Digital Commons Network^™

Connective Tissue Presentation In Two Families Expands The Phenotypic Spectrum Of Pyroxd1 Disorders, Frances J Evesson, Gregory Dziaduch, Samantha J Bryen, Francesca Moore, Sara Pittman, Beena Devanapalli, Leigh B Waddell, Monique M Ryan, Manoj P Menezes, Conrad C Weihl, Adviye Ayper Tolun, Craig Zaidman, Helen Young, Lesley C Adès, Sandra T Cooper

2020-Current year OA Pubs

Recessive variants in the oxidoreductase PYROXD1 are reported to cause a myopathy in 22 affected individuals from 15 families. Here, we describe two female probands from unrelated families presenting with features of a congenital connective tissue disorder including osteopenia, blue sclera, soft skin, joint hypermobility and neuromuscular junction dysfunction in addition to known features of PYROXD1 myopathy including respiratory difficulties, weakness, hypotonia and oromotor dysfunction. Proband AII:1 is compound heterozygous for the recurrent PYROXD1 variant Chr12(GRCh38):g.21452130A>G;NM_024854.5:c.464A>G;p.(N155S) and Chr12(GRCh38):g.21462019_21462022del;NM_024854.5:c.892_895del;p.(V298Mfs*4) and proband BII:1 is compound heterozygous for Chr12(GRCh38):g.21468739-21468741del;NM_024854.5:c.1488_1490del;p.(E496del) and Chr12(GRCh38):g.21467619del;NM_024854.5:c.1254+1del. RNA studies demonstrate c.892_895del;p.(V298Mfs*4) is targeted by nonsense mediated decay …

Intrinsic Tgf-Β Signaling Attenuates Proximal Tubule Mitochondrial Injury And Inflammation In Chronic Kidney Disease, Merve Kayhan, Judith Vouillamoz, Daymé Gonzalez Rodriguez, Milica Bugarski, Yasutaka Mitamura, Julia Gschwend, Christoph Schneider, Andrew Hall, David Legouis, Cezmi A Akdis, Leary Peter, Hubert Rehrauer, Leslie Gewin, Roland H Wenger, Stellor Nlandu Khodo

2020-Current year OA Pubs

Excessive TGF-β signaling and mitochondrial dysfunction fuel chronic kidney disease (CKD) progression. However, inhibiting TGF-β failed to impede CKD in humans. The proximal tubule (PT), the most vulnerable renal segment, is packed with giant mitochondria and injured PT is pivotal in CKD progression. How TGF-β signaling affects PT mitochondria in CKD remained unknown. Here, we combine spatial transcriptomics and bulk RNAseq with biochemical analyses to depict the role of TGF-β signaling on PT mitochondrial homeostasis and tubulo-interstitial interactions in CKD. Male mice carrying specific deletion of Tgfbr2 in the PT have increased mitochondrial injury and exacerbated Th1 immune response in …

Evaluating The Use Of Blood Pressure Polygenic Risk Scores Across Race/Ethnic Background Groups, Nuzulul Kurniansyah, C Charles Gu, Et Al.

2020-Current year OA Pubs

We assess performance and limitations of polygenic risk scores (PRSs) for multiple blood pressure (BP) phenotypes in diverse population groups. We compare "clumping-and-thresholding" (PRSice2) and LD-based (LDPred2) methods to construct PRSs from each of multiple GWAS, as well as multi-PRS approaches that sum PRSs with and without weights, including PRS-CSx. We use datasets from the MGB Biobank, TOPMed study, UK biobank, and from All of Us to train, assess, and validate PRSs in groups defined by self-reported race/ethnic background (Asian, Black, Hispanic/Latino, and White). For both SBP and DBP, the PRS-CSx based PRS, constructed as a weighted sum of PRSs …

