ex vivo model of myelination by seeding OPCs on cerebellar slices, deprived of their endogenous oligodendrocytes. We showed that exogenous OPCs seeded on unmyelinated cerebella, efficiently differentiate and form compact myelin. Spectral confocal reflectance microscopy and electron microscopy analysis revealed that the density of compacted myelin sheaths highly increases all along the culture. Importantly, we defined the appropriate culture time frame to study OPC differentiation and myelination, using accurate quantification resources we generated. Thus, this model is a powerful tool to study the cellular and molecular mechanisms of OPC differentiation and myelination. Moreover, it is suitable for the development and validation of new therapies for myelin‐related disorders such as multiple sclerosis and psychiatric diseases.
Development of an assessment measure for sexual disinhibition in dementia
Authors: Chapman Kimberly R. , Tremont Geoffrey , Spitznagel Mary Beth 
Published: April 2021

AbstractObjectiveSexual disinhibition (SD), a neuropsychiatric symptom characterized by sexually inappropriate comments and/or behaviors, remains under identified in dementia, possibly due to a lack of standardized assessment methods. A recent systematic review of measures used to assess SD proposed four behavioral domains and identified the need for a population‐specific measure. The present study addressed this by examining the underlying factor structure of SD to create a new caregiver‐report measure.MethodsDementia caregivers (n = 622) recruited online were randomly assigned to Initial Validation (n = 311) or Cross‐Validation (n = 311) groups.ResultsInitial Validation revealed five behavioral domains that served as provisional scales for cross‐validation, leading to measure development.ConclusionsThe current study is the first to statistically evaluate the underlying factor structure of SD, resulting in a new measure that can help better characterize and identify SD.
Pharmacokinetics, Safety, and Efficacy of Glecaprevir/Pibrentasvir in Children With Chronic HCV: Part 2 of the DORA Study
Authors: Jonas Maureen M. , Rhee Susan , Kelly Deirdre A. , Del Valle‐Segarra Antonio , Feiterna‐Sperling Cornelia , Gilmour Susan , Gonzalez‐Peralta Regino P. , Hierro Loreto , Leung Daniel H. , Ling Simon C. , Lobzin Yuri , Lobritto Steven , Mizuochi Tatsuki , Narkewicz Michael R. , Sabharwal Vishakha , Wen Jessica , Kei Lon Hoi , Marcinak John , Topp Andrew , Tripathi Rakesh , Sokal Etienne 
Published: April 2021

Background and Aims
Glecaprevir/pibrentasvir (GLE/PIB) has shown high efficacy and safety in chronic HCV‐infected adults and adolescents; data in children were limited. DORA part 2 is a phase 2/3, nonrandomized, open‐label study evaluating the pharmacokinetics, efficacy, and safety of a pediatric formulation of GLE and PIB in children ages 3 to < 12 years.

Approach and Results
Children with chronic HCV infection, genotype 1‐6, with or without compensated cirrhosis, were divided into three cohorts by age—cohort 2 (9 to < 12 years), cohort 3 (6 to < 9 years), and cohort 4 (3 to < 6 years)—and given weight‐based doses of GLE and PIB for 8, 12, or 16 weeks. Primary endpoints were sustained virologic response at posttreatment week 12 (SVR12) and steady‐state exposure; secondary endpoints were rates of persistent viremia, relapse, and reinfection. Safety and laboratory abnormalities were assessed. Final pediatric dosages determined to be efficacious were 250 mg GLE + 100 mg PIB (in children weighing ≥ 30 to < 45 kg), 200 mg GLE + 80 mg PIB (≥ 20 to < 30 kg), and 150 mg GLE + 60 mg PIB (12 to < 20 kg). Of 80 participants enrolled and dosed, 96% (77/80) achieved SVR12. One participant, on the initial dose ratio, relapsed by posttreatment week 4; no participants had virologic failures on the final dose ratio of GLE 50 mg/PIB 20 mg. Two nonresponders prematurely discontinued the study. Most adverse events (AEs) were mild; no drug‐related serious AEs occurred. Pharmacokinetic exposures were comparable to those of adults.

