Medicine and Health Sciences Commons^™

Acute Hyperglycemia Induces Podocyte Apoptosis By Monocyte Tnf-Α Release, A Process Attenuated By Vitamin D And Glp-1 Receptor Agonists, Rong M Zhang, Jisu Oh, Burton M Wice, Adriana Dusso, Carlos Bernal-Mizrachi

2020-Current year OA Pubs

Targeting optimal glycemic control based on hemoglobin A1c (A1c) values reduces but does not abolish the onset of diabetic kidney disease and its progression to chronic kidney disease (CKD). This suggests that factors other than the average glucose contribute to the residual risk. Vitamin D deficiency and frequent episodes of acute hyperglycemia (AH) are associated with the onset of albuminuria and CKD progression in diabetes. This study aimed to determine if moderate levels of AH harm podocytes directly or promote a pro-inflammatory monocyte/macrophage phenotype that leads to podocyte apoptosis, and whether vitamin D deficiency accelerates these processes. We found that …

Identification Of A New Coq4 Spliceogenic Variant Causing Severe Primary Coenzyme Q Deficiency, María Alcázar-Fabra, Abigail K Bartlett, David J Pagliarini, Et Al.

2020-Current year OA Pubs

BACKGROUND AND AIMS: Primary Coenzyme Q (CoQ) deficiency caused by

MATERIALS AND METHODS: Both fibroblasts from a proband with

RESULTS: Here, we report the case of a subject harboring a new variant of the

CONCLUSION: Our results highlight the importance of expanding the genetic analysis beyond the coding sequence to reduce the misdiagnosis of primary CoQ deficiency patients.

Exploring The Differences Between Brca Mutated And Hrwild-Type High Grade Serous Ovarian Cancer: A Multiomic Analysis, Ayesha B Alvero, Sharon Wu, Alex Farrell, Seongho Kim, John J Wallbillich, Ira Winer, Robert Morris, David Spetzler, Matthew L Anderson, Alberto Puccini, Nathaniel L Jones, Thomas J Herzog, Premal H Thaker, Gil Mor, Radhika P Gogoi

2020-Current year OA Pubs

OBJECTIVE: The purpose of this study was to evaluate the transcriptomic profile of BRCA1 mutant (BRCA1mut) and BRCA2 mutant (BRCA2mut) HGSOC compared to homologous recombination wild-type (HRwt) tumors utilizing the CARIS database.

METHODS: Next-generation and Whole Transcriptome Sequencing (WTS; Caris Life Sciences, Phoenix, AZ) was performed on a total of 2745 HGSOC tumor samples. BRCA mutations were defined as variants resulting in loss-of-function of the protein and HRwt was defined as samples wildtype for aberrations in both BRCA1 and BRCA2, as well as for 28 other HR genes. HRwt group was further classified into HRwt/LOH-low (< 16 %) and HRwt/LOH-high (≥16 %). Genomic analysis consists of mutation analysis and measurements of TMB and MSI. Transcriptomic analysis included identification of Differentially expressed genes (DEGs), GSEA and immune deconvolution.

RESULTS: We identified 519 …

Sacubitril/Valsartan Attenuates Inflammation And Myocardial Fibrosis In Takotsubo-Like Cardiomyopathy, Jiangying Kuang, Zhiyi Jia, Tou Kun Chong, Jian Chen, Kan Liu, Xin Wang, Zhaohua Li, Jing Zhang, Yanru Kong, Lin Deng, Martin Cadieras, Yuanyuan Sun, Rong Sun, Qinghua Lu, Yusheng Liu

2020-Current year OA Pubs

BACKGROUND: Takotsubo syndrome (TTS) primarily manifests as a cardiomyopathy induced by physical or emotional stress, remains a poorly understood condition with no established treatments. In this study, we investigated the potential of sacubitril/valsartan (sac/val) to increase the survival of TTS patients and reduce inflammation and myocardial fibrosis in experimental models.

AIM: This study aimed to evaluate whether sac/val could improve survival rates in TTS patients, mitigate cardiac remodeling in vivo, and explore its anti-inflammatory and antifibrotic mechanisms in vitro.