Altered Signaling And Desensitization Responses In Pth1r Mutants Associated With Eiken Syndrome, Ignacio Portales-Castillo, Thomas Dean, Ross W Cheloha, Brendan A Creemer, Jean-Pierre Vilardaga, Sofya Savransky, Ashok Khatri, Harald Jüppner, Thomas J Gardella

2020-Current year OA Pubs

The parathyroid hormone receptor type 1 (PTH1R) is a G protein-coupled receptor that plays key roles in regulating calcium homeostasis and skeletal development via binding the ligands, PTH and PTH-related protein (PTHrP), respectively. Eiken syndrome is a rare disease of delayed bone mineralization caused by homozygous PTH1R mutations. Of the three mutations identified so far, R485X, truncates the PTH1R C-terminal tail, while E35K and Y134S alter residues in the receptor's amino-terminal extracellular domain. Here, using a variety of cell-based assays, we show that R485X increases the receptor's basal rate of cAMP signaling and decreases its capacity to recruit β-arrestin2 upon …

Genomic Approaches To Cancer And Minimal Residual Disease Detection Using Circulating Tumor Dna, Nicholas P. Semenkovich, Jeffrey J. Szymanski, Noah Earland, Pradeep S. Chauhan, Bruna Pellini, Aadel A. Chaudhuri

2020-Current year OA Pubs

Liquid biopsies using cell-free circulating tumor DNA (ctDNA) are being used frequently in both research and clinical settings. ctDNA can be used to identify actionable mutations to personalize systemic therapy, detect post-treatment minimal residual disease (MRD), and predict responses to immunotherapy. ctDNA can also be isolated from a range of different biofluids, with the possibility of detecting locoregional MRD with increased sensitivity if sampling more proximally than blood plasma. However, ctDNA detection remains challenging in early-stage and post-treatment MRD settings where ctDNA levels are minuscule giving a high risk for false negative results, which is balanced with the risk of …

The Sphingolipids Ceramide And Inositol Phosphorylceramide Protect The Leishmania Major Membrane From Sterol-Specific Toxins, Chaitanya S Haram, Samrat Moitra, Rilee Keane, F Matthew Kuhlmann, Cheryl Frankfater, Fong-Fu Hsu, Stephen M Beverley, Kai Zhang, Peter A Keyel

2020-Current year OA Pubs

The accessibility of sterols in mammalian cells to exogenous sterol-binding agents has been well-described previously, but sterol accessibility in distantly related protozoa is unclear. The human pathogen Leishmania major uses sterols and sphingolipids distinct from those used in mammals. Sterols in mammalian cells can be sheltered from sterol-binding agents by membrane components, including sphingolipids, but the surface exposure of ergosterol in Leishmania remains unknown. Here, we used flow cytometry to test the ability of the L. major sphingolipids inositol phosphorylceramide (IPC) and ceramide to shelter ergosterol by preventing binding of the sterol-specific toxins streptolysin O and perfringolysin O and subsequent …

Transcription Regulation By Card In Mycobacteria Is Guided By Basal Promoter Kinetics, Dennis X Zhu, Christina L Stallings

2020-Current year OA Pubs

Bacterial pathogens like Mycobacterium tuberculosis (Mtb) employ transcription factors to adapt their physiology to the diverse environments within their host. CarD is a conserved bacterial transcription factor that is essential for viability in Mtb. Unlike classical transcription factors that recognize promoters by binding to specific DNA sequence motifs, CarD binds directly to the RNA polymerase to stabilize the open complex intermediate (RP

Characterization Of Cell-Type Specific Circular Rnas Associated With Colorectal Cancer Metastasis, Sidi Zhao, Amy Ly, Jacqueline L Mudd, Emily B Rozycki, Jace Webster, Emily Coonrod, Ghofran Othoum, Jingqin Luo, Ha X Dang, Ryan C Fields, Christopher A Maher

