Digital Commons Network^™

Signal Peptidase Complex Mediates Rotavirus Vp7 Processing And Virion Assembly, Xuejiao Zhu, Enkai Li, Liliana Sanchez-Tacuba, Wandy Beatty, Bin Li, Siyuan Ding

2020-Current year OA Pubs

For viruses that replicate in the proximity of or bud at the endoplasmic reticulum (ER) associated membranes, proper processing of their glycoproteins is critical for successful infection. Rotavirus outer capsid protein VP7 is an ER-resident protein. However, its N-terminal signal peptide is removed by an unknown proteolytic mechanism. In this study, we leveraged tandem affinity purification followed by high-resolution mass spectrometry to profile host proteins that interact with VP7. We identified members of the signal peptidase complex (SPC) family as important host factors that facilitate rotavirus infection. CRISPR knockout or siRNA knockdown of distinct SPC subunits resulted in significant decrease …

Synovial Fibroblast Responses To Different Types Of Injury Resulting In Cartilage Repair Or Osteoarthritis, Fraser L Collins, Alexander J Knights, Tristan Maerz, Anke J Roelofs, Cosimo De Bari

2020-Current year OA Pubs

OBJECTIVE: Single-cell RNA-sequencing (scRNA-seq) has advanced our understanding of the heterogeneity of synovial fibroblasts and their roles in tissue repair and osteoarthritis. Here, we compared the fibroblast responses to different types and duration of joint injury in mice.

DESIGN: Published scRNA-seq data of synovial fibroblasts from a model of joint surface injury (JSI, day 6) and two post-traumatic osteoarthritis models, destabilisation of the medial meniscus (DMM, day 7 and 2 months) and anterior cruciate ligament rupture (ACLR, day 7 and day 28), were integrated and analysed using clustering, DEG, gene-set enrichment, regulon, pseudotime trajectory and cell-cycle analyses.

RESULTS: The response …

Intraocular Amyloidosis Presenting With Secondary Glaucoma: A Clinical-Pathologic Report And Literature Review, Joseph B Lin, James C Liu, Rajendra S Apte, George J Harocopos

2020-Current year OA Pubs

PURPOSE: We describe a case of intraocular amyloidosis presenting as secondary glaucoma, highlighting the clinical presentation and pathologic correlates. We also review the medical literature on all prior reported cases and discuss the diagnostic challenges pertinent to this particular case.

OBSERVATIONS: We report the case of a 72-year-old man presenting with medically intractable elevations of intraocular pressure. On clinical examination, the anterior segment was unremarkable, but there were significant vitreous opacities. The patient underwent tube shunt surgery, and a simultaneous aqueous humor biopsy was acellular and nondiagnostic. A subsequent pars plana vitrectomy demonstrated amyloid aggregates on histology. Mass spectrometric analysis …

Atypical Superotemporal Iris And Retinal Coloboma, Katina N Patterson, Margaret M Reynolds, Gregg T Lueder

2020-Current year OA Pubs

PURPOSE: To report our findings in a patient with an atypical case of supertemporal iris and retinal coloboma, and to assess its systemic associations and potential genetic causes.

OBSERVATIONS: A premature female infant born at 31 weeks gestation presented a left eye superotemporal coloboma affecting both the iris and retina. Systemic abnormalities included a left multicystic kidney, hypoplastic left kidney, atrial septal defect, ventricular septal defect, and mild pulmonary valve stenosis. Whole genome sequencing and mitochondrial deoxyribonucleic acid (DNA) sequencing were performed, and both returned negative results.

CONCLUSIONS AND IMPORTANCE: The absence of genetic findings from the negative results of …

Comparison Of Variant Callers Using 60 532 Multi-Ancestry Whole Genome Sequences, Hufeng Zhou, Nathan O Stitziel, Et Al.