METHODS: Clinical cases from the Chinese Takotsubo syndrome (ChiTTS) registry were analyzed to assess patient survival rates. In addition, we used …

Reward Neurocircuitry Predicts Longitudinal Changes In Alcohol Use Following Trauma Exposure, Cecilia A Hinojosa, Stacey L House, Et Al.

2020-Current year OA Pubs

BACKGROUND: Trauma is a risk factor for developing maladaptive alcohol use. Preclinical research has shown that stress alters the processing of midbrain and striatal reward and incentive signals. However, little research has been conducted on alterations in reward-related neurocircuitry posttrauma in humans. Neuroimaging markers may be particularly useful because they can provide insight into the mechanisms that may make an individual vulnerable to developing trauma-related psychopathologies. In this study, we aimed to identify reward-related neural correlates associated with changes in alcohol use after trauma exposure.

METHODS: Participants were recruited from U.S. emergency departments for the AURORA study (n = 286; …

Parameterizing Toxic Stress In Early Childhood: Maternal Depression, Maltreatment, And Hpa-Axis Variation In A Pilot Intervention Study, Rachael E Wagner, Melissa Jonson-Reid, Brett Drake, Patricia L Kohl, Laura Pons, Yi Zhang, Robert T Fitzgerald, Mark L Laudenslager, John N Constantino

2020-Current year OA Pubs

Adverse experiences superseding a child's capacity to sustain regulation of emotion and adaptive function are theorized to constitute "toxic stressors" when they induce a deleterious biological response within an individual. We ascertained presumptive parameters of toxic stress among 164 low-income infants and toddlers (ages 4-48 months) from 132 families enrolled in Early Head Start (EHS). We randomized a subset of these families into a pilot intervention arm of parenting education (the Incredible Years, TIY), which supplemented the EHS curriculum. Official report child abuse and neglect (CAN) and child behavior were serially ascertained over the course of the study. We observed …

Bi-Allelic Lamp3 Variants In Childhood Interstitial Lung Disease: A Surfactant-Related Disease, Camille Louvrier, F Sessions Cole, Jennifer A Wambach, Daniel J Wegner, Et Al.

2020-Current year OA Pubs

BACKGROUND: LAMP3 encodes a lysosomal membrane protein associated with lamellar bodies and has recently been proposed as a candidate gene for childhood interstitial lung diseases (chILD). Here, we identified two LAMP3 variants in a proband with chILD and performed functional validation of these variants as well as the previously reported variants to demonstrate the role of LAMP3 in pathology.

METHODS: LAMP3 variants were identified by exome sequencing. Ex vivo studies included mRNA analysis from nasal brushing and lung tissue and immunohistochemistry from lung biopsy. In vitro functional analyses in the A549 cell line included immunofluorescence staining and expression analysis of …

Transcranial Vibration Stimulation At 40 Hz Induced Neural Activity And Promoted The Coupling Of Global Brain Activity And Cerebrospinal Fluid Flow, Linghan Kong, Wei Jin, Yue Jiang, Fuhua Yan, Jun Liu, Eric C Leuthardt, Guang-Zhong Yang, Yuan Feng

2020-Current year OA Pubs

BACKGROUND: Neuroscience advances have highlighted the potential of non-invasive brain stimulation in influencing cognitive and emotional processes. Conventional stimulation methods such as electrical, magnetic, and ultrasound have been studied intensively, but little is known about the mechanical stimulation.

OBJECTIVE: To investigate the effects of 40 Hz transcranial vibration stimulation (TVS) on human brain activity, specifically focusing on changes in the Amplitude of Low-Frequency Fluctuation (ALFF), fractional ALFF (fALFF) and Regional Homogeneity (ReHo) as measures of spontaneous brain activity. Additionally, this study investigates alterations in the global blood-oxygen-level-dependent (gBOLD) signal and cerebrospinal fluid (CSF) inflow coupling, which serve as indicators of …

Effect Of Midwife-Led Pelvic Floor Muscle Training On Prolapse Symptoms And Quality Of Life In Women With Pelvic Organ Prolapse In Ethiopia: A Cluster-Randomized Controlled Trial, Melese Siyoum, Rahel Nardos, Biniyam Sirak, Theresa Spitznagle, Wondwosen Teklesilasie, Ayalew Astatkie

2020-Current year OA Pubs

BACKGROUND: Pelvic organ prolapse (POP) is a common condition that can significantly impact a woman's quality of life. Pelvic floor muscle training (PFMT) is recommended as a first-line conservative treatment for prolapse, but evidence on its effectiveness from low-resource settings is limited. This study aimed to assess the effect of midwife-led PFMT on prolapse symptoms and health-related quality of life (HRQoL) among women with mild-to-moderate POP in Ethiopia.

