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The Mechanism Of Enantioselective Neurosteroid Actions On Gaba, Hiroki Tateiwa, Satyanarayana M Chintala, Ziwei Chen, Lei Wang, Fatima Amtashar, John Bracamontes, Allison L Germann, Spencer R Pierce, Douglas F Covey, Gustav Akk, Alex S Evers Feb 2023

The Mechanism Of Enantioselective Neurosteroid Actions On Gaba, Hiroki Tateiwa, Satyanarayana M Chintala, Ziwei Chen, Lei Wang, Fatima Amtashar, John Bracamontes, Allison L Germann, Spencer R Pierce, Douglas F Covey, Gustav Akk, Alex S Evers

2020-Current year OA Pubs

The neurosteroid allopregnanolone (ALLO) and pregnanolone (PREG), are equally effective positive allosteric modulators (PAMs) of GABA


Chikungunya Virus And Its Envelope Protein E2 Induce Hyperalgesia In Mice: Inhibition By Anti-E2 Monoclonal Antibodies And By Targeting Trpv1, Carina Z Segato-Vendrameto, Felipe A Pinho-Ribeiro, Et Al. Feb 2023

Chikungunya Virus And Its Envelope Protein E2 Induce Hyperalgesia In Mice: Inhibition By Anti-E2 Monoclonal Antibodies And By Targeting Trpv1, Carina Z Segato-Vendrameto, Felipe A Pinho-Ribeiro, Et Al.

2020-Current year OA Pubs

Chikungunya virus is an arthropod-borne infectious agent that causes Chikungunya fever disease. About 90% of the infected patients experience intense polyarthralgia, affecting mainly the extremities but also the large joints such as the knees. Chronic disease symptoms persist for months, even after clearance of the virus from the blood. Envelope proteins stimulate the immune response against the Chikungunya virus, becoming an important therapeutic target. We inactivated the Chikungunya virus (iCHIKV) and produced recombinant E2 (rE2) protein and three different types of anti-rE2 monoclonal antibodies. Using these tools, we observed that iCHIKV and rE2 protein induced mechanical hyperalgesia (electronic aesthesiometer test) …


Body Mass Index And Molecular Subtypes Of Colorectal Cancer, Neil Murphy, Yin Cao, Et Al. Feb 2023

Body Mass Index And Molecular Subtypes Of Colorectal Cancer, Neil Murphy, Yin Cao, Et Al.

2020-Current year OA Pubs

BACKGROUND: Obesity is an established risk factor for colorectal cancer (CRC), but the evidence for the association is inconsistent across molecular subtypes of the disease.

METHODS: We pooled data on body mass index (BMI), tumor microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, and Jass classification types for 11 872 CRC cases and 11 013 controls from 11 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for covariables.

RESULTS: Higher BMI was associated with increased CRC risk (OR per 5 kg/m2 = 1.18, 95% CI = …


The Impact Of Universal Glove And Gown Use On Clostridioides Difficile Acquisition: A Cluster-Randomized Trial, Daniel J Morgan, Erik R Dubberke, Tiffany Hink, Gwen Paszkiewicz, Carey-Ann D Burnham, Lisa Pineles, Larry Magder, J Kristie Johnson, Surbhi Leekha, Anthony D Harris Feb 2023

The Impact Of Universal Glove And Gown Use On Clostridioides Difficile Acquisition: A Cluster-Randomized Trial, Daniel J Morgan, Erik R Dubberke, Tiffany Hink, Gwen Paszkiewicz, Carey-Ann D Burnham, Lisa Pineles, Larry Magder, J Kristie Johnson, Surbhi Leekha, Anthony D Harris

2020-Current year OA Pubs

BACKGROUND: Clostridioides difficile is the most common cause of healthcare-associated infections in the United States. It is unknown whether universal gown and glove use in intensive care units (ICUs) decreases acquisition of C. difficile.