Conclusions
A pediatric formulation of GLE/PIB was highly efficacious and well tolerated in chronic HCV‐infected children 3 to < 12 years old.
Saroglitazar, a PPAR‐α/γ Agonist, for Treatment of NAFLD: A Randomized Controlled Double‐Blind Phase 2 Trial
Authors: Gawrieh Samer , Noureddin Mazen , Loo Nicole , Mohseni Rizwana , Awasty Vivek , Cusi Kenneth , Kowdley Kris V. , Lai Michelle , Schiff Eugene , Parmar Deven , Patel Pankaj , Chalasani Naga 
Published: April 2021

Background and Aims
NAFLD is characterized by insulin resistance and dysregulated lipid and glucose metabolism. Saroglitazar, a dual peroxisome proliferator activated receptor‐α/γ agonist, improves insulin sensitivity, and lipid and glycemic parameters. Saroglitazar improved NASH histology in animal studies. In this randomized controlled clinical trial, we evaluated the efficacy and safety of saroglitazar in patients with NAFLD/NASH.

Approach and Results
A total of 106 patients with NAFLD/NASH with alanine aminotransferase (ALT) ≥ 50 U/L at baseline and body mass index ≥25 kg/m2 were randomized in a 1:1:1:1 ratio to receive placebo or saroglitazar 1 mg, 2 mg, or 4 mg for 16 weeks. The primary efficacy endpoint was percentage change from baseline in ALT levels at week 16. Liver fat content (LFC) was assessed by MRI proton density fat fraction. The least‐squares mean percent change from baseline in ALT at week 16 was −25.5% (5.8), −27.7% (5.9), and −45.8% (5.7), with saroglitazar 1 mg, 2 mg, and 4 mg, respectively, versus 3.4% (5.6) in placebo (P < 0.001 for all). Compared with placebo, saroglitazar 4 mg improved LFC (4.1% [5.9] vs. −19.7% [5.6]), adiponectin (−0.3 μg/mL [0.3] vs. 1.3 μg/mL [0.3]), homeostatic model assessment–insulin resistance (−1.3 [1.8] vs. −6.3 [1.7]), and triglycerides (−5.3 mg/dL [10.7] vs. −68.7 mg/dL [10.3]) (P < 0.05 for all). Saroglitazar 4 mg also improved lipoprotein particle composition and size and reduced lipotoxic lipid species. Saroglitazar was well‐tolerated. A mean weight gain of 1.5 kg was observed with saroglitazar 4 mg versus 0.3 kg with placebo (P = 0.27).

Conclusions
Saroglitazar 4 mg significantly improved ALT, LFC, insulin resistance, and atherogenic dyslipidemia in participants with NAFLD/NASH. (ClinicalTrials.gov identifier: NCT03061721.)
Cancer Risk in Patients With Biopsy‐Confirmed Nonalcoholic Fatty Liver Disease: A Population‐Based Cohort Study
Authors: Simon Tracey G. , Roelstraete Bjorn , Sharma Rajani , Khalili Hamed , Hagström Hannes , Ludvigsson Jonas F. 
Published: April 2021

Background and Aims
Recent studies link NAFLD to an increased incidence of HCC and extrahepatic cancers. However, earlier studies were small or lacked liver histology, which remains the gold standard for staging NAFLD severity.