2020-Current year OA Pubs

Colorectal cancer (CRC) is the most common gastrointestinal malignancy and a leading cause of cancer deaths in the United States. More than half of CRC patients develop metastatic disease (mCRC) with an average 5-year survival rate of 13%. Circular RNAs (circRNAs) have recently emerged as important tumorigenesis regulators; however, their role in mCRC progression remains poorly characterized. Further, little is known about their cell-type specificity to elucidate their functions in the tumor microenvironment (TME). To address this, we performed total RNA sequencing (RNA-seq) on 30 matched normal, primary and metastatic samples from 14 mCRC patients. Additionally, five CRC cell lines …

The Mitophagy Receptor Bnip3 Is Critical For The Regulation Of Metabolic Homeostasis And Mitochondrial Function In The Nucleus Pulposus Cells Of The Intervertebral Disc, Vedavathi Madhu, Miriam Hernandez-Meadows, Paige K Boneski, Yunping Qiu, Anyonya R Guntur, Irwin J Kurland, Ruteja A Barve, Makarand V Risbud

2020-Current year OA Pubs

The contribution of mitochondria to the metabolic function of hypoxic NP cells has been overlooked. We have shown that NP cells contain networked mitochondria and that mitochondrial translocation of BNIP3 mediates hypoxia-induced mitophagy. However, whether BNIP3 also plays a role in governing mitochondrial function and metabolism in hypoxic NP cells is not known. BNIP3 knockdown altered mitochondrial morphology, and number, and increased mitophagy. Interestingly, BNIP3 deficiency in NP cells reduced glycolytic capacity reflected by lower production of lactate/H

Tarlatamab, A First-In-Class Dll3-Targeted Bispecific T-Cell Engager, In Recurrent Small-Cell Lung Cancer: An Open-Label, Phase I Study, Luis Paz-Ares, Ramaswamy Govindan, Et Al.

2020-Current year OA Pubs

PURPOSE: Small-cell lung cancer (SCLC) is an aggressive malignancy with limited treatments. Delta-like ligand 3 (DLL3) is aberrantly expressed in most SCLC. Tarlatamab (AMG 757), a bispecific T-cell engager molecule, binds both DLL3 and CD3 leading to T-cellb-mediated tumor lysis. Herein, we report phase I results of tarlatamab in patients with SCLC.

PATIENTS AND METHODS: This study evaluated tarlatamab in patients with relapsed/refractory SCLC. The primary end point was safety. Secondary end points included antitumor activity by modified RECIST 1.1, overall survival, and pharmacokinetics.

RESULTS: By July 19, 2022, 107 patients received tarlatamab in dose exploration (0.003 to 100 mg; …

Uridine-Derived Ribose Fuels Glucose-Restricted Pancreatic Cancer, Zeribe C Nwosu, Matthew H Ward, Leah P Shriver, Gary J Patti, Et Al.

2020-Current year OA Pubs

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease notoriously resistant to therapy

Patients With Stricturing Or Penetrating Crohn's Disease Phenotypes Report High Disease Burden And Treatment Needs, Yanni Fan, Ling Zhang, Negar Omidakhsh, Rhonda L Bohn, Jennifer S Thompson, Kimberly G Brodovicz, Parakkal Deepak

2020-Current year OA Pubs

BACKGROUND: Crohn's disease (CD) is a chronic autoimmune disease in which inflammation can progress to complications of stricturing and/or penetrating disease. Real-world data on burden of complicated CD phenotypes are limited.

METHODS: We analyzed cross-sectional data from the SPARC IBD (Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease) registry from 2016 to 2020. Four mutually exclusive phenotype cohorts were created: inflammatory CD (CD-I), complicated CD (stricturing CD, penetrating CD, and stricturing and penetrating CD [CD-SP]). Statistical analyses were performed using CD-I as the reference.

RESULTS: A total of 1557 patients were identified: CD-I (n = 674, 43.3%), …

Deficiency In Galectin-3, -8, And -9 Impairs Immunity To Chronic Mycobacterium Tuberculosis Infection But Not Acute Infection With Multiple Intracellular Pathogens, Huntly M. Morrison, Wandy L. Beatty, Et Al.

