bluuebunny/crossref_metadata_2025_split huggingface dataset:
Decoding the transcriptome of muscular dystrophy due to Ptrf deficiency using single‐nucleus RNA sequencing
Authors: Li Xiaokai , Zhong Zhining , Zhang Ruowei , Zhang Jiaman , Zhang Yu , Zeng Sha , Du Qinjiao , Wang Haoming , Zhang Songling , Lu Lu , Li Mingzhou , Long Keren 
Published: May 2023

AbstractLacking PTRF (polymerase I and transcript release factor), an essential caveolae component, causes a secondary deficiency of caveolins resulting in muscular dystrophy. The transcriptome responses of different types of muscle fibers and mononuclear cells in skeletal muscle to muscular dystrophy caused by Ptrf deletion have not been explored. Here, we created muscular dystrophy mice by Ptrf knockout and applied single‐nucleus RNA sequencing (snRNA‐seq) to unveil the transcriptional changes of the skeletal muscle at single‐nucleus resolution. 11 613 muscle nuclei (WT, 5838; Ptrf KO, 5775) were classified into 12 clusters corresponding to 11 nuclear types. Trajectory analysis revealed the potential transition between type IIb_1 and IIb_2 myonuclei upon muscular dystrophy. Functional enrichment analysis indicated that apoptotic signaling and enzyme‐linked receptor protein signaling pathway were significantly enriched in type IIb_1 and IIb_2 myonuclei of Ptrf KO, respectively. The muscle structure development and the PI3K‐AKT signaling pathway were significantly enriched in type IIa and IIx myonuclei of Ptrf KO. Meanwhile, metabolic pathway analysis showed a decrease in overall metabolic pathway activity of myonuclei subtypes upon muscular dystrophy, with the most decrease in type IIb_1 myonuclei. Gene regulatory network analysis found that the activity of Mef2c, Mef2d, Myf5, and Pax3 regulons was enhanced in type II myonuclei of Ptrf KO, especially in type IIb_2 myonuclei. In addition, we investigated the transcriptome changes in adipocytes and found that muscular dystrophy enhanced the lipid metabolic capacity of adipocytes. Our findings provide a valuable resource for exploring the molecular mechanism of muscular dystrophy due to Ptrf deficiency.
Self-Reported Disadvantage in Medical School Admissions: A Call to Review, Revise, and Further Advance Holistic Review
Authors: Harrison Leila E. , Fletcher Laura , Dunleavy Dana , Price-Johnson Tanisha , Vashi Kundu Roopal , Fogerty Glen T. , Berardi-Demo Linda 
Published: May 2023

Purpose
This study examined how applicants interpret the self-reported disadvantaged (SRD) question in the American Medical College Application Service (AMCAS) application.

Method
Data from 129,262 applicants who applied through AMCAS from 2017 through 2019 were used, including financial and family history, demographic characteristics, and work status and residence. Fifteen applicants from the 2020 and 2021 AMCAS cycles were interviewed about their experiences with the SRD question.

Results
Large effects were found for SRD applicants with fee assistance waivers (h = 0.89), Pell grants (h = 1.21), state or federal aid (h = 1.10), and parents with less education (h = 0.98) and non-SRD applicants with a large proportion of their education paid by family (d = 1.03). Another large difference was found for reported family income distribution (73% of SRD applicants reporting family income < $50,000 vs 15% of non-SRD applicants). More SRD applicants were Black or Hispanic (26% vs 16% and 5% vs 5%), Deferred Action for Childhood Arrivals recipients (11% vs 2%), born outside the United States (32% vs 16%), and raised in a medically underserved area (60% vs 14%). There was a moderate effect for first-generation to college SRD applicants (h = 0.61). SRD applicants had lower Medical College Admission Test scores (d = 0.62) and overall and science grade point averages (d = 0.50 and 0.49, respectively) but no meaningful differences in acceptance or matriculation rates. The interviews identified 5 themes: (1) unclear disadvantage definition; (2) different perceptions of disadvantage and overcoming challenges or obstacles; (3) identification as disadvantaged or not; (4) SRD essay content; and (5) concerns about lack of transparency in how the SRD question is used in admissions.