Approach and Results
We conducted a population‐based cohort study of all adults with histologically defined NAFLD in Sweden from 1966 to 2016 (N = 8,892). NAFLD was defined from prospectively recorded liver histopathology submitted to all 28 Swedish pathology departments and categorized as simple steatosis, nonfibrotic NASH, noncirrhotic fibrosis, and cirrhosis. NAFLD patients were individually matched to ≤5 general population controls without NAFLD by age, sex, calendar year, and county (N = 39,907). Using Cox proportional hazards modeling, we calculated multivariable adjusted HRs (aHRs) and 95% CIs. Over a median of 13.8 years, we documented 1,691 incident cancers among NAFLD patients and 6,733 among controls. Compared with controls, NAFLD patients had significantly increased overall cancer incidence (10.9 vs. 13.8 per 1,000 person‐years [PYs]; difference = 2.9 per 1,000 PYs; aHR, 1.27 [95% CI, 1.18‐1.36]), driven primarily by HCC (difference = 1.1 per 1,000 PYs; aHR, 17.08 [95% CI, 11.56‐25.25]). HCC incidence rates increased monotonically across categories of simple steatosis, nonfibrotic NASH, noncirrhotic fibrosis, and cirrhosis (0.8 per 1,000 PYs, 1.2 per 1,000 PYs, 2.3 per 1,000 PYs, and 6.2 per 1,000 PYs, respectively; P
trend < 0.01) and were further amplified by diabetes (1.2 per 1,000 PYs, 2.9 per 1,000 PYs, 7.2 per 1,000 PYs, and 15.7 per 1,000 PYs, respectively). In contrast, NAFLD was associated with modestly increased rates of pancreatic cancer, kidney/bladder cancer, and melanoma (differences = 0.2 per 1,000 PYs, 0.1 per 1,000 PYs, and 0.2 per 1,000 PYs, respectively), but no other cancers.

Conclusions
Compared with controls, patients with biopsy‐proven NAFLD had significantly increased cancer incidence, attributable primarily to HCC, whereas the contribution of extrahepatic cancers was modest. Although HCC risk was highest with cirrhosis, substantial excess risk was also found with noncirrhotic fibrosis and comorbid diabetes.
Reliability of recharge rates estimated from groundwater age with a simplified analytical approach
Authors: Dong Yanhui , Xie Yueqing , Zhang Jun , Love Andrew J. , Dai Xin 
Published: April 2021

AbstractGroundwater age is often used to estimate groundwater recharge through a simplified analytical approach. This estimated recharge is thought to be representative of the mean recharge between the point of entry and the sampling point. However, given the complexity in actual recharge, whether the mean recharge is reasonable is still unclear. This study examined the validity of the method to estimate long‐term average groundwater recharge and the possibility of obtaining reasonable spatial recharge pattern. We first validated our model in producing reasonable age distributions using a constant flux boundary condition. We then generated different flow fields and age patterns by using various spatially varying flux boundary conditions with different magnitudes and wavelengths. Groundwater recharge was estimated and analysed afterwards using the method at the spatial scale. We illustrated the main findings with a field example in the end. Our results suggest that we can estimate long‐term average groundwater recharge with 10% error in many parts of an aquifer. The size of these areas decreases with the increase in both the amplitude and the wavelength. The chance of obtaining a reasonable groundwater recharge is higher if an age sample is collected from the middle of an aquifer and at downstream areas. Our study also indicates that the method can also be used to estimate local groundwater recharge if age samples are collected close to the water table. However, care must be taken to determine groundwater age regardless of conditions.
Obstetric fistula scoring tool for surgical trainees
Authors: Pope Rachel , Mernoff Rachel , Chalamanda Chisomo , Bengtson Angela M. 
Published: April 2021

AbstractObjectiveTo examine the ability of a previously published risk score to predict incontinence at discharge in women with vesicovaginal fistulas (VVF) and to examine how the score correlates with an independent assessment of surgical skill.MethodsThis is a retrospective cohort study including cases from January to June 2018. We evaluated operative records for factors associated with incontinence at hospital discharge, as well as relationships between a risk score cut‐point of 20 or more and surgical skill level. All women with VVF undergoing vaginal repair were included.ResultsA total of 176 individuals underwent repair; 23 were performed by beginner, 85 by intermediate, 47 by advanced, and 21 by expert surgeons. Factors found significantly associated with incontinence at hospital discharge included Goh classification, fistula size, circumferential fistula, and vaginal scarring. A score of 20 or more predicted residual incontinence with a negative predictive value of 92% (odds ratio 7.75, 95% confidence interval 2.95–22.34). Applying the score cut‐point of 20 or more, we found an increased proportion of “high‐risk” cases allocated to surgeons with an increasing level of expertise.ConclusionThe correlation we observed between a risk score cut‐point of 20 or more, continence status, and an independent assessment of surgical skill is promising. Although the risk score is not meant to replace clinical judgment, it may provide a surgical trainee with an objective method of determining whether to operate or refer for optimal outcomes.
Outcomes of donor versus partner sperm in intrauterine insemination in women aged 38 years and older
Authors: Frank Russell , Steiner Naama , Al Shatti Maryam , Ruiter‐Ligeti Jacob , Dahan Michael H. 
Published: April 2021

