bluuebunny/crossref_metadata_2025_split huggingface dataset:
Decoding muscle-resident Schwann cell dynamics during neuromuscular junction remodeling
Authors: Guzman Steve D , Abu-Mahfouz Ahmad , Davis Carol S , Ruiz Lloyd P , Macpherson Peter C , Brooks Susan V 
Published: October 2023

AbstractUnderstanding neuromuscular junction (NMJ) repair mechanisms is essential for addressing degenerative neuromuscular conditions. Here, we focus on the role of muscle-resident Schwann cells in NMJ reinnervation. In youngSod1-/-mice, a model of progressive NMJ degeneration, we identified a clear NMJ ‘regenerative window’ that allowed us to define regulators of reinnervation and crossingSod1-/-mice withS100GFP-tg mice permitted visualization and analysis of Schwann cells. High-resolution imaging and single-cell RNA sequencing provide a detailed analysis of Schwann cell number, morphology, and transcriptome revealing multiple subtypes, including a previously unrecognized terminal Schwann cell (tSC) population expressing a synapse promoting signature. We also discovered a novel SPP1-driven cellular interaction between myelin Schwann cells and tSCs and show that it promotes tSC proliferation and reinnervation following nerve injury in wild type mice. Our findings offer important insights into molecular regulators critical in NMJ reinnervation that are mediated through tSCs to maintain NMJ function.
Temperature Influences Commensal-Pathogen Dynamics in a Nasal Epithelial Cell Co-culture Model
Authors: Huffines Joshua T. , Boone RaNashia L. , Kiedrowski Megan R. 
Published: October 2023

ABSTRACTChronic rhinosinusitis (CRS) is an inflammatory disease of the paranasal sinuses, and microbial dysbiosis associated with CRS is thought to be a key driver of host inflammation that contributes to disease progression.Staphylococcus aureusis a common upper respiratory tract (URT) pathobiont that is associated with higher carriage rates in CRS populations, whereS. aureussecreted toxins can be identified in CRS tissue samples. Although many genera of bacteria colonize the URT, relatively few account for the majority of sequencing reads. These includeS. aureus, as well as several species belonging to the genusCorynebacterium, includingCorynebacterium propinquumandCorynebacterium pseudodiphtheriticum, which are observed at high relative abundance in the URT of healthy individuals. Studies have examined the bacterial interactions between the major microbionts of the URT andS. aureus, but few have done so in the context of a healthy versus diseased URT environment. Here, we examine the role of temperature in commensal, pathogen, and epithelial dynamics using an air-liquid interface cell culture model mimicking the nasal epithelial environment. The healthy URT temperature changes from the nares to the nasopharynx and is altered during disease. Temperatures representative of the healthy URT increase persistence and aggregate formation of commensalC. propinquum and C. pseudodiphtheriticum, reduceS. aureusgrowth, and lower epithelial cytotoxicity compared to higher temperatures correlating with the diseased CRS sinus. Dual-species colonization revealed species-specific interactions between commensalCorynebacteriumspecies andS. aureusdependent on temperature. Our findings suggest that URT mucosal temperature plays a significant role in mediating polymicrobial and host-bacterial interactions that may exacerbate microbial dysbiosis found in chronic URT disease.IMPORTANCEChronic rhinosinusitis is a complex inflammatory disease with a significant healthcare burden. Although presence ofS. aureusand microbial dysbiosis are considered mediators of inflammation in CRS, no studies have examined the influence of temperature onS. aureusinteractions with the nasal epithelium and the dominant genus of the healthy URT,Corynebacterium. Interactions betweenCorynebacterium speciesandS. aureushave been documented in several studies, but none to date have examined how environmental changes in the URT may alter their interactions with the epithelium or each other. This study utilizes a polarized epithelial cell culture model at air-liquid interface to study the colonization and spatial dynamics ofS. aureusand clinical isolates ofCorynebacteriumfrom people with CRS to characterize the role temperature has in single-and dual-species dynamics on the nasal epithelium.
Comparative Proteomic Study of Retinal Ganglion Cells Undergoing Various Types of Cellular Stressors
Authors: Starr Christopher R. , Mobley James A. , Gorbatyuk Marina S. 
Published: October 2023