METHODS: This was a secondary analysis of a cluster-randomized trial in 20 medical and surgical ICUs in 20 US hospitals from 4 January 2012 to 4 October 2012. After a baseline period, ICUs were randomized to standard practice for glove and gown use versus the intervention of all healthcare workers being required to wear gloves and gowns for all patient contact and when entering any patient …


Structures Of Human Gastrin-Releasing Peptide Receptors Bound To Antagonist And Agonist For Cancer And Itch Therapy, Shuman Peng, Yuting Zhan, Dongqi Zhang, Lu Ren, Anqi Chen, Zhou-Feng Chen, Haitao Zhang Feb 2023

Structures Of Human Gastrin-Releasing Peptide Receptors Bound To Antagonist And Agonist For Cancer And Itch Therapy, Shuman Peng, Yuting Zhan, Dongqi Zhang, Lu Ren, Anqi Chen, Zhou-Feng Chen, Haitao Zhang

2020-Current year OA Pubs

Gastrin releasing peptide receptor (GRPR), a member of the bombesin (BBN) G protein-coupled receptors, is aberrantly overexpressed in several malignant tumors, including those of the breast, prostate, pancreas, lung, and central nervous system. Additionally, it also mediates non-histaminergic itch and pathological itch conditions in mice. Thus, GRPR could be an attractive target for cancer and itch therapy. Here, we report the inactive state crystal structure of human GRPR in complex with the non-peptide antagonist PD176252, as well as two active state cryo-electron microscopy (cryo-EM) structures of GRPR bound to the endogenous peptide agonist gastrin-releasing peptide and the synthetic BBN analog …


Evaluation Of Apparent Diffusion Coefficient Repeatability And Reproducibility For Preclinical Mris Using Standardized Procedures And A Diffusion-Weighted Imaging Phantom, Dariya Malyarenko, Ghoncheh Amouzandeh, Stephen Pickup, Rong Zhou, Henry Charles Manning, Seth T Gammon, Kooresh I Shoghi, James D Quirk, Renuka Sriram, Peder Larson, Michael T Lewis, Robia G Pautler, Paul E Kinahan, Mark Muzi, Thomas L Chenevert Feb 2023

Evaluation Of Apparent Diffusion Coefficient Repeatability And Reproducibility For Preclinical Mris Using Standardized Procedures And A Diffusion-Weighted Imaging Phantom, Dariya Malyarenko, Ghoncheh Amouzandeh, Stephen Pickup, Rong Zhou, Henry Charles Manning, Seth T Gammon, Kooresh I Shoghi, James D Quirk, Renuka Sriram, Peder Larson, Michael T Lewis, Robia G Pautler, Paul E Kinahan, Mark Muzi, Thomas L Chenevert

2020-Current year OA Pubs

Relevant to co-clinical trials, the goal of this work was to assess repeatability, reproducibility, and bias of the apparent diffusion coefficient (ADC) for preclinical MRIs using standardized procedures for comparison to performance of clinical MRIs. A temperature-controlled phantom provided an absolute reference standard to measure spatial uniformity of these performance metrics. Seven institutions participated in the study, wherein diffusion-weighted imaging (DWI) data were acquired over multiple days on 10 preclinical scanners, from 3 vendors, at 6 field strengths. Centralized versus site-based analysis was compared to illustrate incremental variance due to processing workflow. At magnet isocenter, short-term (intra-exam) and long-term (multiday) …


The P97-Ubxd8 Complex Regulates Er-Mitochondria Contact Sites By Altering Membrane Lipid Saturation And Composition, Rakesh Ganji, Joao A Paulo, Yuecheng Xi, Ian Kline, Jiang Zhu, Christoph S Clemen, Conrad C Weihl, John G Purdy, Steve P Gygi, Malavika Raman Feb 2023

The P97-Ubxd8 Complex Regulates Er-Mitochondria Contact Sites By Altering Membrane Lipid Saturation And Composition, Rakesh Ganji, Joao A Paulo, Yuecheng Xi, Ian Kline, Jiang Zhu, Christoph S Clemen, Conrad C Weihl, John G Purdy, Steve P Gygi, Malavika Raman