AbstractObjectiveTo compare pregnancy rates of donor versus partner sperm in intrauterine insemination (IUI) cycles in women aged 38 years and above.MethodsA retrospective cohort study was performed using data from 944 women aged 38–43 years old who underwent a combined 1596 IUI cycles at an academic fertility clinic in Montreal, Canada between February 2009 to April 2018.ResultsPartner sperm was used in 1421 cycles (89.0%), and donor sperm was inseminated in 175 cycles (11.0%). Mean ages of the women were 39.8 (±1.5) and 40.2 (±1.6) years in the partner and donor insemination groups, respectively (P < 0.001). Positive serum (β human chorionic gonadotropin) pregnancy rate in the partner sperm group was 9.0% (n = 128) whereas that in the donor insemination group was 9.7% (n = 17) (P = 0.759). Clinical pregnancy rates were 5.8% (n = 83) and 8.0% (n = 14) in the respective groups (P = 0.260). There were five multiple gestation (twin) pregnancies in the cohort, three in those undergoing IUI with partner sperm and two in those undergoing IUI with donor sperm.ConclusionIn women aged 38–43 years undergoing IUI with controlled ovarian stimulation, using donor sperm, compared with partner sperm, did not increase rate of pregnancy.
The developmental cascade of early parenting, emergence of executive functioning, and emotional symptoms across childhood
Authors: Murphy Yolanda E. , Zhang Xutong , Gatzke‐Kopp Lisa 
Published: April 2021

ABSTRACTMany studies focus on proximal associations between parental sensitivity and emotional well‐being in early childhood, with less data examining how parenting in infancy predicts children's emotional trajectories across childhood, in particular negative emotional symptoms of anxiety and depression. Thus, this study utilized data from The Family Life Project (N = 1015), a prospective study of child development in rural poverty, and assessed whether sensitive parenting in the first 4 years of life predicted child internalizing emotional symptoms (i.e., anxiety and depression) from kindergarten to fifth grade and whether early child executive functioning mediated this relationship. Path models indicated that observation of sensitive parenting predicted a decrease in teachers’ report of child negative emotional symptoms over time and predicted fewer negative emotional symptoms in fifth grade. Moreover, though executive functioning performance did not mediate change in symptoms over time, executive functioning did mediate the relationship between sensitive parenting and fifth‐grade symptoms, suggesting that executive functioning is one mechanism by which early sensitive parenting buffers long‐term emotional development. Findings highlight the importance of early parenting and executive functioning in development of anxiety and depression symptoms and suggests potential targets for transdiagnostic intervention.
Preparation and biological characteristics of a bovine acellular tendon fiber material
Authors: Zhou Shengyuan , Yuan Bo , Huang Wenmao , Tang Yifan , Chen Xiongsheng 
Published: April 2021