2020-Current year OA Pubs

Whole genome sequencing (WGS) studies play a pivotal role in studying the genetic underpinnings of human diseases and traits. High quality and reproducible variant calling is the cornerstone for the success of downstream analyses, including WGS association studies and polygenic risk prediction. This paper compares the data quality, performance, and concordance of two widely used WGS variant callers, the Genome Analysis Toolkit (GATK) and Variant Tool set that discovers short variants (VT), using 60 532 multi-ancestry whole genomes sequenced by the Centers for Common Disease Genomics (CCDGs) of the NHGRI Genome Sequencing Program. Our findings show that both QCed GATK …

Increased Clinical Frailty Is Associated With Aortic-Related Mortality Following Fenestrated And Branched Endovascular Repair For Thoracoabdominal Aortic Aneurysm, Silvia Chen, Elizabeth Ramirez, Blake E Murphy, Anjali Sribalaskandarajah, Martin Bunker, Joel Kruger, Karina A Newhall, Rebecca A Sorber, Sara L Zettervall, Matthew P Sweet

2020-Current year OA Pubs

OBJECTIVE: Clinical frailty is associated with reduced long-term survival after fenestrated and branched endovascular aortic repair (F/BEVAR). This study assesses the impact of phenotypic clinical frailty on perioperative outcomes and cause of death following F/BEVAR for thoracoabdominal aortic aneurysm.

METHODS: Patients who underwent F/BEVAR at a single institution from 2012 to 2024 were identified. The clinical frailty scale (CFS) was used to determine phenotypic frailty. Patients with a preoperative CFS of ≥4 (vulnerable) and a CFS of < 4 were compared. We used χ

RESULTS: We included 233 patients; 60 (25.8%) had a CFS of ≥4 and 173 (74.2%) had a CFS of < 4. Patients with a CFS of ≥4 were more likely to have chronic obstructive pulmonary disease (53% vs 27%) and were treated for slightly larger aneurysms (72 mm vs 68 mm; P = .04). There were no differences in symptomatic presentation, aneurysm extent, or operative complexity between patient groups. Additionally, there were no differences in perioperative complications including 30-day mortality, stroke, and spinal cord ischemia. Patients with a CFS of ≥4 had an increased length of hospitalization (11.3 days vs 6.9 days; P < .01) and were less likely to return to preoperative functional status (62.7% vs 86.1%; P < .01). The 3-year all-cause and aortic-related mortality rates were 35.2% and 5.7%, respectively. Patients with a CFS of ≥4 had a lower survival at 1 year (74% vs 89%), 3 years (39% vs 73%), and 5 years (25% vs 56%), compared with patients with a CFS of < 4 (P < .01). The most common causes of death among both groups were pulmonary comorbidities (14.0%), oncologic conditions (14.0%), cardiovascular comorbidities (11.2%), and procedure-related complications (11.2%). Patients with a CFS of ≥4 were more likely to die from aortic-related mortality (10.3% vs 5.9%; P = .02), pulmonary comorbidities (15.4 vs 13.2%; P = .04), systemic decline (7.7% vs 1.5%; P = .02), and infection (12.8% vs 7.4%; P = .03). Aortic-related mortality for the entire patient cohort was 2.2% and 5.7% at 1 year and 3 years, respectively. Aortic-related deaths among clinically frail patients were often due to an inability to tolerate further aortic operations (eg, arch repair), and secondary to follow-up nonadherence in patients with a CFS of < 4.

CONCLUSIONS: In an expanded …

Parkinson's Disease As A Somato-Cognitive Action Network Disorder, Jianxun Ren, Evan M Gordon, Nico U F Dosenbach, Et Al.

2020-Current year OA Pubs

Parkinson's disease (PD) is an incurable neurological disorder that often begins insidiously with sleep disturbances and somatic symptoms, progressing to whole-body motor and cognitive symptoms

A Quantitative Cell-Based Reporter Links Tdp-43 Aggregation And Dysfunction To Define Pathogenic Mechanisms, Lohany Diax Mamede, Miwei Hu, Jaime Vaquer-Alicea, Amanda R. Titus, Patricia M. Passos, Erica Lantelme, Rachel L French, Paige A. Kirschner, Marc I. Diamond, Timothy M. Miller, Yuna M. Ayala

2020-Current year OA Pubs

TDP-43 pathology is a hallmark of fatal neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43-encephalopathy (LATE). In affected patients, cytoplasmic TDP-43 aggregates are accompanied by disruption of its normal nuclear localization and function. Because TDP-43 is an RNA binding protein that controls transcript processing, including repression of cryptic exon splicing, its loss leads to dysregulation of gene expression. Despite its central significance in disease, the connection between TDP-43 aggregation and dysfunction remains poorly understood, and models to study the underlying mechanisms are limited. Here, we characterize a robust and quantitative cell-based reporter that captures …

From Damage Signals To Immune Modulators: Oxidized Lipids In Immunometabolic Inflammation, Neetu Srivastava, Xiaoxiao Wan