2020-Current year OA Pubs

Macrophages employ an array of pattern recognition receptors to detect and eliminate intracellular pathogens that access the cytosol. The cytosolic carbohydrate sensors Galectin-3, -8, and -9 (Gal-3, Gal-8, and Gal-9) recognize damaged pathogen-containing phagosomes, and Gal-3 and Gal-8 are reported to restrict bacterial growth via autophagy in cultured cells. However, the contribution of these galectins to host resistance during bacterial infection in vivo remains unclear. We found that Gal-9 binds directly to Mycobacterium tuberculosis (Mtb) and Salmonella enterica serovar Typhimurium (Stm) and localizes to Mtb in macrophages. To determine the combined contribution of membrane damage-sensing galectins to immunity, we generated …

Central Carbon Flux Controls Growth/Damage Balance For Streptococcus Pyogenes, Joseph A. Merriman, Wei Xu, Michael G. Caparon

2020-Current year OA Pubs

Microbial pathogens balance growth against tissue damage to achieve maximum fitness. Central carbon metabolism is connected to growth, but how it influences growth/damage balance is largely unknown. Here we examined how carbon flux through the exclusively fermentative metabolism of the pathogenic lactic acid bacterium Streptococcus pyogenes impacts patterns of growth and tissue damage. Using a murine model of soft tissue infection, we systematically examined single and pair-wise mutants that constrained carbon flux through the three major pathways that S. pyogenes employs for reduction of the glycolytic intermediate pyruvate, revealing distinct disease outcomes. Its canonical lactic acid pathway (via lactate dehydrogenase) …

Autophagy Prevents Early Proinflammatory Responses And Neutrophil Recruitment During Mycobacterium Tuberculosis Infection Without Affecting Pathogen Burden In Macrophages, Rachel L. Kinsella, Jacqueline M. Kimmey, Asya Smirnov, Reilly Woodson, Margaret R. Gaggioli, Sthefany M. Chavez, Darren Kreamalmeyer, Christina L. Stallings

2020-Current year OA Pubs

The immune response to Mycobacterium tuberculosis infection determines tuberculosis disease outcomes, yet we have an incomplete understanding of what immune factors contribute to a protective immune response. Neutrophilic inflammation has been associated with poor disease prognosis in humans and in animal models during M. tuberculosis infection and, therefore, must be tightly regulated. ATG5 is an essential autophagy protein that is required in innate immune cells to control neutrophil-dominated inflammation and promote survival during M. tuberculosis infection; however, the mechanistic basis for how ATG5 regulates neutrophil recruitment is unknown. To interrogate what innate immune cells require ATG5 to control neutrophil recruitment …

Biological Rhythms In Covid-19 Vaccine Effectiveness In An Observational Cohort Study Of 1.5 Million Patients, Guy Hazan, Or A. Duek, Hillel Alapi, Huram Mok, Alex Ganninger, Elaine Ostendorf, Carrie Gierasch, Gabriel Chodick, David Greenberg, Jeffrey A. Haspel

2020-Current year OA Pubs

BACKGROUNDCircadian rhythms are evident in basic immune processes, but it is unclear if rhythms exist in clinical endpoints like vaccine protection. Here, we examined associations between COVID-19 vaccination timing and effectiveness.METHODSWe retrospectively analyzed a large Israeli cohort with timestamped COVID-19 vaccinations (n = 1,515,754 patients over 12 years old, 99.2% receiving BNT162b2). Endpoints included COVID-19 breakthrough infection and COVID-19-associated emergency department visits and hospitalizations. Our main comparison was among patients vaccinated during morning (800-1159 hours), afternoon (1200-1559 hours), or evening hours (1600-1959 hours). We employed Cox regression to adjust for differences in age, sex, and comorbidities.RESULTSBreakthrough infections differed based on …

