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Vincristine And Bortezomib Use Distinct Upstream Mechanisms To Activate A Common Sarm1-Dependent Axon Degeneration Program, Stefanie Geisler, Ryan A Doan, Galen C Cheng, Aysel Cetinkaya-Fisgin, Shay X Huang, Ahmet Höke, Jeffrey Milbrandt, Aaron Diantonio

Open Access Publications

Chemotherapy-induced peripheral neuropathy is one of the most prevalent dose-limiting toxicities of anticancer therapy. Development of effective therapies to prevent chemotherapy-induced neuropathies could be enabled by a mechanistic understanding of axonal breakdown following exposure to neuropathy-causing agents. Here, we reveal the molecular mechanisms underlying axon degeneration induced by 2 widely used chemotherapeutic agents with distinct mechanisms of action: vincristine and bortezomib. We showed previously that genetic deletion of SARM1 blocks vincristine-induced neuropathy and demonstrate here that it also prevents axon destruction following administration of bortezomib in vitro and in vivo. Using cultured neurons, we found that vincristine and bortezomib converge …

Mining Biosynthetic Gene Clusters In Virgibacillus Genomes, Ghofran Othoum, Salim Bougouffa, Ameerah Bokhari, Feras F Lafi, Takashi Gojobori, Heribert Hirt, Ivan Mijakovic, Vladimir B Bajic, Magbubah Essack

Open Access Publications

BACKGROUND: Biosynthetic gene clusters produce a wide range of metabolites with activities that are of interest to the pharmaceutical industry. Specific interest is shown towards those metabolites that exhibit antimicrobial activities against multidrug-resistant bacteria that have become a global health threat. Genera of the phylum Firmicutes are frequently identified as sources of such metabolites, but the biosynthetic potential of its Virgibacillus genus is not known. Here, we used comparative genomic analysis to determine whether Virgibacillus strains isolated from the Red Sea mangrove mud in Rabigh Harbor Lagoon, Saudi Arabia, may be an attractive source of such novel antimicrobial agents.

RESULTS: …

An Open-Source, Automated Home-Cage Sipper Device For Monitoring Liquid Ingestive Behavior In Rodents, Elizabeth Godynyuk, Maya N Bluitt, Jessica R Tooley, Alexxai V Kravitz, Meaghan C Creed

Open Access Publications

Measuring ingestive behavior of liquids in rodents is commonly used in studies of reward, metabolism, and circadian biology. Common approaches for measuring liquid intake in real time include computer-tethered lickometers or video-based systems. Additionally, liquids can be measured or weighed to determine the amount consumed without real-time sensing. Here, we built a photobeam-based sipper device that has the following advantages over traditional methods: (1) it is battery powered and fits in vivarium caging to allow home-cage measurements; (2) it quantifies the intake of two different liquids simultaneously for preference studies; (3) it is low cost and easily constructed, enabling high-throughput …

Tyk2 Promotes Malignant Peripheral Nerve Sheath Tumor Progression Through Inhibition Of Cell Death, Wenjing Qin, Abigail Godec, Xiaochun Zhang, Cuige Zhu, Jieya Shao, Yu Tao, Xianzhang Bu, Angela C Hirbe

Open Access Publications

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that arise most commonly in the setting of the Neurofibromatosis Type 1 (NF1) cancer predisposition syndrome. Despite aggressive multimodality therapy, outcomes are dismal and most patients die within 5 years of diagnosis. Prior genomic studies in our laboratory identified tyrosine kinase 2 (TYK2) as a frequently mutated gene in MPNST. Herein, we explored the function of TYK2 in MPNST pathogenesis.

METHODS: Immunohistochemistry was utilized to examine expression of TYK2 in MPNSTs and other sarcomas. To establish a role for TYK2 in MPNST pathogenesis, murine and human TYK2 knockdown and knockout …

Relation Between Central Venous, Peripheral Venous And Arterial Lactate Levels In Patients With Sepsis In The Emergency Department, Dimitrios Velissaris, Vasileios Karamouzos, Nikolaos Dimitrios Pantzaris, Ourania Kyriakopoulou, Charalampos Gogos, Menelaos Karanikolas

Open Access Publications

Background: Sepsis and multi-organ failure remain a major clinical problem with high morbidity and mortality worldwide. Lactate measurement remains part of the initial assessment and management of patients with sepsis. Although arterial blood is most commonly used for lactate measurement, there is increasing use of peripheral venous lactate for initial assessment and for monitoring of response to treatment in patients with sepsis. The aim of this study was to evaluate the relation between lactate levels measured from central line, peripheral vein and arterial line in patients treated for sepsis in the emergency department (ED).