Conclusions
Revising the SRD question by including context, phrasing, and instructions for broader experience categories might be beneficial because of lack of transparency and understanding.
Midterm Development of Ultrasound-unstable Hip Joints After Overhead Traction and Treatment With Tübingen Splint and Fettweis Plaster: A Radiologic Follow-up Analysis Over 5.5 Years
Authors: Oezel Lisa , Kubo Hannes , Krauspe Rüdiger , Pilge Hakan , Holthoff Jan-Philipp , Latz David , Schiffner Erik , Westhoff Bettina 
Published: May 2023

Purpose:
The aim of this study was to determine the success rate for treatment of ultrasound unstable hips (type D, III and IV) with Fettweis plaster in terms of a midterm follow-up from the very beginning in the neonatal period until the age of 4 to 8 years.

Methods:
In total, 69 unstable hips, which were successfully treated with Fettweis plaster and after with a flexion-abduction splint, were included into the study. Hip delvelopment was followed by determining the acetabular index (ACI) on routine pelvic radiographs at the age of 12 to ≤24, 24 to ≤48 and 48 to ≤96 months and the center edge angle on the latter, and classifying both angles according to Tönnis.

Results:
After initially successful treatment, the first radiograph at the age of 12 to ≤24 months showed 39.1% (n=27) hips with normal findings, 33.2% (n=23) hips with slightly dysplastic findings, and 27.5% (n=19) hips with severe dysplastic findings. Comparison between first and second radiograph showed improvement of the ACI in 9/69 hips and between the second and third time point in 20/69 hips. Overall, 20 hip joints showed deteriorations. Hereby, 16 deteriorations took place after the first radiograph and 4 after the second radiograph. Deteriorations were observed independently of the initial hip type (D, III, and IV).

Conclusions:
Midterm results indicate that radiologic controls should be provided to detect deteriorations after finishing treatment. ACI and center edge angle are helpful parameters in the assessment of hip joint development in the age range of 4 to 8 years.

Level of Evidence:
Level III.
Medium-Term Outcomes of Conservative and Surgical Treatments for Stress Urinary Incontinence: A Medicare Claims Analysis
Authors: Hall Evelyn F. , Biller Daniel H. , Buss Joanna L. , Ferzandi Tanaz , Halder Gabriela E. , Muffly Tyler M. , Nickel Katelin B. , Nihira Mikio , Olsen Margaret A. , Wallace Shannon L. , Lowder Jerry L. 
Published: May 2023

Objective
This study aimed to evaluate the 3- to 5-year retreatment outcomes for conservatively and surgically treated urinary incontinence (UI) in a population of women 66 years and older.

Methods
This retrospective cohort study used 5% Medicare data to evaluate UI retreatment outcomes of women undergoing physical therapy (PT), pessary treatment, or sling surgery. The data set used inpatient, outpatient, and carrier claims from 2008 to 2016 in women 66 years and older with fee-for-service coverage. Treatment failure was defined as receiving another UI treatment (pessary, PT, sling, Burch urethropexy, or urethral bulking) or repeat sling. A secondary analysis was performed where additional treatment courses of PT or pessary were also considered a treatment failure. Survival analysis was used to evaluate the time from treatment initiation to retreatment.

Results
Between 2008 and 2013, 13,417 women were included with an index UI treatment, and follow-up continued through 2016. In this cohort, 41.4% received pessary treatment, 31.8% received PT, and 26.8% underwent sling surgery. In the primary analysis, pessaries had the lowest treatment failure rate compared with PT (P<0.001) and sling surgery (P<0.001; survival probability, 0.94 [pessary], 0.90 [PT], 0.88 [sling]). In the analysis where retreatment with PT or a pessary was considered a failure, sling surgery had the lowest retreatment rate (survival probability, 0.58 [pessary], 0.81 [PT], 0.88 [sling]; P<0.001 for all comparisons).