American Academy Of Orthopaedic Surgeons Clinical Practice Guideline Summary: Management Of Anterior Cruciate Ligament Injuries, Robert H. Brophy, Kent Jason Lowry

2020-Current year OA Pubs

Management of Anterior Cruciate Ligament Injuries : Evidence-based Clinical Practice Guideline is based on a systematic review of published studies for the treatment of anterior cruciate ligament injurie in both skeletally mature and immature patients. This guideline contains eight recommendations and seven options to assist orthopaedic surgeons and all qualified physicians managing patients with ACL injuries based on the best current available evidence. It is also intended to serve as an information resource for professional healthcare practitioners and developers of practice guidelines and recommendations. In addition to providing pragmatic practice recommendations, this guideline also highlights gaps in the literature and …

"Brain Age" Predicts Disability Accumulation In Multiple Sclerosis, Matthew R Brier, Zhuocheng Li, Maria Ly, Helmet T Karim, Leda Liang, Weixin Du, John E Mccarthy, Anne H Cross, Tammie L S Benzinger, Robert T Naismith, Salim Chahin

2020-Current year OA Pubs

OBJECTIVE: Neurodegenerative conditions often manifest radiologically with the appearance of premature aging. Multiple sclerosis (MS) biomarkers related to lesion burden are well developed, but measures of neurodegeneration are less well-developed. The appearance of premature aging quantified by machine learning applied to structural MRI assesses neurodegenerative pathology. We assess the explanatory and predictive power of "brain age" analysis on disability in MS using a large, real-world dataset.

METHODS: Brain age analysis is predicated on the over-estimation of predicted brain age in patients with more advanced pathology. We compared the performance of three brain age algorithms in a large, longitudinal dataset ( …

Interleukin-18 Signaling Promotes Activation Of Hepatic Stellate Cells In Mouse Liver Fibrosis, Jana Knorr, Joel D. Schilling, Et Al.

2020-Current year OA Pubs

BACKGROUND AND AIMS: Nucleotide-binding oligomerization domain-like receptor-family pyrin domain-containing 3 (NLRP3) inflammasome activation has been shown to result in liver fibrosis. Mechanisms and downstream signaling remain incompletely understood. Here, we studied the role of IL-18 in hepatic stellate cells (HSCs), and its impact on liver fibrosis.

APPROACH AND RESULTS: We observed significantly increased serum levels of IL-18 (128.4 pg/ml vs. 74.9 pg/ml) and IL-18 binding protein (BP; 46.50 ng/ml vs. 15.35 ng/ml) in patients with liver cirrhosis compared with healthy controls. Single cell RNA sequencing data showed that an immunoregulatory subset of murine HSCs highly expresses Il18 and Il18r1 . …

Longitudinal Analysis Of Change In Mammographic Density In Each Breast And Its Association With Breast Cancer Risk, Shu Jiang, Debbie L Bennett, Bernard A Rosner, Graham A Colditz

2020-Current year OA Pubs

IMPORTANCE: Although breast density is an established risk factor for breast cancer, longitudinal changes in breast density have not been extensively studied to determine whether this factor is associated with breast cancer risk.

OBJECTIVE: To prospectively evaluate the association between change in mammographic density in each breast over time and risk of subsequent breast cancer.

DESIGN, SETTING, AND PARTICIPANTS: This nested case-control cohort study was sampled from the Joanne Knight Breast Health Cohort of 10 481 women free from cancer at entry and observed from November 3, 2008, to October 31, 2020, with routine screening mammograms every 1 to 2 …

Acinetobacter Baumannii Atcc 17978 Encodes A Microcin System With Antimicrobial Properties For Contact-Independent Competition, Fabiana Bisaro, Howard A Shuman, Mario F Feldman, Michael J Gebhardt, Stefan Pukatzki

2020-Current year OA Pubs

No abstract provided.

