Digital Commons Network^™

Macrophage Depletion Protects Against Cisplatin-Induced Ototoxicity And Nephrotoxicity, Cathy Yea Won Sung, Naoki Hayase, Peter S T Yuen, John Lee, Katharine Fernandez, Xuzhen Hu, Hui Cheng, Robert A Star, Mark E Warchol, Lisa L Cunningham

2020-Current year OA Pubs

Cisplatin is a widely used anticancer drug with notable side effects including ototoxicity and nephrotoxicity. Macrophages, the major resident immune cells in the cochlea and kidney, are important drivers of both inflammatory and tissue repair responses. To investigate the roles of macrophages in cisplatin-induced toxicities, we used PLX3397, a U.S. Food and Drug Administration-approved inhibitor of the colony-stimulating factor 1 receptor, to eliminate tissue-resident macrophages. Mice treated with cisplatin alone had considerable hearing loss (ototoxicity) and kidney injury (nephrotoxicity). Macrophage ablation resulted in significantly reduced hearing loss and had greater outer hair cell survival. Macrophage ablation also protected against cisplatin-induced …

Blinatumomab For Mrd-Negative Acute Lymphoblastic Leukemia In Adults, Mark R Litzow, Geoffrey L Uy, Et Al.

2020-Current year OA Pubs

BACKGROUND: Many older adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a relapse despite having a measurable residual disease (MRD)-negative complete remission with combination chemotherapy. The addition of blinatumomab, a bispecific T-cell engager molecule that is approved for the treatment of relapsed, refractory, and MRD-positive BCP-ALL, may have efficacy in patients with MRD-negative remission.

METHODS: In a phase 3 trial, we randomly assigned patients 30 to 70 years of age with

RESULTS: The data and safety monitoring committee reviewed the results from the third efficacy interim analysis and recommended that they be reported. Complete remission with or without full …

Review Of The Impact And Burden Of Urinary Urgency On Adults With Overactive Bladder, Adrian Wagg, A Lenore Ackerman, H Henry Lai, Diane K. Newman

2020-Current year OA Pubs

No abstract provided.

A Correctable Immune Niche For Epithelial Stem Cell Reprogramming And Post-Viral Lung Diseases, Kangyun Wu, Yong Zhang, Huiqing Yin-Declue, Kelly Sun, Dailing Mao, Kuangying Yang, Stephen R. Austin, Erika C. Crouch, Steven L. Brody, Derek E. Byers, Christy M. Hoffmann, Michael E. Hughes, Michael J. Holtzman

2020-Current year OA Pubs

Epithelial barriers are programmed for defense and repair but are also the site of long-term structural remodeling and disease. In general, this paradigm features epithelial stem cells (ESCs) that are called on to regenerate damaged tissues but can also be reprogrammed for detrimental remodeling. Here we identified a Wfdc21-dependent monocyte-derived dendritic cell (moDC) population that functioned as an early sentinel niche for basal ESC reprogramming in mouse models of epithelial injury after respiratory viral infection. Niche function depended on moDC delivery of ligand GPNMB to the basal ESC receptor CD44 so that properly timed antibody blockade of ligand or receptor …

Comparing The Clinical Features Of Lateral And Medial Approaches Of Costoclavicular Technique Versus Traditional Lateral Sagittal Technique As Infraclavicular Brachial Plexus Block Methods: A Randomized Controlled Trial, Emre Sertaç Bingül, Mert Canbaz, Mehmet Güzel, Emine Aysu Şalvız, Bora Edim Akalın, Ömer Berköz, Ebru Emre Demirel, Zerrin Sungur, Meltem Savran Karadeniz

2020-Current year OA Pubs

BACKGROUND: It is aimed to compare the block onset times and performance features of costoclavicular techniques (medial and lateral approach) versus lateral sagittal technique.

METHODS: Patients were randomized into three groups. For costoclavicular techniques, ultrasound probe was placed parallel to clavicle obtaining nerve cords, axillary artery and axillary vein visual from lateral-to-medial, respectively. The block needle was advanced from lateral (Group CLB) or medial (Group CMB) to perform costoclavicular block. For lateral sagittal technique (Group LSB), ultrasound probe was placed sagittal and perpendicular below the coracoid process to obtain sagittal artery image with the cords around. Total 20 ml of …

Pannexin-1 Channel Inhibition Alleviates Opioid Withdrawal In Rodents By Modulating Locus Coeruleus To Spinal Cord Circuitry, Charlie H T Kwok, Tamara Markovic, Nicolas Massaly, Hye Jean Yoon, Jose A Morón, Et Al.