Methods: This prospective study enrolled 31 …

Dhx33 Interacts With Ap-2Β To Regulate Bcl-2 Gene Expression And Promote Cancer Cell Survival, Jiuling Wang, Weimin Feng, Zhen Yuan, Jason D. Weber, Yandong Zhang

Open Access Publications

The RNA helicase DHX33 has been found to be overexpressed in human cancers, where it promotes cancer development. Previous reports have shown that DHX33 deficiency caused cancer cell apoptosis, but the underlying mechanism remains unknown. In this study, we discovered that DHX33 regulates Bcl-2 family protein expression. In multiple human cancer cell lines, DHX33 was found to stimulate the transcription of

Omnipresence Of Inflammasome Activities In Inflammatory Bone Diseases, Yael Alippe, Gabriel Mbalaviele

Open Access Publications

The inflammasomes are intracellular protein complexes that are assembled in response to a variety of perturbations including infections and injuries. Failure of the inflammasomes to rapidly clear the insults or restore tissue homeostasis can result in chronic inflammation. Recurring inflammation is also provoked by mutations that cause the constitutive assembly of the components of these protein platforms. Evidence suggests that chronic inflammation is a shared mechanism in bone loss associated with aging, dysregulated metabolism, autoinflammatory, and autoimmune diseases. Mechanistically, inflammatory mediators promote bone resorption while suppressing bone formation, an imbalance which over time leads to bone loss and increased fracture …

Four-Jointed Knock-Out Delays Renal Failure In An Adpkd Model With Kidney Injury, Chiara Formica, Hester Happé, Kimberley Am Veraar, Andrea Vortkamp, Marion Scharpfenecker, Helen Mcneill, Dorien Jm Peters

Open Access Publications

Autosomal Dominant Polycystic Kidney Disease is characterised by the development of fluid-filled cysts in the kidneys which lead to end-stage renal disease (ESRD). In the majority of cases, the disease is caused by a mutation in the Pkd1 gene. In a previous study, we demonstrated that renal injury can accelerate cyst formation in Pkd1 knock-out (KO) mice. In that study, we found that after injury four-jointed (Fjx1), an upstream regulator of planar cell polarity and the Hippo pathway, was aberrantly expressed in Pkd1 KO mice compared to WT. Therefore, we hypothesised a role for Fjx1 in injury/repair and cyst formation. …

Best Practices For Bioinformatic Characterization Of Neoantigens For Clinical Utility, Megan M Richters, Huiming Xia, Katie M Campbell, William E Gillanders, Obi L Griffith, Malachi Griffith

Open Access Publications

Neoantigens are newly formed peptides created from somatic mutations that are capable of inducing tumor-specific T cell recognition. Recently, researchers and clinicians have leveraged next generation sequencing technologies to identify neoantigens and to create personalized immunotherapies for cancer treatment. To create a personalized cancer vaccine, neoantigens must be computationally predicted from matched tumor-normal sequencing data, and then ranked according to their predicted capability in stimulating a T cell response. This candidate neoantigen prediction process involves multiple steps, including somatic mutation identification, HLA typing, peptide processing, and peptide-MHC binding prediction. The general workflow has been utilized for many preclinical and clinical …

Comparative Genomics Of Antibiotic-Resistant Uropathogens Implicates Three Routes For Recurrence Of Urinary Tract Infections, Robert Thänert, Kimberly A Reske, Tiffany Hink, Meghan A Wallace, Bin Wang, Drew J Schwartz, Sondra Seiler, Candice Cass, Carey-Ann D. Burnham, Erik R Dubberke, Jennie H Kwon, Gautam Dantas