AbstractRetinal ganglion cell (RGC) damage serves as a key indicator of various retinal degenerative diseases, including diabetic retinopathy (DR), glaucoma, retinal arterial and retinal vein occlusions, as well as inflammatory and traumatic optic neuropathies. Despite the growing body of data on the RGC proteomics associated with these conditions, there has been no dedicated study conducted to compare the molecular signaling pathways involved in the mechanism of neuronal cell death. Therefore, we launched the study using two different insults leading to RGC death: glutamate excitotoxicity and optic nerve crush (ONC). C57BL/6 mice were used for the study and underwent NMDA- and ONC-induced damage. Twenty-four hours after ONC and 1 hour after NMDA injection, we collected RGCs using CD90.2 coupled magnetic beads, prepared protein extracts, and employed LC-MS for the global proteomic analysis of RGCs. Statistically significant changes in proteins were analyzed to identify changes to cellular signaling resulting from the treatment. We identified unique and common alterations in protein profiles in RGCs undergoing different types of cellular stresses. Our study not only identified both unique and shared proteomic changes but also laid the groundwork for the future development of a therapeutic platform for testing gene candidates for DR and glaucoma.
Single-cell RNA sequencing unveils the hidden powers of zebrafish kidney for generating both hematopoiesis and adaptive antiviral immunity
Authors: Hu Chongbin , Zhang Nan , Hong Yun , Tie Ruxiu , Fan Dongdong , Lin Aifu , Chen Ye , Xiang Lixin , Shao Jianzhong 
Published: October 2023

AbstractThe vertebrate kidneys play two evolutionary conserved roles in waste excretion and osmoregulation. Besides, the kidney of fish is considered as a functional ortholog of mammalian bone marrow that serves as a hematopoietic hub for generating blood cell lineages and immunological responses. However, knowledge about the properties of kidney hematopoietic cells, and the functionality of kidney in fish immune systems remain to be elucidated. To this end, our present study generated a comprehensive atlas with 59 hematopoietic stem/progenitor cell (HSPC) and immune-cell types from zebrafish kidney via single-cell transcriptome profiling analysis. These populations included almost all known cells associated with innate and adaptive immunity, and displayed differential responses to viral infection, indicating their diverse functional roles in antiviral immunity. Remarkably, HSPCs were found to have extensive reactivities to viral infection, and the trained immunity can be effectively induced in certain HSPCs. In addition, the antigen-stimulated adaptive immunity can be fully generated in kidney, suggesting kidney acting as a secondary lymphoid organ. These results indicated that fish kidney is a dual-functional entity with functionalities of both primary and secondary lymphoid organs. Our findings illustrated the unique features of fish immune system, and highlighted the multifaced biology of kidney in ancient vertebrates.
Biomechanical stress analysis of Type-A aortic dissection at pre-dissection, post-dissection, and post-repair states
Authors: Sun Christina , Qin Tongran , Kalyanasundaram Asanish , Elefteriades John , Sun Wei , Liang Liang 
Published: October 2023

ABSTRACTAcute type A aortic dissection remains a deadly and elusive condition, with risk factors such as hypertension, bicuspid aortic valves, and genetic predispositions. As existing guidelines for surgical intervention based solely on aneurysm diameter face scrutiny, there is a growing need to consider other predictors and parameters, including wall stress, in assessing dissection risk. Through our research, we aim to elucidate the biomechanical underpinnings of aortic dissection and provide valuable insights into its prediction and prevention.We applied finite element analysis (FEA) to assess stress distribution on a rare dataset comprising computed tomography (CT) images obtained from eight patients at three stages of aortic dissection: pre-dissection (preD), post-dissection (postD), and post-repair (postR). Our findings reveal significant increases in both mean and peak aortic wall stresses during the transition from the preD state to the postD state, reflecting the mechanical impact of dissection. Surgical repair effectively restores aortic wall diameter to pre-dissection levels, documenting its effectiveness in mitigating further complications. Furthermore, we identified stress concentration regions within the aortic wall that closely correlated with observed dissection borders, offering insights into high-risk areas.This study demonstrates the importance of considering biomechanical factors when assessing aortic dissection risk. Despite some limitations, such as uniform wall thickness assumptions and the absence of dynamic blood flow considerations, our patient-specific FEA approach provides valuable mechanistic insights into aortic dissection. These findings hold promise for improving predictive models and informing clinical decisions to enhance patient care.
Non-pharmacological interventions aimed at promoting the mental health of children and adolescents during the COVID-19 pandemic
Authors: Quiroga Carolina Villanova , Caobelli Anna Clara Sarmento Leite , Rodrigues Gabriela Veiga Alano , Viola Thiago Wendt 
Published: October 2023