2020-Current year OA Pubs

Opioid withdrawal is a liability of chronic opioid use and misuse, impacting people who use prescription or illicit opioids. Hyperactive autonomic output underlies many of the aversive withdrawal symptoms that make it difficult to discontinue chronic opioid use. The locus coeruleus (LC) is an important autonomic centre within the brain with a poorly defined role in opioid withdrawal. We show here that pannexin-1 (Panx1) channels expressed on microglia critically modulate LC activity during opioid withdrawal. Within the LC, we found that spinally projecting tyrosine hydroxylase (TH)-positive neurons (LC

Instrumentation Failure In Adult Spinal Deformity Patients, David P Falk, Ravi Agrawal, Bijan Dehghani, Rohit Bhan, Sachin Gupta, Munish C Gupta

2020-Current year OA Pubs

In recent years, advances in the surgical treatment of adult spinal deformity (ASD) have led to improved outcomes. Although these advances have helped drive the development of deformity surgery to meet the rising volume of patients seeking surgical treatment, many challenges have yet to be solved. Instrumentation failure remains one of the most common major complications following deformity surgery, associated with significant morbidity due to elevated re-operation rates among those experiencing mechanical complications. The two most frequently encountered subtypes of instrumentation failure are rod fracture (RF) and proximal junctional kyphosis/proximal junctional failure (PJK/PJF). While RF and PJK/PJF are both modes …

Lipid-Associated Macrophages Reshape Bat Cell Identity In Obesity, Francesca Sciarretta, Wentong Jia, Jonathan R Brestoff, Et Al.

2020-Current year OA Pubs

Obesity and type 2 diabetes cause a loss in brown adipose tissue (BAT) activity, but the molecular mechanisms that drive BAT cell remodeling remain largely unexplored. Using a multilayered approach, we comprehensively mapped a reorganization in BAT cells. We uncovered a subset of macrophages as lipid-associated macrophages (LAMs), which were massively increased in genetic and dietary model of BAT expansion. LAMs participate in this scenario by capturing extracellular vesicles carrying damaged lipids and mitochondria released from metabolically stressed brown adipocytes. CD36 scavenger receptor drove LAM phenotype, and CD36-deficient LAMs were able to increase brown fat genes in adipocytes. LAMs released …

A Pre-Vaccination Immune Metabolic Interplay Determines The Protective Antibody Response To A Dengue Virus Vaccine, Adam-Nicolas Pelletier, Gabriela Pacheco Sanchez, Abdullah Izmirly, Mark Watson, Tiziana Di Pucchio, Karina Inacio Carvalho, Abdelali Filali-Mouhim, Eustache Paramithiotis, Maria Do Carmo S T Timenetsky, Alexander Roberto Precioso, Jorge Kalil, Michael S Diamond, Elias K Haddad, Esper G Kallas, Rafick Pierre Sekaly

2020-Current year OA Pubs

Protective immunity to dengue virus (DENV) requires antibody response to all four serotypes. Systems vaccinology identifies a multi-OMICs pre-vaccination signature and mechanisms predictive of broad antibody responses after immunization with a tetravalent live attenuated DENV vaccine candidate (Butantan-DV/TV003). Anti-inflammatory pathways, including TGF-β signaling expressed by CD68

Transcriptional Analysis Of Primary Ciliary Dyskinesia Airway Cells Reveals A Dedicated Cilia Glutathione Pathway, Jeffrey R. Koenitzer, Deepesh Kumar Gupta, Wang Kyaw Twan, Huihui Xu, Nicholas Hadas, Finn J. Hawkins, Mary Lou Beermann, Gervette M. Penny, Nathan T. Wamsley, Andrew Berical, Michael B. Major, Susan K. Dutcher, Steven L. Brody, Amjad Horani