Open Access Publications

The rise of antimicrobial resistance in uropathogens has complicated the management of urinary tract infections (UTIs), particularly in patients who are afflicted by recurrent episodes of UTIs. Antimicrobial-resistant (AR) uropathogens persistently colonizing individuals at asymptomatic time points have been implicated in the pathophysiology of UTIs. The dynamics of uropathogen persistence following the resolution of symptomatic disease are, however, mostly unclear. To further our understanding, we determined longitudinal AR uropathogen carriage and clonal persistence of uropathogenic

Obstructive Sleep Apnoea, Positive Airway Pressure Treatment And Postoperative Delirium: Protocol For A Retrospective Observational Study, Christopher R King, Krisztina E Escallier, Yo-El S Ju, Nan Lin, Ben Julian Palanca, Sherry Lynn Mckinnon, Michael Simon Avidan

Open Access Publications

INTRODUCTION: Obstructive sleep apnoea (OSA) is common among older surgical patients, and delirium is a frequent and serious postoperative complication. Emerging evidence suggests that OSA increases the risk for postoperative delirium. We hypothesise that OSA is an independent risk factor for postoperative delirium, and that in patients with OSA, perioperative adherence to positive airway pressure (PAP) therapy decreases the incidence of postoperative delirium and its sequelae. The proposed retrospective cohort analysis study will use existing datasets to: (i) describe and compare the incidence of postoperative delirium in surgical patients based on OSA diagnosis and treatment with PAP; (ii) assess whether …

Mucosal Infection Rewires Tnfɑ Signaling Dynamics To Skew Susceptibility To Recurrence, Lu Yu, Valerie P. O'Brien, Jonathan Livny, Denise Dorsey, Nirmalya Bandyopadhyay, Marco Colonna, Michael G. Caparon, Elisha D.O. Roberson, Scott J. Hultgren, Thomas Hannan

Open Access Publications

A mucosal infectious disease episode can render the host either more or less susceptible to recurrent infection, but the specific mechanisms that tip the balance remain unclear. We investigated this question in a mouse model of recurrent urinary tract infection and found that a prior bladder infection resulted in an earlier onset of tumor necrosis factor-alpha (TNFɑ)-mediated bladder inflammation upon subsequent bacterial challenge, relative to age-matched naive mice. However, the duration of TNFɑ signaling activation differed according to whether the first infection was chronic (Sensitized) or self-limiting (Resolved). TNFɑ depletion studies revealed that transient early-phase TNFɑ signaling in Resolved mice …

Bjc Today

BJC Today

No abstract provided.

Noroviruses Subvert The Core Stress Granule Component G3bp1 To Promote Viral Vpg-Dependent Translation, Myra Hosmillo, Jia Lu, Michael R. Mcallaster, James B. Eaglesham, Xinjie Wang, Edward Emmott, Patricia Domingues, Yasmin Chaudhry, Tim J. Fitzmaurice, Matthew K.H. Tung, Marc Dominik Panas, Gerald Mcinerney, Nicolas Locker, Craig B. Wilen, Ian G. Goodfellow

Open Access Publications

Knowledge of the host factors required for norovirus replication has been hindered by the challenges associated with culturing human noroviruses. We have combined proteomic analysis of the viral translation and replication complexes with a CRISPR screen, to identify host factors required for norovirus infection. The core stress granule component G3BP1 was identified as a host factor essential for efficient human and murine norovirus infection, demonstrating a conserved function across the

A Single-Nuclei Rna Sequencing Study Of Mendelian And Sporadic Ad In The Human Brain, Jorge L Del-Aguila, Zeran Li, Umber Dube, Kathie A Mihindukulasuriya, John P Budde, Maria Victoria Fernandez, Laura Ibanez, Joseph Bradley, Fengxian Wang, Kristy Bergmann, Richard Davenport, John C Morris, David M Holtzman, Richard J Perrin, Bruno A Benitez, Joseph Dougherty, Carlos Cruchaga, Oscar Harari

Open Access Publications

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia. This neurodegenerative disorder is associated with neuronal death and gliosis heavily impacting the cerebral cortex. AD has a substantial but heterogeneous genetic component, presenting both Mendelian and complex genetic architectures. Using bulk RNA-seq from the parietal lobes and deconvolution methods, we previously reported that brains exhibiting different AD genetic architecture exhibit different cellular proportions. Here, we sought to directly investigate AD brain changes in cell proportion and gene expression using single-cell resolution.