2020-Current year OA Pubs

The intimate association between the endoplasmic reticulum (ER) and mitochondrial membranes at ER-Mitochondria contact sites (ERMCS) is a platform for critical cellular processes, particularly lipid synthesis. How contacts are remodeled and the impact of altered contacts on lipid metabolism remains poorly understood. We show that the p97 AAA-ATPase and its adaptor ubiquitin-X domain adaptor 8 (UBXD8) regulate ERMCS. The p97-UBXD8 complex localizes to contacts and its loss increases contacts in a manner that is dependent on p97 catalytic activity. Quantitative proteomics and lipidomics of ERMCS demonstrates alterations in proteins regulating lipid metabolism and a significant change in membrane lipid saturation …


Antitumour Activity Of Neratinib In Patients With Her2-Mutant Advanced Biliary Tract Cancers, James J Harding, Haeseong Park, Et Al. Feb 2023

Antitumour Activity Of Neratinib In Patients With Her2-Mutant Advanced Biliary Tract Cancers, James J Harding, Haeseong Park, Et Al.

2020-Current year OA Pubs

HER2 mutations are infrequent genomic events in biliary tract cancers (BTCs). Neratinib, an irreversible, pan-HER, oral tyrosine kinase inhibitor, interferes with constitutive receptor kinase activation and has activity in HER2-mutant tumours. SUMMIT is an open-label, single-arm, multi-cohort, phase 2, 'basket' trial of neratinib in patients with solid tumours harbouring oncogenic HER2 somatic mutations (ClinicalTrials.gov: NCT01953926). The primary objective of the BTC cohort, which is now complete, is first objective response rate (ORR) to neratinib 240 mg orally daily. Secondary objectives include confirmed ORR, clinical benefit rate, progression-free survival, duration of response, overall survival, safety and tolerability. Genomic analyses were exploratory. …


Widespread Contribution Of Transposable Elements To The Rewiring Of Mammalian 3d Genomes, Mayank N K Choudhary, Kara Quaid, Xiaoyun Xing, Heather Schmidt, Ting Wang Feb 2023

Widespread Contribution Of Transposable Elements To The Rewiring Of Mammalian 3d Genomes, Mayank N K Choudhary, Kara Quaid, Xiaoyun Xing, Heather Schmidt, Ting Wang

2020-Current year OA Pubs

Transposable elements (TEs) are major contributors of genetic material in mammalian genomes. These often include binding sites for architectural proteins, including the multifarious master protein, CTCF, which shapes the 3D genome by creating loops, domains, compartment borders, and RNA-DNA interactions. These play a role in the compact packaging of DNA and have the potential to facilitate regulatory function. In this study, we explore the widespread contribution of TEs to mammalian 3D genomes by quantifying the extent to which they give rise to loops and domain border differences across various cell types and species using several 3D genome mapping technologies. We …


Preclinical Efficacy Of A Parp-1 Targeted Auger-Emitting Radionuclide In Prostate Cancer, Sreeja Sreekumar, Dong Zhou, Cedric Mpoy, Elsa Schenk, Jalen Scott, Jeffrey M Arbeit, Jinbin Xu, Buck E Rogers Feb 2023

Preclinical Efficacy Of A Parp-1 Targeted Auger-Emitting Radionuclide In Prostate Cancer, Sreeja Sreekumar, Dong Zhou, Cedric Mpoy, Elsa Schenk, Jalen Scott, Jeffrey M Arbeit, Jinbin Xu, Buck E Rogers

2020-Current year OA Pubs

There is an unmet need for better therapeutic strategies for advanced prostate cancer. Poly (ADP-ribose) polymerase-1 (PARP-1) is a chromatin-binding DNA repair enzyme overexpressed in prostate cancer. This study evaluates whether PARP-1, on account of its proximity to the cell's DNA, would be a good target for delivering high-linear energy transfer Auger radiation to induce lethal DNA damage in prostate cancer cells. We analyzed the correlation between PARP-1 expression and Gleason score in a prostate cancer tissue microarray. A radio-brominated Auger emitting inhibitor ([


Netprophet 3: A Machine Learning Framework For Transcription Factor Network Mapping And Multi-Omics Integration, Dhoha Abid, Michael R Brent Feb 2023

Netprophet 3: A Machine Learning Framework For Transcription Factor Network Mapping And Multi-Omics Integration, Dhoha Abid, Michael R Brent

2020-Current year OA Pubs

MOTIVATION: Many methods have been proposed for mapping the targets of transcription factors (TFs) from gene expression data. It is known that combining outputs from multiple methods can improve performance. To date, outputs have been combined by using either simplistic formulae, such as geometric mean, or carefully hand-tuned formulae that may not generalize well to new inputs. Finally, the evaluation of accuracy has been challenging due to the lack of genome-scale, ground-truth networks.