2020-Current year OA Pubs

Primary ciliary dyskinesia (PCD) is a genetic condition that results in dysmotile cilia. The repercussions of cilia dysmotility and gene variants on the multiciliated cell remain poorly understood. We used single-cell RNA-Seq, proteomics, and advanced microscopy to compare primary culture epithelial cells from patients with PCD, their heterozygous mothers, and healthy individuals, and we induced pluripotent stem cells (iPScs) generated from a patient with PCD. Transcriptomic analysis revealed unique signatures in PCD airway cells compared with their mothers' cells and the cells of healthy individuals. Gene expression in heterozygous mothers' cells diverged from both control and PCD cells, marked by …

A Comparative Analysis Of Sars-Cov-2 Variants Of Concern (Voc) Spike Proteins Interacting With Hace2 Enzyme, Jiawei Chen, Lingtao Chen, Heng Quan, Soongoo Lee, Kaniz Fatama Khan, Ying Xie, Qiaomu Li, Maria Valero, Zhiyu Dai, Yixin Xie

2020-Current year OA Pubs

In late 2019, the emergence of a novel coronavirus led to its identification as SARS-CoV-2, precipitating the onset of the COVID-19 pandemic. Many experimental and computational studies were performed on SARS-CoV-2 to understand its behavior and patterns. In this research, Molecular Dynamic (MD) simulation is utilized to compare the behaviors of SARS-CoV-2 and its Variants of Concern (VOC)-Alpha, Beta, Gamma, Delta, and Omicron-with the hACE2 protein. Protein structures from the Protein Data Bank (PDB) were aligned and trimmed for consistency using Chimera, focusing on the receptor-binding domain (RBD) responsible for ACE2 interaction. MD simulations were performed using Visual Molecular Dynamics …

Targeted Degradation Of Extracellular Mitochondrial Aspartyl-Trna Synthetase Modulates Immune Responses, Benjamin S Johnson, Janet S Lee, Et Al.

2020-Current year OA Pubs

The severity of bacterial pneumonia can be worsened by impaired innate immunity resulting in ineffective pathogen clearance. We describe a mitochondrial protein, aspartyl-tRNA synthetase (DARS2), which is released in circulation during bacterial pneumonia in humans and displays intrinsic innate immune properties and cellular repair properties. DARS2 interacts with a bacterial-induced ubiquitin E3 ligase subunit, FBXO24, which targets the synthetase for ubiquitylation and degradation, a process that is inhibited by DARS2 acetylation. During experimental pneumonia, Fbxo24 knockout mice exhibit elevated DARS2 levels with an increase in pulmonary cellular and cytokine levels. In silico modeling identified an FBXO24 inhibitory compound with immunostimulatory …

Reconciling Shared Versus Context-Specific Information In A Neural Network Model Of Latent Causes, Qihong Lu, Tan T Nguyen, Qiong Zhang, Uri Hasson, Thomas L Griffiths, Jeffrey M Zacks, Samuel J Gershman, Kenneth A Norman

2020-Current year OA Pubs

It has been proposed that, when processing a stream of events, humans divide their experiences in terms of inferred latent causes (LCs) to support context-dependent learning. However, when shared structure is present across contexts, it is still unclear how the "splitting" of LCs and learning of shared structure can be simultaneously achieved. Here, we present the Latent Cause Network (LCNet), a neural network model of LC inference. Through learning, it naturally stores structure that is shared across tasks in the network weights. Additionally, it represents context-specific structure using a context module, controlled by a Bayesian nonparametric inference algorithm, which assigns …

Effects Of Protein Restriction On Insulin-Like Growth Factor (Igf)-1 In Men With Prostate Cancer: Results From A Randomized Clinical Trial, Maria L Cagigas, Giovanni Fiorito, Beatrice Bertozzi, Andrius Masedunskas, Edda Cava, Francesco Spelta, Nicola Veronese, Valeria Tosti, Gayathiri Rajakumar, Tiana Pelaia, Arnold D Bullock, Robert S Figenshau, Gerald L Andriole, Luigi Fontana

2020-Current year OA Pubs

BACKGROUND: Insulin-like growth factor (IGF)-1 and its binding proteins are important in cancer growth, especially in prostate cancer. Observational studies suggest that protein restriction can lower IGF-1 levels. However, it is unclear whether an isocaloric protein-restricted diet affects IGF-1 and IGFBPs in men with prostate cancer.