Peptidoglycan Recognition In Drosophila Is Mediated By Lysmd3/4, Mark Snee, Jason Wever, Jennifer Guyton, Ryan Beehler-Evans, Christine C Yokoyama, Craig A Micchelli

2020-Current year OA Pubs

Microbial recognition is a key step in regulating the immune signaling pathways of multicellular organisms. Peptidoglycan, a component of the bacterial cell wall, exhibits immune stimulating activity in both plants and animals. Lysin motif domain (LysMD) family proteins are ancient peptidoglycan receptors that function in bacteriophage and plants. This report focuses on defining the role of LysMD-containing proteins in animals. Here, we characterize a novel transmembrane LysMD family protein. Loss-of-function mutations at the lysMD3/4 locus in Drosophila are associated with systemic innate immune activation following challenge, so we refer to this gene as immune active (ima). We show that Ima …

Replicative Acinetobacter Baumannii Strains Interfere With Phagosomal Maturation By Modulating The Vacuolar Ph, Jesus S. Distel, Gisela Di Venanzio, Joseph J. Mackel, David A. Rosen, Mario F. Feldman

2020-Current year OA Pubs

Bacterial pneumonia is a common infection of the lower respiratory tract that can afflict patients of all ages. Multidrug-resistant strains of Acinetobacter baumannii are increasingly responsible for causing nosocomial pneumonias, thus posing an urgent threat. Alveolar macrophages play a critical role in overcoming respiratory infections caused by this pathogen. Recently, we and others have shown that new clinical isolates of A. baumannii, but not the common lab strain ATCC 19606 (19606), can persist and replicate in macrophages within spacious vacuoles that we called Acinetobacter Containing Vacuoles (ACV). In this work, we demonstrate that the modern A. baumannii clinical isolate 398, …

Finding Motifs Using Dna Images Derived From Sparse Representations, Shane K Chu, Gary D Stormo

2020-Current year OA Pubs

MOTIVATION: Motifs play a crucial role in computational biology, as they provide valuable information about the binding specificity of proteins. However, conventional motif discovery methods typically rely on simple combinatoric or probabilistic approaches, which can be biased by heuristics such as substring-masking for multiple motif discovery. In recent years, deep neural networks have become increasingly popular for motif discovery, as they are capable of capturing complex patterns in data. Nonetheless, inferring motifs from neural networks remains a challenging problem, both from a modeling and computational standpoint, despite the success of these networks in supervised learning tasks.

RESULTS: We present a …

Participant- And Disease-Related Factors As Independent Predictors Of Treatment Outcomes In The Restore-Imi 2 Clinical Trial: A Multivariable Regression Analysis, Ignacio Martin-Loeches, Andrew F Shorr, Marin H Kollef, Jiejun Du, Maria C Losada, Amanda Paschke, C Andrew Deryke, Michael Wong, Erin H Jensen, Luke F Chen

2020-Current year OA Pubs

BACKGROUND: In the RESTORE-IMI 2 trial, imipenem/cilastatin/relebactam (IMI/REL) was noninferior to piperacillin/tazobactam in treating hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia. This post hoc analysis was conducted to determine independent predictors of efficacy outcomes in the RESTORE-IMI 2 trial, to assist in treatment decision making.

METHODS: A stepwise multivariable regression analysis was conducted to identify variables that were independently associated with day 28 all-cause mortality (ACM), favorable clinical response at early follow-up (EFU), and favorable microbiologic response at end of treatment (EOT). The analysis accounted for the number of baseline infecting pathogens and in vitro susceptibility to randomized treatment.