2020-Current year OA Pubs

Oxidized lipids, once viewed as byproducts of oxidative stress, are now recognized as critical mediators linking metabolism, redox imbalance, and immunity. Generated through enzymatic and nonenzymatic oxidation of polyunsaturated fatty acids, oxidized phospholipids, lipid aldehydes, and oxidized lipoproteins act as context-dependent signals regulating immune activation, resolution, and metabolic adaptation. In metabolic inflammation, these lipids engage scavenger and Toll-like receptors to influence macrophage polarization, dendritic-cell function, and T-cell differentiation. Their context and concentration determine whether oxidized lipids amplify inflammation or promote immune tolerance. Accumulation of these species connects oxidative stress to immune dysfunction, contributing to diseases, such as atherosclerosis, obesity, diabetes, …

Patient And Chondral Defect-Specific Characteristics And Associated Matrix-Induced Autologous Chondrocyte Implantation Conversion Rates Following Biopsy, Derrick M Knapik, Daniel C Touhey, S Ryan Pierson, Christopher K Bozorgmehr, Matthew V Smith, Matthew J Matava, Robert H Brophy

2020-Current year OA Pubs

BACKGROUND: Focal chondral defects in the knee lead to swelling, discomfort, and mechanical symptoms, resulting in disability and loss of function. Matrix-induced autologous chondrocyte implantation (MACI) has emerged as a viable treatment option, with satisfactory clinical outcomes reported compared with microfracture. Patient and lesion-specific variables associated with MACI after biopsy remain largely underreported.

PURPOSE: To examine patient- and defect-specific characteristics associated with conversion to MACI after biopsy from a single institution.

STUDY DESIGN: Cohort study; Level of evidence, 3.

METHODS: A retrospective chart review of prospectively collected data from June 2018 to March 2025 was performed. Inclusion criteria included patients …

Real-World Experience With Selexipag In Patients With Pulmonary Arterial Hypertension: Treatment Patterns And Outcomes Across Baseline Risk Strata (Sphere And Exposure Studies), Pilar Escribano Subias, Murali M Chakinala, Et Al.

2020-Current year OA Pubs

BACKGROUND: Treatment strategies for pulmonary arterial hypertension (PAH) depend on patients' 1-year mortality risk; however, real-world practices and outcomes remain inadequately described.

OBJECTIVE: We aimed to investigate real-world experience with selexipag, an oral selective prostacyclin I2 receptor agonist used to treat PAH.

METHODS: This analysis of two large, prospective, observational studies: SPHERE (NCT03278002; USA; completed) and EXPOSURE (EUPAS19085; Europe and Canada; ongoing, data cutoff November 2021) included adults newly initiating selexipag with follow-up available.

RESULTS: Of 1366 selexipag users, 894 met eligibility criteria. At selexipag initiation, the median (Q1-Q3) age was 61 (48-70) years and the time since diagnosis was …

Active Bone Marrow Dose Reconstruction In A Large-Scale Cohort Study Of Cancer Patients Treated With Photon Radiotherapy, Keith T Griffin, Kishan J Pithadia, Yeon Soo Yeom, Lior Braunstein, Kelly L Bolton, Lindsay M Morton, Choonsik Lee

2020-Current year OA Pubs

BACKGROUND: Previous studies have investigated the dose-response relationship between external beam radiotherapy (EBRT) and leukemia by reconstructing the mean active bone marrow (ABM) dose as part of the exposure assessment. However, no prior study has leveraged electronic medical records (EMR) to reconstruct ABM dose and dose-volume in an EBRT patient population.

PURPOSE: To support future studies on the relationship between radiation exposure and adverse health effects among EBRT patients, we demonstrate methods to retrospectively calculate ABM dose and dose-volume metrics in a large patient cohort using EMR.