ABSTRACTBackgroundInterventions to promote mental health in pediatrics need to be effective, especially in crisis contexts. This systematic review proposes compile and analyze the findings of non-pharmacological interventions conducted in samples of children and adolescents during the COVID-19 pandemic, focusing on mental health.MethodThe research was carried out in PsycINFO, PubMed and Web of Science databases for empirical studies, including interventions in which measures of outcome variables were collected at least twice (pre and post). The studies’ samples were children and adolescents up to 19 years old, and interventions were developed throughout the COVID-19 pandemic. After eligibility analyses, 16 studies were included in this review.ResultsStudies used different theoretical approaches, focusing on promotion, prevention and treatment in mental health in specifics contexts. Some were delivered online, in-person, or in hybrid formats. Particularly, depression, the most frequently assessed outcome, demonstrated more favorable results within the interventions. However, due to considerable risk of bias, the analysis of results of many included studies should be performed with caution.ConclusionsMost of the interventions necessitate further validation. However, the emergence of interventions during crises, such as the COVID-19 pandemic, provides an opportunity to expand evidence-based mental health practices, paving the way for their application in other crisis situations. Given that mental health prevention and promotion practices can be integrated into the roles of all healthcare providers, possessing insight into the most suitable evidence-based interventions can elevate the quality of care delivered.
A conserved N-terminal motif of CUL3 mediates assembly and licenses E3 ligase activation of CRL3KLHL22
Authors: Wang Weize , Liang Ling , Dai Zonglin , Zuo Peng , Yu Shang , Lv Yishuo , Ding Dian , Chen Hongyi , Jin Yan , Mao Youdong , Yin Yuxin 
Published: October 2023

AbstractThe CUL3-RING E3 ubiquitin ligases (CRL3s) play an essential role in response to extracellular nutrition and stress stimuli. The ubiquitin ligase function of CRL3s is activated through E3-E3 dimerization. However, how and why such a dimeric assembly is required for its ligase activity remains elusive. Here, we report the cryo-EM structure of the dimeric CRL3KLHL22complex and reveal a conserved N-terminal motif in CUL3 that mediates the dimerization assembly and licenses the activation of CRL3KLHL22. Deletion of the CUL3 N-terminal motif leads to non-stochiometric assembly and impairs E3 activity of both CRL3KLHL22and several other CRL3s. In addition, we found that the dynamics of dimeric E3-E3 superassembly generates a variable ubiquitination zone, potentially facilitating substrate recognition and ubiquitination. These findings demonstrate a CUL3 N-terminal motif-dependent E3-E3 superassembly mechanism and provide insights into the assembly and activation of CRL3s.
Exploiting Intrinsic Noise for Heterogeneous Cell Control Under Time Delays and Model Uncertainties
Authors: May M P , Munsky B 
Published: October 2023

AbstractThe majority of previous research in synthetic biology has focused on enabling robust control performance despite the presence of noise, while the understanding for how controllers may exploit that noise remains incomplete. Motivated by Maxwell’s Demon, we previously proposed a cellular control regime in which the exploitation of stochastic noise can break symmetry between and allow for specific control of multiple cells using a single input signal (i.e., single-input-multiple-output or SIMO control). The current work extends that analysis to include uncertain stochastic systems where system dynamics are are affected by time delays, intrinsic noises, and model uncertainty. We find that noise-exploiting controllers can remain highly effective despite coarse approximations to the model’s scale or incorrect estimations or extrinsic noise in key model parameters, and these controllers can even retain performance under substantial observer or actuator time delays. We also demonstrate how SIMO controllers could drive multi-cell systems to follow different trajectories with different phases and frequencies. Together, these findings suggest that noise-exploiting control should be possible even in the practical case where models are always approximate, where parameters are always uncertain, and where observations are corrupted by errors.
PKHD1L1, A Gene Involved in the Stereocilia Coat, Causes Autosomal Recessive Nonsyndromic Hearing Loss
Authors: Redfield Shelby E. , De-la-Torre Pedro , Zamani Mina , Wang Hanjun , Khan Hina , Morris Tyler , Shariati Gholamreza , Karimi Majid , Kenna Margaret A. , Seo Go Hun , Xu Hongen , Lu Wei , Naz Sadaf , Galehdari Hamid , Indzhykulian Artur A. , Shearer A. Eliot , Vona Barbara 
Published: October 2023