RESULTS: We developed NetProphet3, which combines scores from multiple analyses automatically, using a tree boosting algorithm trained on TF binding location data. We also developed three independent, …


Ssris Differentially Modulate The Effects Of Pro-Inflammatory Stimulation On Hippocampal Plasticity And Memory Via Sigma 1 Receptors And Neurosteroids, Yukitoshi Izumi, Angela M Reiersen, Eric J Lenze, Steven J Mennerick, Charles F Zorumski Feb 2023

Ssris Differentially Modulate The Effects Of Pro-Inflammatory Stimulation On Hippocampal Plasticity And Memory Via Sigma 1 Receptors And Neurosteroids, Yukitoshi Izumi, Angela M Reiersen, Eric J Lenze, Steven J Mennerick, Charles F Zorumski

2020-Current year OA Pubs

Certain selective serotonin reuptake inhibitors (SSRIs) have anti-inflammatory effects in preclinical models, and recent clinical studies suggest that fluvoxamine can prevent deterioration in patients with COVID-19, possibly through activating sigma 1 receptors (S1Rs). Here we examined potential mechanisms contributing to these effects of fluvoxamine and other SSRIs using a well-characterized model of pro-inflammatory stress in rat hippocampal slices. When hippocampal slices are exposed acutely to lipopolysaccharide (LPS), a strong pro-inflammatory stimulus, basal synaptic transmission in the CA1 region remains intact, but induction of long-term potentiation (LTP), a form of synaptic plasticity thought to contribute to learning and memory, is completely …


Presence Of Trans-Fatty Acids Containing Ingredients In Pre-Packaged Foods And The Availability Of Reported Trans-Fat Levels In Kenya And Nigeria, Liping Huang, Adedayo E Ojo, Judith Kimiywe, Alex Kibet, Boni M Ale, Clementina E Okoro, Jimmy Louie, Fraser Taylor, Mark D Huffman, Dike B Ojji, Jason H Y Wu, Matti Marklund Feb 2023

Presence Of Trans-Fatty Acids Containing Ingredients In Pre-Packaged Foods And The Availability Of Reported Trans-Fat Levels In Kenya And Nigeria, Liping Huang, Adedayo E Ojo, Judith Kimiywe, Alex Kibet, Boni M Ale, Clementina E Okoro, Jimmy Louie, Fraser Taylor, Mark D Huffman, Dike B Ojji, Jason H Y Wu, Matti Marklund

2020-Current year OA Pubs

In most African countries, the prevalence of industrially produced


Fixed-Dose Combination Therapy-Based Protocol Compared With Free Pill Combination Protocol: Results Of A Cluster Randomized Trial, Olutobi A Sanuade, Mark D Huffman, Et Al. Feb 2023

Fixed-Dose Combination Therapy-Based Protocol Compared With Free Pill Combination Protocol: Results Of A Cluster Randomized Trial, Olutobi A Sanuade, Mark D Huffman, Et Al.

2020-Current year OA Pubs

Fixed-dose combination (FDC) therapy is recommended for hypertension management in Nigeria based on randomized trials at the individual level. This cluster-randomized trial evaluates effectiveness and safety of a treatment protocol that used two-drug FDC therapy as the second and third steps for hypertension control compared with a protocol that used free pill combinations. From January 2021 to June 2021, 60 primary healthcare centers in the Federal Capital Territory of Nigeria were randomized to a protocol using FDC therapy as second and third steps compared with a protocol that used the same medications in free pill combination therapy for these steps. …


Multi-Ancestry Transcriptome-Wide Association Analyses Yield Insights Into Tobacco Use Biology And Drug Repurposing, Fang Chen, Lisa De Las Fuentes, Et Al. Feb 2023

Multi-Ancestry Transcriptome-Wide Association Analyses Yield Insights Into Tobacco Use Biology And Drug Repurposing, Fang Chen, Lisa De Las Fuentes, Et Al.