METHODS: We retrieved complete EMR for 639 individuals (five pediatric and 634 adult) …

Single Zonular Fiber Extraction And Characterization: A Platform For Biomechanical, Biochemical And Structural Analyses, Riley Forinash, Sean Staggs, Steven Bassnett, Juan Rodriguez

2020-Current year OA Pubs

Zonular fibers are essential for suspending the lens within the eye and, in primates, for transmitting forces generated by the ciliary body to drive ocular accommodation. Despite their biomechanical importance, the response of these fibers to sudden strains, and the molecular basis of their exceptional durability remain poorly understood. This is due, in part, to the absence of tools for studying them in isolation. Here, we present a custom-built, cost-effective apparatus designed to isolate, manipulate, and characterize individual zonular fibers under controlled physical and chemical conditions. The apparatus enables quantification of elastic moduli, stress-relaxation behavior, Poisson's ratio, and response to …

Comparing Ckd Populations With T1d And T2d: A Perspective Based On The Fine-One And Fidelity Populations, Hiddo J L Heerspink, Janet B Mcgill, Et Al.

2020-Current year OA Pubs

Chronic kidney disease (CKD) is a common comorbidity of both type 1 diabetes (T1D) and type 2 diabetes (T2D) and is associated with increased mortality, end-stage kidney disease and cardiovascular disease risk. Despite standard-of-care treatment with renin-angiotensin system inhibitors added to blood pressure and glycaemic control, people with CKD and T1D have a residual risk of CKD progression. Advances in therapeutic management have been limited over the past 3 decades, especially compared with CKD in T2D, for which new treatment options have emerged in the last 5 years. In this review article we discuss the similarities and differences between T1D …

What Constitutes Risk In Implementation Research? Perspectives From A Qualitative Key-Informant Study, Emmanuel K Tetteh, Gifty Aboagye-Mensah, Nwaliweaku Anidi, Elvin H Geng, Byron J Powell, Enola K Proctor, Mark D Huffman, Alison L Antes

2020-Current year OA Pubs

BACKGROUND: As implementation research increasingly occurs within routine care settings, determining what constitutes minimal risk is critical to ensuring that ethical oversight is appropriate and proportional. Current regulatory definitions often do not reflect the unique features of implementation studies, including implementation strategy-related risks and system-level effects. Yet, little empirical evidence exists on how researchers themselves interpret minimal risk in this context.

METHODS: We conducted semi-structured qualitative interviews with 11 key informants, including investigators with experience in domestic and global implementation research. Participants were recruited through purposive sampling. Interviews explored how participants interpret the concept of minimal risk, identify risk-related concerns, …

Laser Interstitial Thermal Therapy And Adjuvant Pembrolizumab In Recurrent High-Grade Astrocytoma: A Phase 1/Randomized Phase 2b Trial, Jian L Campian, Omar H Butt, Yifei Xu, Jingxia Liu, William A Leidig, Tanner Johanns, George Ansstas, Alice Y Zhou, Sangami Pugazenthi, Jiayi Huang, Milan G Chheda, Albert H Kim, Eric C Leuthardt, Et Al.

2020-Current year OA Pubs

Immune checkpoint inhibitors (ICIs) show minimal efficacy in recurrent high-grade astrocytoma (rHGA). Laser interstitial thermal therapy (LITT), a minimally invasive cytoreductive approach, may prime rHGA for ICI response. A phase 1/randomized phase 2b trial (ClinicalTrials.gov: NCT02311582 ) was designed to test pembrolizumab in combination with LITT in patients with rHGA. Nine patients were enrolled in the phase I dose-escalation lead-in study. No dose-limiting toxicities were observed and 200 mg of pembrolizumab every three weeks was determined as the recommended phase 2 dose. The phase 2b study was initially designed to randomize (up to 45) patients 1:1 to either LITT followed …

Recognizing Structural And Social Determinants Of Health In The Diagnosis And Care Of Dementia, Shana D Stites, Sharnita Midgett, Nisha Patel, Kimberly Halberstadter, Rosalie Schumann, Marissa L Streitz, Yidan Shi, John C Morris, Jason Flatt, Crystal M Glover, Dawn Mechanic-Hamilton

2020-Current year OA Pubs

Structural and social determinants of health are environmental conditions that affect individuals' health and functioning across the life course. These determinants are salient factors at the apex of individual psychology, community variables, and larger sociological factors, exerting prominent effects on individuals' wellbeing. The National Institute on Aging seeks to understand their influence on aging and Alzheimer's disease. We propose that the benefits of doing so may reach beyond knowledge of disease mechanisms - it may also improve clinical outcomes. We describe efforts introducing structural and social determinants of health data into the national network of Alzheimer's disease research centers. We …

Estimating The Baseline Age When Longitudinal Changes In Biomarkers Accelerate: Application To An Imaging Study Of Preclinical Alzheimer Disease, Chengjie Xiong, Folasade Agboola, Jingqin Luo