Conclusions
In this administrative database analysis, there was a small but statistically significant difference in treatment failure among women undergoing sling surgery, PT, or pessary treatment, but pessary use was commonly associated with the need for repeat pessary fittings.
A handheld luminometer with sub-attomole limit of detection for distributed applications in global health
Authors: Lebel Paul , Elledge Susanna , Wiener Diane M. , Jeyakumar Ilakkiyan , Phelps Maíra , Jacobsen Axel , Huynh Emily , Charlton Chris , Puccinelli Robert , Mondal Prasenjit , Saha Senjuti , Tato Cristina M. , Gómez-Sjöberg Rafael 
Published: May 2023

AbstractLuminescence is ubiquitous in biology research and medicine. Conceptually simple, the detection of luminescence nonetheless faces technical challenges because relevant signals can exhibit exceptionally low radiant power densities. Although low light detection is well-established in centralized laboratory settings, the cost, size, and environmental requirements of high-performance benchtop luminometers are not compatible with geographically-distributed global health studies or resource-constrained settings. Here we present the design and application of a ∼$700 US handheld, battery-powered luminometer with performance on par with high-end benchtop instruments. By pairing robust and inexpensive Silicon Photomultiplier (SiPM) sensors with a low-profile shutter system, our design compensates for sensor non-idealities and thermal drift, achieving a limit of detection of 1.6E-19 moles of firefly luciferase, or approximately 1fW of radiant optical power. Using these devices, we performed split luciferase serology studies to monitor sars-cov-2 antibodies in a cohort in the United States, as well as a field study in Bangladesh.
Right Heart Remodeling After Pulmonary Valve Replacement in Patients with Pulmonary Atresia or Critical Stenosis with Intact Ventricular Septum
Authors: Irwin Margaret , Reynolds Lindsey , Binney Geoffrey , Lipsitz Stuart , Ghelani Sunil J , Harrild David M , Baird Christopher W , Geva Tal , Brown David W. 
Published: May 2023

AbstractBackgroundPatients with pulmonary atresia or critical pulmonary stenosis with intact ventricular septum (PA/IVS) and biventricular circulation may require pulmonary valve replacement (PVR). Right ventricular (RV) remodeling after PVR is well-described in tetralogy of Fallot (TOF); we sought to investigate RV changes in PA/IVS using cardiac magnetic resonance imaging (CMR).MethodsA retrospective cohort of PA/IVS patients who underwent PVR at Boston Children’s Hospital from 1995-2021 with CMR before and after PVR was matched 1:3 with TOF patients by age at PVR. Median regression modeling was performed with post-PVR indexed RV end-diastolic volume (RVEDVi) as the primary outcome.Results20 PA/IVS patients (cases) were matched with 60 TOF (controls), with median age at PVR 14 years. Pre-PVR RVEDVi was similar between groups; cases had higher RV ejection fraction (EF; 51.4 vs 48.6%, p=0.03). Pre-PVR RV free wall and LV longitudinal strain (LS) were similar, although LV mid-cavity circumferential strain (CS) was decreased in cases (−15.6 vs -17.1, p=0.001). At median 2 years after PVR, RVEDVi was similarly reduced; cases continued to have higher RV EF (52.3% vs 46.9%, p=0.007) with less reduction in RV mass (Δ4.5 vs 9.6 g/m2, p=0.004). Post PVR, RV and LV LS remained unchanged and LV CS was similar, though lower in cases.ConclusionCompared with TOF patients, PA/IVS patients demonstrate similar RV remodeling after PVR, with lesser reduction in RV mass and comparatively higher RVEF. While no differences were detected in peak systolic RV or LV strain values, further investigation of diastolic parameters is needed.Clinical Perspective-This paper provides new insights on the remodeling of the right heart in patients pulmonary atresia with intact ventricular septum or critical pulmonary stenosis, namely that compared with tetralogy of Fallot patients, these patients demonstrate overall similar right ventricular remodeling following pulmonary valve replacement.-CMR strain imaging found no significant pre-post pulmonary valve replacement differences in right ventricular or left ventricular systolic parameters
Spatiotemporal kinetics of CAF-1-dependent chromatin maturation ensures transcription fidelity during S-phase
Authors: Chen Boning , MacAlpine Heather K. , Hartemink Alexander J. , MacAlpine David M. 
Published: May 2023