METHODS: In this academic, single-center, parallel-group, prospective, randomized, open-label, blinded end-point trial, 38 consenting overweight (BMI 30.5 ± 5.5 kg/m

RESULTS: Contrary to our hypothesis, feeding individuals an isocaloric protein-restricted diet did not result in a significant reduction in serum IGF-1. Moreover, there was no observed increase in serum IGFBP-1 or IGFBP-3 concentration.

CONCLUSION: …

Senescent Cancer-Associated Fibroblasts In Pancreatic Adenocarcinoma Restrict Cd8+ T Cell Activation And Limit Responsiveness To Immunotherapy In Mice, Benjamin Assouline, Sheila A Stewart, Et Al.

2020-Current year OA Pubs

Senescent cells within tumors and their stroma exert complex pro- and anti-tumorigenic functions. However, the identities and traits of these cells, and the potential for improving cancer therapy through their targeting, remain poorly characterized. Here, we identify a senescent subset within previously-defined cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinomas (PDAC) and in premalignant lesions in mice and humans. Senescent CAFs isolated from mouse and humans expressed elevated levels of immune-regulatory genes. Depletion of senescent CAFs, either genetically or using the Bcl-2 inhibitor ABT-199 (venetoclax), increased the proportion of activated CD8

Implantable And Semi-Implantable Biosensors For Minimally Invasive Disease Diagnosis, Yameng Xu, Jingyuan Zhang, Wilson Z. Ray, Matthew R. Macewan

2020-Current year OA Pubs

No abstract provided.

Instrumental Variable And Colocalization Analyses Identify Endotrophin And Htra1 As Potential Therapeutic Targets For Coronary Artery Disease, Paul C Lee, In-Hyuk Jung, Shreeya Thussu, Ved Patel, Ryan Wagoner, Kendall H Burks, Junedh Amrute, Jared S Elenbaas, Chul Joo Kang, Erica P Young, Philipp E Scherer, Nathan O Stitziel

2020-Current year OA Pubs

Coronary artery disease (CAD) remains a leading cause of disease burden globally, and there is a persistent need for new therapeutic targets. Instrumental variable (IV) and genetic colocalization analyses can help identify novel therapeutic targets for human disease by nominating causal genes in genome-wide association study (GWAS) loci. We conducted cis-IV analyses for 20,125 genes and 1,746 plasma proteins with CAD using molecular trait quantitative trait loci variant (QTLs) data from three different studies. 19 proteins and 119 genes were significantly associated with CAD risk by IV analyses and demonstrated evidence of genetic colocalization. Notably, our analyses validated well-established targets …

Targeted Co-Expression Networks For The Study Of Traits, A Gómez-Pascual, G Rocamora-Pérez, L Ibanez, J A Botía

2020-Current year OA Pubs

Weighted Gene Co-expression Network Analysis (WGCNA) is a widely used approach for the generation of gene co-expression networks. However, networks generated with this tool usually create large modules with a large set of functional annotations hard to decipher. We have developed TGCN, a new method to create Targeted Gene Co-expression Networks. This method identifies the transcripts that best predict the trait of interest based on gene expression using a refinement of the LASSO regression. Then, it builds the co-expression modules around those transcripts. Algorithm properties were characterized using the expression of 13 brain regions from the Genotype-Tissue Expression project. When …

Trackins (Trk-Targeting Drugs): A Novel Therapy For Different Diseases, George N Chaldakov, Luigi Aloe, Stanislav G Yanev, Marco Fiore, Anton B Tonchev, Manlio Vinciguerra, Nikolai T Evtimov, Peter Ghenev, Krikor Dikranian

2020-Current year OA Pubs

Many routes may lead to the transition from a healthy to a diseased phenotype. However, there are not so many routes to travel in the opposite direction; that is, therapy for different diseases. The following pressing question thus remains: what are the pathogenic routes and how can be they counteracted for therapeutic purposes? Human cells contain >500 protein kinases and nearly 200 protein phosphatases, acting on thousands of proteins, including cell growth factors. We herein discuss neurotrophins with pathogenic or metabotrophic abilities, particularly brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), pro-NGF, neurotrophin-3 (NT-3), and their receptor Trk (tyrosine receptor …