2020-Current year OA Pubs

BACKGROUND: Biomarkers are routinely measured from human biospecimens and imaging scans in Alzheimer disease (AD) research. Age is a well-known risk factor for AD. Detecting the baseline age at which the longitudinal change in biomarkers starts to accelerate is important to design preventive interventions. METHODS: We analyzed longitudinal biomarker data by a random intercept and random slope model where the slope (longitudinal rate of change) was modeled as a piecewise linear and continuous function of baseline age. We proposed to estimate the baseline age at the intersection of the two linear functions by multiple methods: maximum (profile) likelihood, minimum squared …

Applying Frame-Is To Characterize Provider-Led Adaptations To A Cervical Cancer Prevention Intervention In Kenya, Harriet Fridah Adhiambo, Katherine Thomas, Megan M Coe, Lynda Oluoch, Valary Ihaji, Mary Bernadette Kerubo, Alex Kinyua, Sarah Njoroge, Kenneth Ngure, Michelle Shin, Thomas A Odeny, Bryan Weiner, Nelly Mugo, Sarah Gimbel

2020-Current year OA Pubs

BACKGROUND: Implementation strategies that are contextually refined are essential for optimizing the delivery of evidence-based interventions (EBI) to prevent cervical cancer in low-resource settings. This paper reports the application of the Framework for Reporting Adaptations and Modifications to Evidence-based Implementation Strategies (FRAME-IS) to capture and disseminate strategy adaptations made to a single-visit, screen-and-treat approach with thermal ablation (SV-SAT + TA) strategy aimed at establishing sustainable cervical cancer prevention services in Kenya.

METHODS: A FRAME-IS-based tracking spreadsheet was developed to document bundled site-specific implementation strategy adaptations and across 10 facilities. Data was collected during technical assistants' (TAs) site visits, phone calls, …

Ketogenic Diet Dampens Excitatory Neurotransmission By Shrinking Synaptic Vesicle Pools, Marion I Stunault, Pan-Yue Deng, Anjali Yadav, Erica M Periandri, Francisca N De Luna Vitorino, Michael B Thomsen, Jasmin Sponagel, Amelia J Barfield, Renzelle J Ponce, Layla Foroughi, Benjamin A Garcia, Gabor Egervari, Vitaly A Klyachko, Ghazaleh Ashrafi

2020-Current year OA Pubs

Ketogenic diet (KD) is used for the treatment of drug-resistant childhood epilepsy and has been proposed to improve outcomes in neurodegenerative diseases. However, the mechanisms by which KD alters brain circuitry remain unclear. Here, we investigated the impact of KD on hippocampal function through integrative analysis of gene expression and neurotransmission. We found that KD induces extensive transcriptional reprogramming, including altered expression of numerous synaptic genes. Proteomic and genomic profiling revealed significant changes in histone modifications, particularly at promoters of KD-regulated genes. Electrophysiological recordings showed that KD reduces excitatory synaptic gain and short-term plasticity at CA3-CA1 synapses, dampening the summation …

Regional Brain Age Is Decreased In Children With Sickle Cell Anemia, Amy E Mirro, Landon C Power, Jinli Wang, Paula Germino-Watnick, Heather Roberts, Yonca Cam, Kristin P Guilliams, Slim Fellah, Yasheng Chen, Hongyu An, Jin-Moo Lee, Andria L Ford, Melanie E Fields

2020-Current year OA Pubs

DeepBrainNet, a machine learning tool, uses magnetic resonance imaging (MRI) to predict an individual's brain age, allowing calculation of the brain age gap (predicted chronological age) for use as a biomarker of brain health. We tested the DeepBrainNet tool in sickle cell anemia (SCA) on 210 brain MRIs from 130 children (90 with SCA; 40 healthy controls) to investigate the hypothesis that children with SCA would have a younger predicted brain age than healthy controls as an index of aberrant brain development. DeepBrainNet estimates brain age from 80 axial slices of each brain, with the median used as global brain …

Feasibility, Acceptability And Implementation Of A Whole-Family Mental Health Intervention For Displaced Adolescent Girls In Colombia: A Mixed-Methods Pilot Randomized Controlled Trial, Ilana Seff, Arturo Harker Roa, Byron Powell, Natalia Cordoba, Carolina Rodriguez, Julianne Deitch, Elvia Tamaity Ariza Pena, Feven Gebrekidan, Lindsay Stark