METHODS: We generated unsorted single-nuclei RNA sequencing data from brain tissue. We leveraged the tissue donated from …

Toxoplasma Gondii Infection Drives Conversion Of Nk Cells Into Ilc1-Like Cells, Eugene Park, Swapneel Patel, Qiuling Wang, Prabhakar Andhey, Konstantin Zaitsev, Sophia Porter, Maxwell Hershey, Michael Bern, Beatrice Plougastel-Douglas, Patrick Collins, Marco Colonna, Kenneth M. Murphy, Eugene Oltz, Maxim Artyomov, L David Sibley, Wayne M. Yokoyama

Open Access Publications

Innate lymphoid cells (ILCs) were originally classified based on their cytokine profiles, placing natural killer (NK) cells and ILC1s together, but recent studies support their separation into different lineages at steady-state. However, tumors may induce NK cell conversion into ILC1-like cells that are limited to the tumor microenvironment and whether this conversion occurs beyond this environment remains unknown. Here, we describe

Association Of Baseline Inflammatory Biomarkers With Cancer Mortality In The Regards Cohort, Tomi Akinyemiju, Justin X. Moore, Maria Pisu, Michael Goodman, Virginia J. Howard, Monika Safford, Susan C. Gilchrist, Mary Cushman, Leann Long, Suzanne E. Judd

Open Access Publications

This study examines the association between inflammatory biomarkers and risk of cancer mortality by race. Data were obtained from 1,856 participants in the prospective REGARDS cohort who were cancer-free at baseline, and analyzed in relation to cancer mortality prospectively. Biomarkers were log-transformed and categorized into tertiles due to non-normal distributions, and Cox proportional hazard regression models were utilized to compute hazard ratios with 95% confidence intervals using robust sandwich methods. Individuals in the highest tertile of IL-6 had over a 12-fold increased risk of cancer mortality (HR: 12.97, 95% CI: 3.46-48.63); those in the highest tertile of IL-8 had over …

Measurement Repeatability Of 18 F-Fdg Pet/Ct Versus 18 F-Fdg Pet/Mri In Solid Tumors Of The Pelvis, Tyler J Fraum, Kathryn J Fowler, John P Crandall, Richard A Laforest, Amber Salter, Hongyu An, Michael A Jacobs, Perry W Grigsby, Farrokh Dehdashti, Richard L Wahl

Open Access Publications

Knowledge of the within-subject variability of

Analysis Of An Improved Cyanophora Paradoxa Genome Assembly, Dana C Price, Ursula W Goodenough, Robyn Roth, Jae-Hyeok Lee, Thamali Kariyawasam, Marek Mutwil, Camilla Ferrari, Fabio Facchinelli, Steven G Ball, Ugo Cenci, Cheong Xin Chan, Nicole E Wagner, Hwan Su Yoon, Andreas P M Weber, Debashish Bhattacharya

Open Access Publications

Glaucophyta are members of the Archaeplastida, the founding group of photosynthetic eukaryotes that also includes red algae (Rhodophyta), green algae, and plants (Viridiplantae). Here we present a high-quality assembly, built using long-read sequences, of the ca. 100 Mb nuclear genome of the model glaucophyte Cyanophora paradoxa. We also conducted a quick-freeze deep-etch electron microscopy (QFDEEM) analysis of C. paradoxa cells to investigate glaucophyte morphology in comparison to other organisms. Using the genome data, we generated a resolved 115-taxon eukaryotic tree of life that includes a well-supported, monophyletic Archaeplastida. Analysis of muroplast peptidoglycan (PG) ultrastructure using QFDEEM shows that PG is …

Novel Cell Adhesion/Migration Pathways Are Predictive Markers Of Hdac Inhibitor Resistance In Cutaneous T Cell Lymphoma, Jared M Andrews, Jennifer A Schmidt, Kenneth R Carson, Amy C Musiek, Neha Mehta-Shah, Jacqueline E Payton

Open Access Publications

BACKGROUND: Treatment for Cutaneous T Cell Lymphoma (CTCL) is generally not curative. Therefore, selecting therapy that is effective and tolerable is critical to clinical decision-making. Histone deacetylase inhibitors (HDACi), epigenetic modifier drugs, are commonly used but effective in only ~30% of patients. There are no predictive markers of HDACi response and the CTCL histone acetylation landscape remains unmapped. We sought to identify pre-treatment molecular markers of resistance in CTCL that progressed on HDACi therapy.