AbstractIdentification of genes associated with nonsyndromic hearing loss is a crucial endeavor given the substantial number of individuals who remain without a diagnosis after even the most advanced genetic testing.PKHD1L1was established as necessary for the formation of the cochlear hair-cell stereociliary coat and causes hearing loss in mice and zebrafish when mutated. We sought to determine if biallelic variants inPKHD1L1also cause hearing loss in humans.Exome sequencing was performed on DNA of four families segregating autosomal recessive nonsyndromic sensorineural hearing loss. Compound heterozygous p.[(Gly129Ser)];p.[(Gly1314Val)] and p.[(Gly605Arg)];p[(Leu2818TyrfsTer5)], homozygous missense p.(His2479Gln) and nonsense p.(Arg3381Ter) variants were identified inPKHD1L1that were predicted to be damaging usingin silicopathogenicity prediction methods.In vitrofunctional analysis of two missense variants was performed using purified recombinant PKHD1L1 protein fragments. We then evaluated protein thermodynamic stability with and without the missense variants found in one of the families and performed a minigene splicing assay for another variant.In silicomolecular modelling using AlphaFold2 and protein sequence alignment analysis were carried out to further explore potential variant effects on structure.In vitrofunctional assessment indicated that both engineered PKHD1L1 p.(Gly129Ser) and p.(Gly1314Val) mutant constructs significantly reduced the folding and structural stabilities of the expressed protein fragments, providing further evidence to support pathogenicity of these variants. Minigene assay of the c.1813G>A p.(Gly605Arg) variant, located at the boundary of exon 17, revealed exon skipping leading to an in-frame deletion of 48 amino acids.In silicomolecular modelling exposed key structural features that might suggest PKHD1L1 protein destabilization.Multiple lines of evidence collectively associatePKHD1L1with nonsyndromic mild-moderate to severe sensorineural hearing loss.PKHD1L1testing in individuals with mild-moderate hearing loss may identify further affected families.
Clinical interpretation ofKCNH2variants using a robust PS3/BS3 functional patch clamp assay
Authors: Thomson Kate L. , Jiang Connie , Richardson Ebony , Westphal Dominik S. , Burkard Tobias , Wolf Cordula M. , Vatta Matteo , Harrison Steven M. , Ingles Jodie , Bezzina Connie R. , Kroncke Brett M. , Vandenberg Jamie I. , Ng Chai-Ann 
Published: October 2023

SummaryLong QT syndrome (LQTS), caused by the dysfunction of cardiac ion channels, increases the risk of sudden death in otherwise healthy young people. For many variants in LQTS genes there is insufficient evidence to make a definitive genetic diagnosis. We have established a robust functional patch clamp assay to facilitate classification of missense variants inKCNH2, one of the key LQTS genes. A curated set of 30 benign and 30 pathogenic missense variants were used to establish the range of normal and abnormal function. The extent to which variants reduced protein function was quantified using Z-scores; the number of standard deviations from the mean of the normalised current density of the set of benign variant controls. A Z-score of –2 defined the threshold for abnormal loss-of-function, which corresponds to 55% wild-type function. More extreme Z-scores were observed for variants with a greater loss-of-function effect. We propose that the Z-score for each variant can be used to inform the application and weighting of abnormal and normal functional evidence criteria (PS3 and BS3) within the American College of Medical Genetics and Genomics (ACMG) variant classification framework. The validity of this approach was demonstrated using a series of 18KCNH2missense variants detected in a childhood onset LQTS cohort, where the level of function assessed using our assay correlated to the Schwartz score (a scoring system used to quantify the probability of a clinical diagnosis of LQTS1) and the length of the QTc interval.
Brain network hypersensitivity underlies pain crises in sickle cell disease
Authors: Joo Pangyu , Kim Minkyung , Kish Brianna , Nair Vidhya Vijayakrishnan , Tong Yunjie , Harte Steven E , Harris Richard E , Lee UnCheol , Wang Ying 
Published: October 2023