2020-Current year OA Pubs

Adolescent girls affected by displacement face substantial mental-health risks. The Sibling Support for Adolescent Girls in Emergencies (SSAGE) is a 12-week, gender-transformative, family-based program designed to improve adolescent girls' mental health in humanitarian settings. This mixed-methods pilot randomized controlled trial (RCT) assessed SSAGE's feasibility, acceptability and potential effects among 186 Venezuelan migrant and Colombian returnee families in Colombia. Adolescent girls aged 13-19 years, their male siblings and caregivers participated in parallel sessions on gender dynamics, communication and relationships. Implementation outcomes drew on the Mental Health Implementation Science Tools (acceptability and feasibility subscales), attendance records and qualitative interviews. Analyses followed an …

Benefit Of Rituximab Maintenance After First-Line Bendamustine-Rituximab In Patients With Mantle Cell Lymphoma, Yucai Wang, Imran A Nizamuddin, Brad S Kahl, Et Al.

2020-Current year OA Pubs

The benefit of rituximab maintenance after first-line (1L) bendamustine-rituximab (BR) in patients with mantle cell lymphoma (MCL) remains uncertain, with inconsistent results from the phase 2 MAINTAIN trial and several retrospective studies. We conducted a large retrospective study at 27 US and Canadian academic centers to examine the benefit of rituximab maintenance after BR. A total of 911 patients received 1L BR between 2010 and 2020, and 703 had an objective response and no evidence of disease progression at the 3-month post-BR landmark. Among those, 394 (56%) received rituximab maintenance and 309 (44%) did not, with largely similar baseline patient …

Economic Evaluation Of Perioperative Pembrolizumab Plus Standard Of Care As Treatment For Resectable Locally Advanced Head And Neck Squamous Cell Carcinoma In The United States, Feng Qian, Arielle G Bensimon, Anjela Tzontcheva, Kimberly Benjamin, Ravindra Uppaluri, Douglas Adkins, Geoffrey Johnson, Catherine Fernan, Dandan Zheng, Yuexin Tang, Biruk Chafamo, Dominic Muston

2020-Current year OA Pubs

AIMS: In the phase 3 KEYNOTE-689 trial (NCT03765918) among patients with resectable locally advanced head and neck squamous cell carcinoma (LA HNSCC), perioperative pembrolizumab (pembrolizumab before surgery, then continued with standard-of-care [SOC] radiotherapy +/- cisplatin after surgery followed by pembrolizumab alone) significantly prolonged event-free survival vs. SOC alone, both in the intention-to-treat population and PD-L1 combined positive score (CPS) ≥1 subgroup. Perioperative pembrolizumab + SOC received Food and Drug Administration approval in June 2025 for resectable LA HNSCC expressing PD-L1 (CPS ≥ 1). The present study evaluated the cost-effectiveness of perioperative pembrolizumab + SOC versus SOC in this indication, from …

Stereotactic Adaptive Radiation Therapy For Borderline Resectable Or Locally Advanced Pancreatic Cancer To Minimize Gastrointestinal Toxicity (Artia-Pancreas): Protocol For A Single-Arm Prospective Trial, Lauren E Henke, Hyun Kim, Eric Laugeman, Steven Kohlmyer, Claire Mccann, Kate Pietrovito, Kenneth Russell, Jennifer Woo, Alex T Price

2020-Current year OA Pubs

BACKGROUND: Computed tomography (CT)-guided online stereotactic adaptive radiotherapy (CT-STAR) allows for ablative radiation doses to be delivered to selected patients with borderline resectable (BR) or locally advanced pancreatic cancer (LAPC) or unresectable pancreatic cancer. However, the use of CT-STAR to deliver an ablative dose to the pancreas while minimizing gastrointestinal (GI) side effects to reduce acute and late toxicity rates compared to historic controls has yet to be prospectively evaluated.