METHODS: Purified T cells from 39 pre/post-treatment peripheral blood samples and skin biopsies from 20 patients were subjected to RNA-seq and ChIP-seq for histone acetylation marks …

Precision Delivery Of Ras-Inhibiting Sirna To Kras Driven Cancer Via Peptide-Based Nanoparticles, Matthew S. Strand, Bradley A. Krasnick, Hua Pan, Xiuli Zhang, Ye Bi, Candace Brooks, Christopher Wetzel, Narendra Sankpal, Timothy Fleming, S Peter Goedegebuure, David G. Denardo, William E. Gillanders, William G. Hawkins, Samuel A. Wickline, Ryan C. Fields

Open Access Publications

Over 95% of pancreatic adenocarcinomas (PDACs), as well as a large fraction of other tumor types, such as colorectal adenocarcinoma, are driven by KRAS activation. However, no direct RAS inhibitors exist for cancer therapy. Furthermore, the delivery of therapeutic agents of any kind to PDAC in particular has been hindered by the extensive desmoplasia and resultant drug delivery challenges that accompanies these tumors. Small interfering RNA (siRNA) is a promising modality for anti-neoplastic therapy due to its precision and wide range of potential therapeutic targets. Unfortunately, siRNA therapy is limited by low serum half-life, vulnerability to intracellular digestion, and transient …

Spinal V2b Neurons Reveal A Role For Ipsilateral Inhibition In Speed Control, Rebecca A. Callahan, Richard Roberts, Mohini Sengupta, Yukiko Kimura, Shin-Ichi Higashijima, Martha W. Bagnall

Open Access Publications

The spinal cord contains a diverse array of interneurons that govern motor output. Traditionally, models of spinal circuits have emphasized the role of inhibition in enforcing reciprocal alternation between left and right sides or flexors and extensors. However, recent work has shown that inhibition also increases coincident with excitation during contraction. Here, using larval zebrafish, we investigate the V2b (Gata3+) class of neurons, which contribute to flexor-extensor alternation but are otherwise poorly understood. Using newly generated transgenic lines we define two stable subclasses with distinct neurotransmitter and morphological properties. These V2b subclasses synapse directly onto motor neurons with differential targeting …

Targeting Sporadic And Neurofibromatosis Type 1 (Nf1) Related Refractory Malignant Peripheral Nerve Sheath Tumors (Mpnst) In A Phase Ii Study Of Everolimus In Combination With Bevacizumab (Sarc016), Brigitte C. Widemann, Anglea C. Hirbe, Et Al

Open Access Publications

No abstract provided.

Bjc Today

BJC Today

No abstract provided.

Ml277 Specifically Enhances The Fully Activated Open State Of Kcnq1 By Modulating Vsd-Pore Coupling, Panpan Hou, Jingyi Shi, Kelli Mcfarland White, Yuan Gao, Jianmin Cui

Open Access Publications

Upon membrane depolarization, the KCNQ1 potassium channel opens at the intermediate (IO) and activated (AO) states of the stepwise voltage-sensing domain (VSD) activation. In the heart, KCNQ1 associates with KCNE1 subunits to form I

Identification Of An Alternating-Access Dynamics Mutant Of Emre With Impaired Transport, Chao Wu, Samantha A Wynne, Nathan E Thomas, Eva-Maria Uhlemann, Christopher G Tate, Katherine A Henzler-Wildman

Open Access Publications

Proteins that perform active transport must alternate the access of a binding site, first to one side of a membrane and then to the other, resulting in the transport of bound substrates across the membrane. To better understand this process, we sought to identify mutants of the small multidrug resistance transporter EmrE with reduced rates of alternating access. We performed extensive scanning mutagenesis by changing every amino acid residue to Val, Ala, or Gly, and then screening the drug resistance phenotypes of the resulting mutants. We identified EmrE mutants that had impaired transport activity but retained the ability to bind …