AbstractAcellular tendon matrix is an ideal substitute for constructing tissue engineering ligaments, but using detergents causes damage to collagen and fibrin during the process of decellularization. In this study, fresh tendons were lyophilized and separated into fresh tendon fiber (FTF) bundles, and then the cellular components in FTF were removed to prepare acellular tendon fiber (ATF) without adding chemical detergent. H&E staining and DAPI fluorescence microscopy showed no nucleus and DNA residue. Compared with FTFs, the DNA content of ATFs was significantly lower without the collagen content change before and after decellularization. The microstructure of collagen fibrils in ATFs was intact under scanning electron microscopy (SEM), and the maximum tensile load and elastic modulus between FTFs and ATFs were not statistically different. The ATF bundles were cultured with SD rat tenocytes for 72 hr and cells attachment to fiber surfaces were observed under SEM. ATF bundles were then implanted into paraspinal muscles, and histological analysis showed fibroblast‐like cells within the ATFs and was similar to the control group (fresh tendon autograft) in morphology. H&E staining showed that the number of lymphocytes and plasma cells in ATF was less than that in fresh tendon autograft. ATF bundles were twisted into linear fiber materials by hand, of which the maximum breaking strength was similar to silk with same diameter. These findings demonstrated that ATFs retain their original fibril structure and mechanical properties after decellularization by trypsin and pancreatic deoxyribonuclease without detergent. Lyophilized ATFs linear fiber material provides the possibility of preparing personalized ligament and other tissue engineering scaffolds.
Formulation and characterization of hydroxyapatite‐based composite with enhanced compressive strength and controlled antibiotic release
Authors: Ait Said Hamid , Noukrati Hassan , Oudadesse Hassane , Ben Youcef Hicham , Lefeuvre Bertrand , Hakkou Rachid , Lahcini Mohammed , Barroug Allal 
Published: April 2021

AbstractA composite based on hydroxyapatite (HA) and chitosan (CS) combined with ciprofloxacin (CIP) was formulated by the solid–liquid mixing method. The optimization of the solid to the liquid ratio and the use of chitosan in a small amount (≤5 wt%) promoted the preparation of stable and rigid monoliths. A synergistic effect of CS and CIP contents on the compressive strength of the CIP‐loaded composite was evidenced. The compressive strength of the fabricated biocomposite ranged in values from 1 to 6 MPa, comparable to those reported for cancellous bone. The improvement of the mechanical properties with the increase of the rate of organic components was correlated with the diminution of the surface area and the reduction in the pore volume of the specimens. On the other hand, the in vitro release experiments of the antibiotic indicated a sustained and controlled release of CIP over 10 days. Moreover, in vitro antibacterial tests performed on the biocomposite HA‐CS5‐CIP showed significant inhibition of Staphylococcus aureus and Escherichia coli pathogens. According to the showed results, the formulated composite with three‐phase components could be a promising material for bone repair and local antibiotic release for the treatment of bone infections.
Albumin covering maintains endothelial function upon magnetic iron oxide nanoparticles intravenous injection in rats
Authors: Toropova Yana G. , Zelinskaya Irina A. , Gorshkova Mariya N. , Motorina Daria S. , Korolev Dmitriy V. , Velikonivtsev Fedor S. , Gareev Kamil G. 
Published: April 2021

AbstractMagnetic iron oxide nanoparticles (IONP) present the promising instrument for broad‐spectrum of clinical applications, for example, targeted drug delivery. Reactivity of nanoparticles depends on their surface area and material. In the blood plasma IONP are getting covered with an albumin crown, so it was decided to test this shell for biocompatibility. Male Wistar rats were anesthetized and underwent laparotomy. Abdominal aorta was connected to external hemodynamic loop with regulated blood flow. Hind body quarter got step‐like blood flow changing from 30 to 150 mmHg and back. This was followed with i.v. injection of IONP, albumin solution or albumin‐covered IONP and consequent similar flow changes. Central hemodynamics—heart rate and mean arterial pressure were registered throughout the experiment and no significant changes in these parameters were observed. Hind paw microcirculation level had the same dynamic in all groups under changing blood flow conditions. At the end, venous blood was collected for endothelin‐1 and NO evaluation that showed similar changes and no endothelial damage. Mesenteric arteries and femoral artery reactivity were evaluated with wire myography. Mesenteric arteries had the most relaxing function preservation after albumin‐covered IONP injection. Given data reveal advantage of albumin‐coated IONP so this can be used for further investigations as a vascular‐safe vehicle.