METHODS AND FINDINGS: A community-based, parallel-groups, two-arm cluster-randomized controlled trial was conducted in Dale and Wonsho districts of Sidama Region, Ethiopia. Women with symptomatic POP stages I-III were randomized by cluster to …

Treatment Of Non-Hodgkin Lymphoma With Point-Of-Care Manufactured Car T Cells: A Dual Institution, Phase 1 Trial, Armin Ghobadi, Linda Eissenberg, John Dipersio, Et Al.

2020-Current year OA Pubs

BACKGROUND: Point-of-care manufacture of chimeric antigen receptor (CAR)-T cells can significantly reduce the time from apheresis to infusion. We conducted a dual-institution phase I trial aimed evaluating the safety and feasibility of this manufacturing model.

METHODS: CASE 2417 was a phase I clinical trial. Adults with relapsed or refractory CD19 positive non-Hodgkin lymphoma (R/R NHL) treated with ≥2 prior systemic therapies were eligible. MB-CART-19 is an anti-CD19 CAR T-cell product manufactured using the CliniMACS Prodigy device with 4-1BB and CD3ζ costimulatory domains. Lymphodepletion included fludarabine 25 mg/m

FINDINGS: Thirty-one patients were enrolled between July 2018 and January 2021. Twenty-four (77%) …

Cardiotoxicity Following Thoracic Radiotherapy For Lung Cancer, Gerard M Walls, Carmen Bergom, Joshua D Mitchell, Stacey L Rentschler, Geoffrey D Hugo, Pamela P Samson, Clifford G Robinson

2020-Current year OA Pubs

Radiotherapy is the standard of care treatment for unresectable NSCLC, combined with concurrent chemotherapy and adjuvant immunotherapy. Despite technological advances in radiotherapy planning and delivery, the risk of damage to surrounding thoracic tissues remains high. Cardiac problems, including arrhythmia, heart failure and ischaemic events, occur in 20% of patients with lung cancer who undergo radiotherapy. As survival rates improve incrementally for this cohort, minimising the cardiovascular morbidity of RT is increasingly important. Problematically, the reporting of cardiac endpoints has been poor in thoracic radiotherapy clinical trials, and retrospective studies have been limited by the lack of standardisation of nomenclature and …

Emergence Of Infective Endocarditis Due To Serratia Spp.: Results Of A Multicenter Cohort, Leah Madeline Mccrary, Douglas Slain, Sunish Shah, Bobbi Jo Stoner, Ashley H Marx, Asher J Schranz

2020-Current year OA Pubs

BACKGROUND: Infective endocarditis due to

METHODS: This was a retrospective analysis of adults treated for S-IE at 4 academic health systems in different US states from 2015 to 2021. Multivariable logistic regression analyzed the association of inpatient mortality with procedural management and combination antibiotic treatment.

RESULTS: A total of 159 cases of S-IE were identified with a qualitative overall increase across the period, and a peak in 2019, although trends varied by site. Seventy-five were due to IDU, 57% involved a single left-sided valve, and inpatient mortality was 21%. In adjusted analyses, including 117 cases from 3 sites, lower inpatient …

Zanubrutinib Versus Bendamustine And Rituximab In Patients With Treatment-Naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Median 5-Year Follow-Up Of Sequoia, Mazyar Shadman, Brad S Kahl, Et Al.

2020-Current year OA Pubs

No abstract provided.