A Sparse Covarying Unit That Describes Healthy And Impaired Human Gut Microbiota Development, Arjun S Raman, Jeanette L Gehrig, Siddarth Venkatesh, Hao-Wei Chang, Matthew C Hibberd, Sathish Subramanian, Michael J Barratt, Jeffrey I Gordon, Et Al

Open Access Publications

Characterizing the organization of the human gut microbiota is a formidable challenge given the number of possible interactions between its components. Using a statistical approach initially applied to financial markets, we measured temporally conserved covariance among bacterial taxa in the microbiota of healthy members of a Bangladeshi birth cohort sampled from 1 to 60 months of age. The results revealed an "ecogroup" of 15 covarying bacterial taxa that provide a concise description of microbiota development in healthy children from this and other low-income countries, and a means for monitoring community repair in undernourished children treated with therapeutic foods. Features of …

Effects Of Microbiota-Directed Foods In Gnotobiotic Animals And Undernourished Children, Jeanette L Gehrig, Siddarth Venkatesh, Hao-Wei Chang, Matthew C Hibberd, Vanderlene L Kung, Jiye Cheng, Robert Y Chen, Sathish Subramanian, Carrie A Cowardin, Martin F Meier, David O'Donnell, Michael Talcott, Larry D Spears, Clay F Semenkovich, Christopher Sawyer, Richard D Head, Michael J Barratt, Jeffrey I Gordon, Et Al

Open Access Publications

To examine the contributions of impaired gut microbial community development to childhood undernutrition, we combined metabolomic and proteomic analyses of plasma samples with metagenomic analyses of fecal samples to characterize the biological state of Bangladeshi children with severe acute malnutrition (SAM) as they transitioned, after standard treatment, to moderate acute malnutrition (MAM) with persistent microbiota immaturity. Host and microbial effects of microbiota-directed complementary food (MDCF) prototypes targeting weaning-phase bacterial taxa underrepresented in SAM and MAM microbiota were characterized in gnotobiotic mice and gnotobiotic piglets colonized with age- and growth-discriminatory bacteria. A randomized, double-blind controlled feeding study identified a lead MDCF …

A Stem-Cell-Derived Platform Enables Complete Cryptosporidium Development In Vitro And Genetic Tractability, Georgia Wilke, Lisa J Funkhouser-Jones, Yi Wang, Soumya Ravindran, Qiuling Wang, Wandy L Beatty, Megan T Baldridge, Kelli L Vandussen, Bang Shen, Mark S Kuhlenschmidt, Theresa B Kuhlenschmidt, William H Witola, Thaddeus S Stappenbeck, L. David Sibley

Open Access Publications

Despite being a frequent cause of severe diarrheal disease in infants and an opportunistic infection in immunocompromised patients, Cryptosporidium research has lagged due to a lack of facile experimental methods. Here, we describe a platform for complete life cycle development and long-term growth of C. parvum in vitro using "air-liquid interface" (ALI) cultures derived from intestinal epithelial stem cells. Transcriptomic profiling revealed that differentiating epithelial cells grown under ALI conditions undergo profound changes in metabolism and development that enable completion of the parasite life cycle in vitro. ALI cultures support parasite expansion > 100-fold and generate viable oocysts that are transmissible …

A Guinea Fowl Genome Assembly Provides New Evidence On Evolution Following Domestication And Selection In Galliformes, Alain Vignal, Simon Boitard, Noémie Thébault, Guiguigbaza-Kossigan Dayo, Valentine Yapi-Gnaore, Issaka Youssao Abdou Karim, Cécile Berthouly-Salazar, Nóra Pálinkás-Bodzsár, Daniel Guémené, Francoise Thibaud-Nissen, Wesley C Warren, Michèle Tixier-Boichard, Xavier Rognon

Open Access Publications

The helmeted guinea fowl Numida meleagris belongs to the order Galliformes. Its natural range includes a large part of sub-Saharan Africa, from Senegal to Eritrea and from Chad to South Africa. Archaeozoological and artistic evidence suggest domestication of this species may have occurred about 2,000 years BP in Mali and Sudan primarily as a food resource, although villagers also benefit from its capacity to give loud alarm calls in case of danger, of its ability to consume parasites such as ticks and to hunt snakes, thus suggesting its domestication may have resulted from a commensal association process. Today, it is …