AbstractProper maintenance of epigenetic information after replication is dependent on the rapid assembly and maturation of chromatin. Chromatin Assembly Complex 1 (CAF-1) is a conserved histone chaperone that deposits (H3-H4)2tetramers as part of the replication-dependent chromatin assembly process. Loss of CAF-1 leads to a delay in chromatin maturation, albeit with minimal impact on steady-state chromatin structure. However, the mechanisms by which CAF-1 mediates the deposition of (H3-H4)2tetramers and the phenotypic consequences of CAF-1-associated assembly defects are not well understood. We used nascent chromatin occupancy profiling to track the spatiotemporal kinetics of chromatin maturation in both wild-type (WT) and CAF-1 mutant yeast cells. Our results show that loss of CAF-1 leads to a heterogeneous rate of nucleosome assembly, with some nucleosomes maturing at near WT kinetics and others exhibiting significantly slower maturation kinetics. The slow-to-mature nucleosomes are enriched in intergenic and poorly transcribed regions, suggesting that transcription-dependent assembly mechanisms can reset the slow-to-mature nucleosomes following replication. Nucleosomes with slow maturation kinetics are also associated with poly(dA:dT) sequences, which implies that CAF-1 deposits histones in a manner that counteracts resistance from the inflexible DNA sequence, promoting the formation of histone octamers as well as ordered nucleosome arrays. In addition, we demonstrate that the delay in chromatin maturation is accompanied by a transient and S-phase specific loss of gene silencing and transcriptional regulation, revealing that the DNA replication program can directly shape the chromatin landscape and modulate gene expression through the process of chromatin maturation.
Inhibitory G proteins play multiple roles to polarize sensory hair cell morphogenesis
Authors: Jarysta Amandine , Tadenev Abigail L.D. , Day Matthew , Krawchuk Barry , Low Benjamin E. , Wiles Michael V. , Tarchini Basile 
Published: May 2023

ABSTRACTInhibitory G alpha (GNAI or Gαi) proteins are critical for the polarized morphogenesis of sensory hair cells and for hearing. The extent and nature of their actual contributions remains unclear, however, as previous studies did not investigate all GNAI proteins and included non-physiological approaches. Pertussis toxin can downregulate functionally redundant GNAI1, GNAI2, GNAI3 and GNAO proteins, but may also induce unrelated defects. Here we directly and systematically determine the role(s) of each individual GNAI protein in mouse auditory hair cells. GNAI2 and GNAI3 are similarly polarized at the hair cell apex with their binding partner GPSM2, whereas GNAI1 and GNAO are not detected. InGnai3mutants, GNAI2 progressively fails to fully occupy the subcellular compartments where GNAI3 is missing. In contrast, GNAI3 can fully compensate for the loss of GNAI2 and is essential for hair bundle morphogenesis and auditory function. Simultaneous inactivation ofGnai2andGnai3recapitulates for the first time two distinct types of defects only observed so far with pertussis toxin: 1) a delay or failure of the basal body to migrate off-center in prospective hair cells, and 2) a reversal in the orientation of some hair cell types. We conclude that GNAI proteins are critical for hair cells to break planar symmetry and to orient properly before GNAI2/3 regulate hair bundle morphogenesis with GPSM2.
Genetically Identical Mice Express Alternative Reproductive Tactics Depending on Social Conditions in the Field
Authors: Zipple Matthew N. , Vogt Caleb C. , Sheehan Michael J 
Published: May 2023

AbstractIn many species, establishing and maintaining a territory is critical to survival and reproduction, and an animal’s ability to do so is strongly influenced by the presence and density of competitors. Here we manipulate social conditions to study the alternative reproductive tactics displayed by genetically identical, age-matched laboratory mice competing for territories under ecologically realistic social environmental conditions. We introduced adult males and females of the laboratory mouse strain (C57BL/6J) into a large, outdoor field enclosure containing defendable resource zones under one of two social conditions. We first created a low-density social environment, such that the number of available territories exceeded the number of males. After males established stable territories, we introduced a pulse of intruder males and observed the resulting defensive and invasive tactics employed. In response to this change in social environment, males with large territories invested more in patrolling but were less effective at excluding intruder males as compared to males with small territories. Intruding males failed to establish territories and displayed an alternative tactic featuring greater exploration as compared to genetically identical territorial males. Alternative tactics did not lead to equal reproductive success—males that acquired territories experienced greater survival and had greater access to females.
Bayesian target optimisation for high-precision holographic optogenetics
Authors: Triplett Marcus A. , Gajowa Marta , Adesnik Hillel , Paninski Liam 
Published: May 2023