Rates Of Hospitalization And Death Due To Covid-19 In Us Veterans With Sars-Cov-2 Infection In The Xbb-, Jn.1-, And Kp-Predominant Eras, Taeyoung Choi, Yan Xie, Ziyad Al-Aly

2020-Current year OA Pubs

Between September 2023 and October 2024, severe acute respiratory syndrome coronavirus 2 evolved through 3 variant-predominant eras: XBB, JN.1, and KP. Among 130 263 Department of Veterans Affairs patients with coronavirus disease 2019, hospitalization odds declined for JN.1 (0.81; 95% CI, 0.74-0.89) and KP (0.80; 95% CI, 0.72-0.88) compared with XBB, with consistently low in-hospital death rates across all eras.

Visual Field Progression In The Ocular Hypertension Treatment Study, Mae O Gordon, Dale K Heuer, Eve J Higginbotham, Richard K Parrish, Lei Liu, James D Brandt, Julia B Huecker, J Phillip Miller, Chamila Perera, Chris Xie, John L Keltner, Chris A Johnson, Stuart K Gardiner, Jeffrey M Liebmann, Michael A Kass

2020-Current year OA Pubs

PURPOSE: To determine the rate of visual field (VF) loss before and after the diagnosis of primary open angle glaucoma (POAG) in the Ocular Hypertension Treatment Study (OHTS).

DESIGN: Prespecified analyses of data collected prospectively in a clinical trial with extended follow-up.

SETTING AND PARTICIPANTS: Participants who developed POAG during OHTS 1 and 2 (February 1994 to December 2008) constitute an inception cohort. Follow-up data were collected in OHTS 3 (January 2016-April 2019). Analyses were performed from July 2021 to August 2022.

INTERVENTION: In OHTS 1 and 2, visual field (VF) tests were performed every 6 months and stereoscopic optic …

Integrative Analysis Of The 3d Genome And Epigenome In Mouse Embryonic Tissues, Miao Yu, Yang E Li, Et Al.

2020-Current year OA Pubs

While a rich set of putative cis-regulatory sequences involved in mouse fetal development have been annotated recently on the basis of chromatin accessibility and histone modification patterns, delineating their role in developmentally regulated gene expression continues to be challenging. To fill this gap, here we mapped chromatin contacts between gene promoters and distal sequences across the genome in seven mouse fetal tissues and across six developmental stages of the forebrain. We identified 248,620 long-range chromatin interactions centered at 14,138 protein-coding genes and characterized their tissue-to-tissue variations and developmental dynamics. Integrative analysis of the interactome with previous epigenome and transcriptome datasets …

Genomics Of Pediatric Cardiomyopathy, Teresa M Lee, Stephanie M Ware, Alicia M Kamsheh, Surbhi Bhatnagar, Mohammed Absi, Elyse Miller, Enkhsaikhan Purevjav, Kaitlin A Ryan, Jeffrey A Towbin, Steven E Lipshultz

2020-Current year OA Pubs

Cardiomyopathy in children is a leading cause of heart failure and cardiac transplantation. Disease-associated genetic variants play a significant role in the development of the different subtypes of disease. Genetic testing is increasingly being recognized as the standard of care for diagnosing this heterogeneous group of disorders, guiding management, providing prognostic information, and facilitating family-based risk stratification. The increase in clinical and research genetic testing within the field has led to new insights into this group of disorders. Mutations in genes encoding sarcomere, cytoskeletal, Z-disk, and sarcolemma proteins appear to play a major role in causing the overlapping clinical phenotypes …

Genetically Engineered Brain Organoids Recapitulate Spatial And Developmental States Of Glioblastoma Progression, Matthew Ishahak, Rowland H Han, Devi Annamalai, Timothy Woodiwiss, Colin Mccornack, Ryan T Cleary, Patrick A Desouza, Xuan Qu, Sonika Dahiya, Albert H Kim, Jeffrey R Millman

2020-Current year OA Pubs

Glioblastoma (GBM) is an aggressive form of brain cancer that is highly resistant to therapy due to significant intra-tumoral heterogeneity. The lack of robust in vitro models to study early tumor progression has hindered the development of effective therapies. Here, this study develops engineered GBM organoids (eGBOs) harboring GBM subtype-specific oncogenic mutations to investigate the underlying transcriptional regulation of tumor progression. Single-cell and spatial transcriptomic analyses revealed that these mutations disrupt normal neurodevelopment gene regulatory networks resulting in changes in cellular composition and spatial organization. Upon xenotransplantation into immunodeficient mice, eGBOs form tumors that recapitulate the transcriptional and spatial landscape …