Whole Cervix Imaging Of Collagen, Muscle, And Cellularity In Term And Preterm Pregnancy, Wenjie Wu, Zhexian Sun, Hansong Gao, Yuan Nan, Stephanie Pizzella, Haonan Xu, Josephine Lau, Yiqi Lin, Hui Wang, Pamela K Woodard, Hannah R Krigman, Qing Wang, Yong Wang

2020-Current year OA Pubs

Cervical softening and dilation are critical for the successful term delivery of a fetus, with premature changes associated with preterm birth. Traditional clinical measures like transvaginal ultrasound and Bishop scores fall short in predicting preterm births and elucidating the cervix's complex microstructural changes. Here, we introduce a magnetic resonance diffusion basis spectrum imaging (DBSI) technique for non-invasive, comprehensive imaging of cervical cellularity, collagen, and muscle fibers. This method is validated through ex vivo DBSI and histological analyses of specimens from total hysterectomies. Subsequently, retrospective in vivo DBSI analysis at 32 weeks of gestation in ten term deliveries and seven preterm …

Whole-Genome Sequences Reveal Zygotic Composition In Chimeric Twins, Christopher J Yoon, Obi L Griffith, Malachi Griffith, Et Al.

2020-Current year OA Pubs

While most dizygotic twins have a dichorionic placenta, rare cases of dizygotic twins with a monochorionic placenta have been reported. The monochorionic placenta in dizygotic twins allows in utero exchange of embryonic cells, resulting in chimerism in the twins. In practice, this chimerism is incidentally identified in mixed ABO blood types or in the presence of cells with a discordant sex chromosome. Here, we applied whole-genome sequencing to one triplet and one twin family to precisely understand their zygotic compositions, using millions of genomic variants as barcodes of zygotic origins. Peripheral blood showed asymmetrical contributions from two sister zygotes, where …

Chromatin Conformation And Histone Modification Profiling Across Human Kidney Anatomic Regions, Haikuo Li, Dian Li, Benjamin D Humphreys

2020-Current year OA Pubs

The three major anatomic regions of the human kidney include the cortex, medulla and papilla, with different functions and vulnerabilities to kidney diseases. Epigenetic mechanisms underlying these anatomic structures are incompletely understood. Here, we performed chromatin conformation capture with Hi-C and histone modification H3K4me3/H3K27me3 Cleavage Under Targets and Release Using Nuclease (CUT&RUN) sequencing on the kidney cortex, medulla and papilla dissected from one individual donor. Nuclear suspensions were generated from each region and split subjected to paired Hi-C and CUT&RUN sequencing. We evaluated the quality of next-generation sequencing data, Hi-C chromatin contact matrices and CUT&RUN peak calling. H3K4me3 and H3K27me3 …

Involvement Of The Choroid Plexus In Alzheimer's Disease Pathophysiology: Findings From Mouse And Human Proteomic Studies, Aurore Delvenne, Suzanne E Schindler, Et Al.

2020-Current year OA Pubs

BACKGROUND: Structural and functional changes of the choroid plexus (ChP) have been reported in Alzheimer's disease (AD). Nonetheless, the role of the ChP in the pathogenesis of AD remains largely unknown. We aim to unravel the relation between ChP functioning and core AD pathogenesis using a unique proteomic approach in mice and humans.

METHODS: We used an APP knock-in mouse model, APP

RESULTS: ChP tissue proteome was dysregulated in APP

CONCLUSIONS: Together, our findings support the hypothesis of ChP dysfunction in AD. These ChP changes were related to amyloid pathology. Therefore, the ChP could become a novel promising therapeutic target …

A Randomized Controlled Trial Testing The Effects Of A Social Needs Navigation Intervention On Health Outcomes And Healthcare Utilization Among Medicaid Members With Type 2 Diabetes, Amy Mcqueen, David Von Nordheim, Charlene Caburnay, Linda Li, Cynthia Herrick, Lauren Grimes, Darrell Broussard, Rachel E Smith, Dana Lawson, Yan Yan, Matthew Kreuter

2020-Current year OA Pubs

Health systems are increasingly assessing and addressing social needs with referrals to community resources. The objective of this randomized controlled trial was to randomize adult Medicaid members with type 2 diabetes to receive usual care (

Mucosal Signatures Of Pathogenic T Cells In Hla-B*27+ Anterior Uveitis And Axial Spondyloarthritis, Michael A. Paley, Lynn M. Hassman, Grace L. Paley, Nicole Linskey, Ryan Agnew, Paulo Henrique Arantes De Faria, Annie Feng, Sophia Y. Li, Elisha D. O. Roberson, Philip A. Ruzycki, Ekaterina Esaulova, Jennifer Laurent, Lacey Feigl-Lenzen, Luke E. Springer, Chang Liu, Wayne M. Yokoyama, Et Al.