OBJECTIVE: The primary objective of this prospective, single-arm, multicenter phase 2 clinical trial (Adaptive Radiation Therapy Individualized Approach [ARTIA]-Pancreas) is to evaluate the rate of acute grade 3+ GI toxicity …

Strain-Level Heterogeneity In Gardnerella Urinary Tract Persistence And Pathogenesis In An In Vivo Model Is Consistent With Comparative Phylogenomic Analyses, Lokesh Kumar, Sonia N Whang, Deborah K Verges, Robert F Potter, Nicole M Gilbert

2020-Current year OA Pubs

BACKGROUND: Gardnerella is a bacterial genera commonly present in the female urogenital tract, especially in bacterial vaginosis. Gardnerella are frequently detected in urine collected directly from the bladder and have been implicated in urinary incontinence and recurrent urinary tract infections. Understanding the contribution of Gardnerella to pathogenesis is complicated by its genetic heterogeneity and a shortage of data from in vivo models. One clinical isolate of Gardnerella triggered urothelial exfoliation and promoted urinary tract infection by uropathogenic E. coli in a mouse model. This study was designed to compare diverse Gardnerella strains in vivo to identify genomic variation associated with …

Genetic Modifiers Of Apoe-Ε4-Associated Cognitive Decline, Alex G Contreras, Carlos Cruchaga, Et Al.

2020-Current year OA Pubs

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease. However, APOE-ε4 is not deterministic, highlighting the need to identify additional genetic and environmental factors. APOE-ε4 has been linked to accelerated cognitive decline, so we sought to investigate genetic factors that modify APOE-ε4-associated cognitive decline. We conduct cross-ancestry APOE-ε4-stratified and interaction GWAS using harmonized cognitive data from 32,778 participants, including 29,354 non-Hispanic White and 3,424 non-Hispanic Black individuals. Our primary outcome is late-life cognition, measured using harmonized composite scores for memory, executive function, and language, modeled as continuous traits reflecting both normative cognitive aging and disease-related decline. …

The Effect Of Increased Weight Loading On Body Weight Is Partly Dependent On Piezo1 In Osteoblast-Lineage Cells And Trka Signaling, Daniel Hägg, Lei Li, Alec T Beeve, Erica L Scheller, Jakob Bellman, Fredrik Anesten, Jovana Zlatkovic, Adrià Dalmau Gasull, Ferran Font-Gironès, Sofia Movérare-Skrtic, John-Olov Jansson, Claes Ohlsson

2020-Current year OA Pubs

UNLABELLED: Obesity is a complex disease driven by multiple factors, and a deeper understanding of its underlying mechanisms could enable the development of novel treatments. Based on our previous experimental studies, we have proposed a homeostatic mechanism regulating adiposity involving mechano-sensing of body weight by osteoblast-lineage cells in the lower extremities. However, the molecular mechanism underlying this proposed weight-sensing pathway remains to be elucidated. Recent studies have demonstrated that Piezo1-mediated mechano-sensing in osteoblast-lineage cells, as well as TrkA-dependent signaling, are essential for the normal bone anabolic response to high-intensity mechanical loading. We hypothesized that these pathways within bone may also …

Cell-Cell Communication As Underlying Principle Governing Color Pattern Formation In Teleost Fishes, Marleen Klann, Lila Solnica-Krezel, Et Al.

2020-Current year OA Pubs

The diverse pigmentation patterns of animals are crucial for predation avoidance and behavioral display. This diversity arises from interactions among distinct pigment cell types, yet mechanisms generating pattern variation across teleost fishes remain incompletely understood. In zebrafish, Turing models have been proposed to explain stripe patterns, but it is unclear if they apply to other fishes. Here, we investigate the Snowflake mutant of the anemonefish Amphiprion ocellaris, which displays enlarged white bars with irregular boundaries. Using genome-wide association mapping and targeted sequencing, we identify a missense mutation (E42K) in gja5b, encoding the gap junction protein Connexin 41.8. CRISPR/Cas9-mediated genome editing …

Accurate Interpretation Of Within-Host Dissemination Using Barcoded Bacteria, Rachel T Giorgio, My T Le, Ting Zhang, Caitlyn L Holmes, Karthik Hullahalli

2020-Current year OA Pubs

Bacterial dissemination across tissues is a critically important process influencing infection outcomes. Monitoring within-host dissemination is challenging because conventional measures of bulk bacterial burden cannot distinguish between lineages that are shared between tissues and those that replicate locally. This limitation can be overcome using barcoded bacteria, where deep sequencing of the barcode locus and comparisons of barcodes between tissues define which lineages spread within the host. Numerous studies have used barcoded bacteria to generate high-resolution maps of dissemination. However, since multiple cells in the infectious inoculum can contain identical barcodes, inferences about dissemination can be confounded when distinct lineages from …