AbstractSickle cell disease (SCD) is a genetic disorder causing blood vessel blockages and painful Vaso-occlusive crises (VOCs). VOCs, characterized by severe pain due to blocked blood flow, are recurrent and unpredictable, posing challenges for preventive strategies. In this study we propose explosive synchronization (ES), a phenomenon characterized by abrupt brain network phase transitions, as a novel approach to address this challenge. We hypothesized that the accumulated disruptions in the brain network induced by SCD might lead to strengthened ES and hypersensitivity. We explored ES’s relationship with patient reported outcome measures (PROMs) and VOCs by analyzing EEG data from 25 SCD patients and 18 matched controls. SCD patients exhibited significantly lower alpha wave frequency than controls. SCD patients under painful pressure stimulation showed correlation between frequency disassortativity (FDA), an ES condition, and three important PROMs. Furthermore, patients who had a higher frequency of VOCs in the preceding 12 months presented with stronger FDA. The timing of VOC occurrence relative to EEG recordings was significantly associated to FDA. We also conducted computational modeling on SCD brain network to study FDA’s role in network sensitivity. Stronger FDA correlated with higher responsivity and complexity in our model. Simulation under noisy environment showed that higher FDA could be linked to increased occurrence frequency of crisis. This study establishes connections between SCD pain and the universal network mechanism, ES, offering a strong theoretical foundation. This understanding will aid predicting VOCs and refining pain management for SCD patients.
Effects of COVID-19 mRNA vaccination on HIV viremia and reservoir size
Authors: Duncan Maggie C. , Omondi F. Harrison , Kinloch Natalie N. , Lapointe Hope R. , Speckmaier Sarah , Moran-Garcia Nadia , Lawson Tanya , DeMarco Mari L. , Simons Janet , Holmes Daniel T. , Lowe Christopher F. , Bacani Nic , Sereda Paul , Barrios Rolando , Harris Marianne , Romney Marc G. , Montaner Julio S.G. , Brumme Chanson J. , Brockman Mark A. , Brumme Zabrina L. 
Published: October 2023

AbstractObjectiveThe immunogenic nature of COVID-19 mRNA vaccines led to some initial concern that these could stimulate the HIV reservoir. We analyzed changes in plasma HIV loads (pVL) and reservoir size following COVID-19 mRNA vaccination in 62 people with HIV (PWH) receiving antiretroviral therapy (ART), and analyzed province-wide trends in pVL before and after the mass vaccination campaign.DesignLongitudinal observational cohort and province-wide analysis.Methods62 participants were sampled pre-vaccination, and one month after their first and second COVID-19 immunizations. Vaccine-induced anti-SARS-CoV-2-Spike antibodies in serum were measured using the Roche Elecsys Anti-S assay. HIV reservoirs were quantified using the Intact Proviral DNA Assay; pVL were measured using the cobas 6800 (LLOQ:20 copies/mL). The province-wide analysis included all 290,401 pVL performed in British Columbia, Canada between 2012-2022.ResultsPre-vaccination, the median intact reservoir size was 77 (IQR:20-204) HIV copies/million CD4+ T-cells, compared to 74 (IQR:27-212) and 65 (IQR:22-174) post-first and -second dose, respectively (all comparisons p>0.07). Pre-vaccination, 82% of participants had pVL<20 copies/mL (max:110 copies/mL), compared to 79% post-first dose (max:183 copies/mL) and 85% post-second dose (max:79 copies/mL) (p>0.4). The magnitude of the vaccine-elicited anti-SARS-CoV-2-Spike antibody response did not correlate with changes in reservoir size nor detectable pVL frequency (p>0.6). We found no evidence linking the COVID-19 mass vaccination campaign to population-level increases in detectable pVL frequency among all PWH in the province, nor among those who maintained pVL suppression on ART.ConclusionWe found no evidence that COVID-19 mRNA vaccines induced changes in HIV reservoir size nor plasma viremia.