AbstractTwo-photon optogenetics has transformed our ability to probe the structure and function of neural circuits. However, achieving precise optogenetic control of neural ensemble activity has remained fundamentally constrained by the problem of off-target stimulation (OTS): the inadvertent activation of nearby non-target neurons due to imperfect confinement of light onto target neurons. Here we propose a novel computational approach to this problem called Bayesian target optimisation. Our approach uses nonparametric Bayesian inference to model neural responses to optogenetic stimulation, and then optimises the laser powers and optical target locations needed to achieve a desired activity pattern with minimal OTS. We validate our approach in simulations and using data fromin vitroexperiments, showing that Bayesian target optimisation considerably reduces OTS across all conditions we test. Together, these results establish our ability to overcome OTS, enabling optogenetic stimulation with substantially improved precision.
Implications of variable synaptic weights for rate and temporal coding of cerebellar outputs
Authors: Wu Shuting , Wardak Asem , Khan Mehak M. , Chen Christopher H. , Regehr Wade G. 
Published: May 2023

AbstractPurkinje cell (PC) synapses onto cerebellar nuclei (CbN) neurons convey signals from the cerebellar cortex to the rest of the brain. PCs are inhibitory neurons that spontaneously fire at high rates, and many uniform sized PC inputs are thought to converge onto each CbN neuron to suppress or eliminate firing. Leading theories maintain that PCs encode information using either a rate code, or by synchrony and precise timing. Individual PCs are thought to have limited influence on CbN neuron firing. Here, we find that single PC to CbN synapses are highly variable in size, and using dynamic clamp and modelling we reveal that this has important implications for PC-CbN transmission. Individual PC inputs regulate both the rate and timing of CbN firing. Large PC inputs strongly influence CbN firing rates and transiently eliminate CbN firing for several milliseconds. Remarkably, the refractory period of PCs leads to a brief elevation of CbN firing prior to suppression. Thus, PC-CbN synapses are suited to concurrently convey rate codes, and generate precisely-timed responses in CbN neurons. Variable input sizes also elevate the baseline firing rates of CbN neurons by increasing the variability of the inhibitory conductance. Although this reduces the relative influence of PC synchrony on the firing rate of CbN neurons, synchrony can still have important consequences, because synchronizing even two large inputs can significantly increase CbN neuron firing. These findings may be generalized to other brain regions with highly variable sized synapses.
The temporal and genomic scale of selection following hybridization
Authors: Groh Jeffrey , Coop Graham 
Published: May 2023

1AbstractGenomic evidence supports an important role for selection in shaping patterns of introgression along the genome, but frameworks for understanding the dynamics underlying these patterns within hybrid populations have been lacking. Here, we develop methods based on the Wavelet Transform to understand the spatial genomic scale of local ancestry variation and its association with recombination rates. We present theory and use simulations to show how wavelet-based decompositions of ancestry variance along the genome and the correlation between ancestry and recombination reflect the joint effects of recombination, genetic drift, and genome-wide selection against introgressed alleles. Due to the clock-like effect of recombination in hybrids breaking up parental haplotypes, drift and selection produce predictable patterns of local ancestry variation at varying spatial genomic scales through time. Using wavelet approaches to identify the genomic scale of variance in ancestry and its correlates, we show that these methods can detect temporally localized effects of drift and selection. We apply these methods to previously published datasets from hybrid populations of swordtail fish (Xiphophorus) and baboons (Papio), and to inferred Neanderthal introgression in modern humans. Across systems, we find that upwards of 20% of the variation in local ancestry at the broadest genomic scales can be attributed to systematic selection against introgressed alleles, consistent with strong selection acting on early-generation hybrids. We also see signals of selection at fine genomic scales and much longer time scales. However, we show that our ability to confidently infer selection at fine scales is likely limited by inherent biases in current methods for estimating local ancestry from genomic similarity. Wavelet approaches will become widely applicable as genomic data from systems with introgression become increasingly available, and can help shed light on generalities of the genomic consequences of interspecific hybridization.