2020-Current year OA Pubs

HLA-B*27 was one of the first HLA alleles associated with an autoimmune disease, i.e., axial spondyloarthritis (axSpA) and acute anterior uveitis (B27AAU), which cause joint and eye inflammation, respectively. Gastrointestinal inflammation has been suggested as a trigger of axSpA. We recently identified a bacterial peptide (YeiH) that can be presented by HLA-B*27 to expanded public T cell receptors in the joint in axSpA and the eye in B27AAU. While YeiH is present in enteric microbiota and pathogens, additional evidence that pathogenic T cells in HLA-B*27-associated autoimmunity may have had a prior antigenic encounter within the gastrointestinal tract remains lacking. Here, …

Cerebrospinal Fluid-Based Spatial Statistics: Towards Quantitative Analysis Of Cerebrospinal Fluid Pseudodiffusivity, Yutong Chen, Hui Hong, Arash Nazeri, Hugh S Markus, Xiao Luo

2020-Current year OA Pubs

BACKGROUND: Cerebrospinal fluid (CSF) circulation is essential in removing metabolic wastes from the brain and is an integral component of the glymphatic system. Abnormal CSF circulation is implicated in neurodegenerative diseases. Low b-value magnetic resonance imaging quantifies the variance of CSF motion, or pseudodiffusivity. However, few studies have investigated the relationship between the spatial patterns of CSF pseudodiffusivity and cognition.

METHODS: We introduced a novel technique, CSF-based spatial statistics (CBSS), to automatically quantify CSF pseudodiffusivity in each sulcus, cistern and ventricle. Using cortical regions as landmarks, we segmented each CSF region. We retrospectively analyzed a cohort of 93 participants with …

Brilacidin, A Novel Antifungal Agent Against Cryptococcus Neoformans, Camila Diehl, Dong-Gyu Kim, Tamara L Doering, Et Al.

2020-Current year OA Pubs

UNLABELLED:

IMPORTANCE: Invasive fungal infections have a high mortality rate causing more deaths annually than tuberculosis or malaria. Cryptococcosis, one of the most prevalent fungal diseases, is generally characterized by meningitis and is mainly caused by two closely related species of basidiomycetous yeasts,

A Reinterpretation Of The Relationship Between Persistent And Resurgent Sodium Currents, Samuel P Brown, Ryan J Lawson, Jonathan D Moreno, Joseph L Ransdell

2020-Current year OA Pubs

The resurgent sodium current (I

Cellular Endosomal Potassium Ion Flux Regulates Arenavirus Uncoating During Virus Entry, Amelia B Shaw, Hiu Nam Tse, Owen Byford, Grace Plahe, Alex Moon-Walker, Samantha E Hover, Erica Ollmann Saphire, Sean P J Whelan, Jamel Mankouri, Juan Fontana, John N Barr

2020-Current year OA Pubs

Lymphocytic choriomeningitis virus (LCMV) is an enveloped and segmented negative-sense RNA virus classified within the

Terahertz Tunable Three-Dimensional Photonic Jets, Behrooz Rezaei, Babak Yahyapour, Arash Darafsheh

2020-Current year OA Pubs

Highly localized electromagnetic field distributions near the "shadow-side" surface of certain transparent mesoscale bodies illuminated by light waves are called photonic jets. We demonstrated formation of three-dimensional (3D) tunable photonic jets in terahertz regime (terajets, TJs) by dielectric micro-objects -including spheres, cylinders, and cubes-coated with a bulk Dirac semimetal (BDS) layer, under uniform beam illumination. The optical characteristics of the produced TJs can be modulated dynamically through tuning the BDS layer's index of refraction via changing its Fermi energy. It is demonstrated that the Fermi energy of BDS layer has a significant impact on tuning the optical characteristics of the …