RESULTS: Vasopressor use, …

Irritability Moderates The Association Between Cognitive Flexibility Task Performance And Related Prefrontal Cortex Activation In Young Children, Yanwei Li, Adam S Grabell, Susan B Perlman

2020-Current year OA Pubs

The association between cognitive flexibility and related neural functioning has been inconsistent. This is particularly true in young children, where previous studies have found heterogenous results linking behavior and neural function, raising the possibility of unexplored moderators. The current study explored the moderating role of dimensional irritability in the association between cognitive flexibility task performance and prefrontal activation in young children. A total of 106 3- to 7-year-old children were recruited to complete a custom-designed, child-adapted, cognitive flexibility task, and 98 of them were included in the data analysis. The children's dorsolateral prefrontal cortex activation was monitored using functional near-infrared …

Leukemia Relapse Via Genetic Immune Escape After Allogeneic Hematopoietic Cell Transplantation, Simona Pagliuca, Francesca Ferraro, Et Al.

2020-Current year OA Pubs

Graft-versus-leukemia (GvL) reactions are responsible for the effectiveness of allogeneic hematopoietic cell transplantation as a treatment modality for myeloid neoplasia, whereby donor T- effector cells recognize leukemia neoantigens. However, a substantial fraction of patients experiences relapses because of the failure of the immunological responses to control leukemic outgrowth. Here, through a broad immunogenetic study, we demonstrate that germline and somatic reduction of human leucocyte antigen (HLA) heterogeneity enhances the risk of leukemic recurrence. We show that preexistent germline-encoded low evolutionary divergence of class II HLA genotypes constitutes an independent factor associated with disease relapse and that acquisition of clonal somatic …

Scanning Electron Microscopy Of Human Islet Cilia, Alexander J Polino, Sanja Sviben, Isabella Melena, David W Piston, Jing W Hughes

2020-Current year OA Pubs

Human islet primary cilia are vital glucose-regulating organelles whose structure remains uncharacterized. Scanning electron microscopy (SEM) is a useful technique for studying the surface morphology of membrane projections like cilia, but conventional sample preparation does not reveal the submembrane axonemal structure, which holds key implications for ciliary function. To overcome this challenge, we combined SEM with membrane-extraction techniques to examine primary cilia in native human islets. Our data show well-preserved cilia subdomains which demonstrate both expected and unexpected ultrastructural motifs. Morphometric features were quantified when possible, including axonemal length and diameter, microtubule conformations, and chirality. We further describe a ciliary …

Starvation Sensing By Mycobacterial Rela/Spot Homologue Through Constitutive Surveillance Of Translation, Yunlong Li, Soneya Majumdar, Ryan Treen, Manjuli R Sharma, Jamie Corro, Howard B Gamper, Swati R Manjari, Jerome Prusa, Nilesh K Banavali, Christina L Stallings, Ya-Ming Hou, Rajendra K Agrawal, Anil K Ojha

2020-Current year OA Pubs

The stringent response, which leads to persistence of nutrient-starved mycobacteria, is induced by activation of the RelA/SpoT homolog (Rsh) upon entry of a deacylated-tRNA in a translating ribosome. However, the mechanism by which Rsh identifies such ribosomes in vivo remains unclear. Here, we show that conditions inducing ribosome hibernation result in loss of intracellular Rsh in a Clp protease-dependent manner. This loss is also observed in nonstarved cells using mutations in Rsh that block its interaction with the ribosome, indicating that Rsh association with the ribosome is important for Rsh stability. The cryo-EM structure of the Rsh-bound 70S ribosome in …

Peptide-Based Nanoparticles For Systemic Extrahepatic Delivery Of Therapeutic Nucleotides, Samuel A Wickline, Kirk K Hou, Hua Pan

2020-Current year OA Pubs

Peptide-based nanoparticles (PBN) for nucleotide complexation and targeting of extrahepatic diseases are gaining recognition as potent pharmaceutical vehicles for fine-tuned control of protein production (up- and/or down-regulation) and for gene delivery. Herein, we review the principles and mechanisms underpinning self-assembled formation of PBN, cellular uptake, endosomal release, and delivery to extrahepatic disease sites after systemic administration. Selected examples of PBN that have demonstrated recent proof of concept in disease models in vivo are summarized to offer the reader a comparative view of the field and the possibilities for clinical application.