Comparison Of 2 Thromboelastography Methods Using Patient And Control Samples, Robert Frick, Brittany Washburn, Dennis Plocher, Jonathan K Zoller, Jason Gillihan, Michael Dombrowski, Charles Eby, Christopher W Farnsworth

2020-Current year OA Pubs

BACKGROUND: Viscoelastic testing at point-of-care is associated with reduced blood loss and blood product transfusions. The ROTEM (Werfen) sigma is a cartridge-based system that may facilitate point-of-care use, but limited studies exist comparing the sigma with the predicated ROTEM delta.

OBJECTIVES: We compared the performance of the ROTEM delta with that of the sigma.

METHODS: Citrated blood was collected from 20 healthy donors and patients during liver transplants (

RESULTS: The coefficient of variation was < 10% for all assays/parameters except for the thromboelastometry with extrinsic activation (EXTEM) clotting time (10.3%) and EXTEM amplitude (A)5 (10.2%). Reference intervals for the delta and sigma were comparable to manufacturer claims. The Pearson r comparing the delta and sigma exceeded .85 for all parameters/assays except for thromboelastometry with cytochalasin D-mediated platelet inhibition (FIBTEM) A10 (.77; 95% CI, .66-.86), FIBTEM A20 (.78; 95% CI, .65-.87), and thromboelastometry with heparinase clotting time (.77; 95% CI, .61-.87). No difference was observed in extrapolated thresholds from the delta-guided algorithm. However, extrapolated sigma A5 parameters for EXTEM were 5 mm lower, and for FIBTEM were 1 mm lower than delta A10 parameters.

CONCLUSION: The ROTEM delta and sigma devices had comparable performance. A negative bias was observed in the FIBTEM assay with lower extrapolated clinical decision points …

Vitamin K Deficiency Bleeding In Children With Cholestatic Liver Disease: A Systematic Review And Meta-Analysis, Anusak Sakwit, Pongpak Pongphitcha, Patcharee Komvilaisak, Masayuki Ochiai, Daijiro Takahashi, Shutaro Suga, Ampaiwan Chuansumrit, Marisol Betensky, Stephen P Pereira, Amber Afzal, C Heleen Van Ommen, Neil Goldenberg, Sasivimol Rattanasiri, Nongnuch Sirachainan

2020-Current year OA Pubs

Vitamin K deficiency (VKD) in cholestatic liver disease affects up to 23% of pediatric patients. While several vitamin K (VK) prophylaxis regimens have been proposed, optimal therapeutic strategies remain undefined. The study aimed to identify the most effective VK prophylaxis for children with cholestatic liver disease. We conducted a systematic review of articles focusing on studies of children aged < 18 years with cholestatic liver disease who reported outcomes of either VKD or vitamin K deficiency bleeding (VKDB) after VK prophylaxis. The articles were sourced from PubMed, Scopus, and Embase. A meta-analysis was performed to determine the prevalence of VKD and the efficacy of each prophylactic protocol in preventing VKD/VKDB. The study was registered on PROSPERO (CRD 42021270048). Of the 889 articles, 37 were selected (2 comparative studies, 6 noncomparative studies, and 29 case reports/series). The results from the comparative studies indicated a lower incidence of VKD in the parenteral than that in the oral VK. The meta-analysis of the noncomparative studies showed the prevalence of VKD in high prothrombin induced by vitamin K absence-II group was 56% (95% CI, 45%-68%;

Patient-Reported Social Risk Factor Screening Among Rheumatology Outpatients, Alissa Chandler, Mohammed Hamid, Ziqiao Jiao, Kelsey Hulcher, Isha Sharma, Patrice Odom, Andrew Robinson, Sara Kellahan, Maura Kepper, Colleen Dostal, Senada Fenelon, Seth Eisen, Daphne Lew, Alfred H J Kim

2020-Current year OA Pubs

OBJECTIVE: The purpose of this study was to pilot test a patient-reported social risk factor (SRF) screening tool among rheumatology outpatients and to examine the distribution of SRFs in this population.

METHODS: A SRF screening tool was completed electronically by patients. Patients were screened for four core SRF domains (financial strain, housing instability, food insecurity, and transportation needs) and four supplemental SRF domains (physical inactivity, social isolation, stress, and depression). Data from the electronic health record were extracted for patients with at least one domain screened who were seen by participating rheumatology providers between January 1 and October 31, 2023. …

Local Genetic Covariance Analysis With Lipid Traits Identifies Novel Loci For Early-Onset Alzheimer's Disease, Nicholas R. Ray, Joseph Bradley, Elanur Yilmaz, Caghan Kizil, Jiji T. Kurup, Eden R. Martin, Hans-Ulrich Klein, Brian W Kunkle, David A. Bennett, Philip L. De Jager, Alzheimer’S Disease Genetics Consortium, Gary W. Beecham, Carlos Cruchaga, Christiane Reitz

2020-Current year OA Pubs

The genetic component of early-onset Alzheimer disease (EOAD), accounting for ~10% of all Alzheimer's disease (AD) cases, is largely unexplained. Recent studies suggest that EOAD may be enriched for variants acting in the lipid pathway. The current study examines the shared genetic heritability between EOAD and the lipid pathway using genome-wide multi-trait genetic covariance analyses. Summary statistics were obtained from the GWAS meta-analyses of EOAD by the Alzheimer's Disease Genetics Consortium (n=19,668) and five blood lipid traits by the Global Lipids Genetics Consortium (n=1,320,016). The significant results were compared between the EOAD and lipids GWAS and genetic covariance analyses were …

Loncastuximab In High-Risk And Heavily Pretreated Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Real-World Analysis From 21 Us Centers, Viktoriya Zelikson, Behzad Amoozgar, Brad Kahl, Et Al.

2020-Current year OA Pubs

Outcomes in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) are poor. Loncastuximab- teserine (Lonca) is an antibody-drug conjugate which was approved by the Food and Drug Administration for the treatment of patients with R/R DLBCL who have received at least two prior lines of therapy, based on the results of the LOTIS-2 trial. However, there are limited data regarding its efficacy in the real-world setting. This retrospective study included 21 US centers and evaluated outcomes of patients with R/R DLBCL treated with Lonca. Our analysis comprises 187 patients with notably higher-risk baseline features compared to those of the …

Norovirus Co-Opts Ninj1 For Selective Protein Secretion, Jaewon Song, Wandy L Beatty, Anthony Orvedahl, Et Al.

2020-Current year OA Pubs

Plasma membrane rupture by Ninjurin-1 (NINJ1) executes programmed cell death, releasing large cellular damage-associated molecular patterns (DAMPs). However, the regulation and selectivity of NINJ1-mediated DAMP release remain unexplored. Here, we uncover that murine norovirus (MNoV) strategically co-opts NINJ1 to selectively release the intracellular viral protein NS1, while NINJ1-mediated plasma membrane rupture simultaneously bulk-releases various cellular DAMPs. Host caspase-3 cleaves the precursor NS1/2, leading to NS1 secretion via an unconventional pathway. An unbiased CRISPR screen identifies NINJ1 as an essential factor for NS1 secretion. During infection, NINJ1 is recruited to the viral replication site, where it oligomerizes and forms speckled bodies, …

Myelin-Reactive Cd8+ T Cells Influence Conventional Dendritic Cell Subsets Towards A Mature And Regulatory Phenotype In Experimental Autoimmune Encephalomyelitis, Mohit Upadhye, Connor R Wilhelm, Kai J Rogers, Chakrapani Vemulawada, Nicholas Borcherding, Alexander W Boyden, Kevin L Legge, Nitin J Karandikar

2020-Current year OA Pubs

Multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system, is modeled in mice as experimental autoimmune encephalomyelitis (EAE). While CD4

Accelerating Earlier Access To Anti-Tnf-Α Agents With Biosimilar Medicines In The Management Of Inflammatory Bowel Disease, Gionata Fiorino, Ashwin Ananthakrishnan, Russell D Cohen, Raymond K Cross, Parakkal Deepak, Francis A Farraye, Jonas Halfvarson, A Hillary Steinhart

2020-Current year OA Pubs

Data indicate that earlier initiation of anti-tumor necrosis factor alpha (anti-TNF-α) biologic medicines may prevent progression to irreversible bowel damage and improve outcomes for patients with inflammatory bowel disease (IBD), particularly Crohn's disease. However, the high cost of such therapies may restrict access and prevent timely treatment of IBD. Biosimilar anti-TNF-α medicines may represent a valuable opportunity for cost savings and optimized patient outcomes by improving access to advanced therapies and allowing earlier anti-TNF-α treatment initiation. Biosimilar anti-TNF-α medicines have been shown to offer consistent therapeutic outcomes to their reference medicines, yet despite entering the IBD treatment armamentarium over 10 …

Developing Evaluation Metrics To Measure The Us National Institute Of Health Plans To Enhance Diverse Perspectives: A Protocol For A Consensus-Based Study, Yulia A Levites Strekalova, Sanjay Jain, Pinaki Sarder

2020-Current year OA Pubs

INTRODUCTION: The diversity of participating investigators representing diverse disciplines, career stages, stakeholder groups, regions and types of institutions is essential for the success of large-scale research programmes. In 2021, the National Institutes of Health introduced a requirement for some of its large grants to include a separate section that describes the project's plan for enhancing diverse perspectives (PEDPs). Our project aims to develop consensus-based PEDP evaluation metrics and instruments that can be systematically and sustainably collected across the projects.

METHODS AND ANALYSIS: Evaluation work is organised into three objectives. First, shared knowledge about PEDP infrastructures, activities and outcomes will be …

The Hao-Fountain Syndrome Protein Usp7 Regulates Neuronal Connectivity In The Brain Via A Novel P53-Independent Ubiquitin Signaling Pathway, Hao Chen, Cole J Ferguson, Dylan C Mitchell, Isabel Risch, Amanda Titus, Joao A Paulo, Andrew Hwang, Loren K Beck, Tsen-Hsuan Lin, Sheng-Kwei Song, Carla M Yuede, Hiroko Yano, Obi L Griffith, Malachi Griffith, Steven P Gygi, Azad Bonni, Albert H Kim, Et Al.

2020-Current year OA Pubs

Mutation or deletion of the deubiquitinase USP7 causes Hao-Fountain syndrome (HAFOUS), which is characterized by speech delay, intellectual disability, and aggressive behavior and highlights important unknown roles of USP7 in the nervous system. Here, we conditionally delete USP7 in glutamatergic neurons in the mouse forebrain, triggering disease-relevant phenotypes, including sensorimotor deficits, impaired cognition, and aggressive behavior. Although USP7 deletion induces p53-dependent neuronal apoptosis, most behavioral abnormalities in USP7 conditional knockout mice persist following p53 loss. Strikingly, USP7 deletion perturbs the synaptic proteome and dendritic spinogenesis independent of p53. Integrated proteomics and biochemical analyses identify the RNA splicing factor Ppil4 as …

Phospho-Relay Feedback Loops Control Egress Vs. Intracellular Development In Toxoplasma Gondii, Ja E Claywell, Yong Fu, L David Sibley

2020-Current year OA Pubs

The intracellular parasite Toxoplasma gondii alternates between a motile invasive and a quiescent intracellular replicative form, yet how these transitions are regulated is unknown. A positive feedback loop involving protein kinase G (PKG) and calcium-dependent PKs (CDPKs) controls motility, invasion, and egress by Toxoplasma gondii, while PKA isoform c1 (PKAc1) counteracts this pathway. Shortly after invasion, PKAc1 is activated by cyclic AMP (cAMP) produced by adenylate cyclases, leading to the suppression of the PKG/CDPK pathway. PKAc1 further activates phosphodiesterase 2, which selectively consumes cAMP, thus forming a negative feedback loop, causing transient activation of PKAc1. Perturbation of cyclic GMP (cGMP) …

Agouti And Bmp Signaling Drive A Naturally Occurring Fate Conversion Of Melanophores To Leucophores In Zebrafish, Delai Huang, Emaan H. Kapadia, Yipeng Liang, Leah P. Shriver, Shengkun Dai, Gary J. Patti, Bruno M. Humbel, Vincent Laudet, David M. Parichy

2020-Current year OA Pubs

No abstract provided.