2020-Current year OA Pubs

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with …


Missed Opportunities In The Diagnosis Of Tuberculosis Meningitis, Niamh Simmons, Margaret A Olsen, Joanna Buss, Thomas C Bailey, Carlos Mejia-Chew Feb 2023

Missed Opportunities In The Diagnosis Of Tuberculosis Meningitis, Niamh Simmons, Margaret A Olsen, Joanna Buss, Thomas C Bailey, Carlos Mejia-Chew

2020-Current year OA Pubs

BACKGROUND: Tuberculosis meningitis (TBM) has high mortality and morbidity. Diagnostic delays can impact TBM outcomes. We aimed to estimate the number of potentially missed opportunities (MOs) to diagnose TBM and determine its impact on 90-day mortality.

METHODS: This is a retrospective cohort of adult patients with a central nervous system (CNS) TB

RESULTS: Of 893 patients with TBM, median age at diagnosis was 50 years (interquartile range, 37-64), 61.3% were male, and 35.2% had Medicaid as primary payer. Overall, 407 (45.6%) had a prior hospital or ED visit with an MO code. In-hospital 90-day mortality was not different between those …


The Ntpase Activity Of The Double Fyve Domain-Containing Protein 1 Regulates Lipid Droplet Metabolism., Victoria A. Ismail, Teri Naismith, David J. Kast Feb 2023

The Ntpase Activity Of The Double Fyve Domain-Containing Protein 1 Regulates Lipid Droplet Metabolism., Victoria A. Ismail, Teri Naismith, David J. Kast

2020-Current year OA Pubs

Lipid droplets (LDs) are transient lipid storage organelles that can be readily tapped to resupply cells with energy or lipid building blocks and therefore play a central role in cellular metabolism. However, the molecular factors and underlying mechanisms that regulate the growth and degradation of LDs are poorly understood. It has emerged that proteins that establish contacts between LDs and the endoplasmic reticulum play a critical role in regulating LD metabolism. Recently, the autophagy-related protein, double FYVE domain-containing protein 1 (DFCP1/ZFYVE1) was shown to reside at the interface of the endoplasmic reticulum and LDs, however, little is known about the …


Dissecting Cell Identity Via Network Inference And In Silico Gene Perturbation, Kenji Kamimoto, Blerta Stringa, Christy M Hoffmann, Kunal Jindal, Lilianna Solnica-Krezel, Samantha A Morris Feb 2023

Dissecting Cell Identity Via Network Inference And In Silico Gene Perturbation, Kenji Kamimoto, Blerta Stringa, Christy M Hoffmann, Kunal Jindal, Lilianna Solnica-Krezel, Samantha A Morris

2020-Current year OA Pubs

Cell identity is governed by the complex regulation of gene expression, represented as gene-regulatory networks


The Tetraspanin Transmembrane Protein Cd53 Mediates Dyslipidemia And Integrates Inflammatory And Metabolic Signaling In Hepatocytes, Cassandra B Higgins, Joshua A Adams, Matthew H Ward, Zev J Greenberg, Małgorzata Milewska, Jiameng Sun, Yiming Zhang, Luana Chiquetto Paracatu, Qian Dong, Samuel Ballentine, Weikai Li, Ilona Wandzik, Laura G Schuettpelz, Brian J Debosch Feb 2023

The Tetraspanin Transmembrane Protein Cd53 Mediates Dyslipidemia And Integrates Inflammatory And Metabolic Signaling In Hepatocytes, Cassandra B Higgins, Joshua A Adams, Matthew H Ward, Zev J Greenberg, Małgorzata Milewska, Jiameng Sun, Yiming Zhang, Luana Chiquetto Paracatu, Qian Dong, Samuel Ballentine, Weikai Li, Ilona Wandzik, Laura G Schuettpelz, Brian J Debosch

2020-Current year OA Pubs

Tetraspanins are transmembrane signaling and proinflammatory proteins. Prior work demonstrates that the tetraspanin, CD53/TSPAN25/MOX44, mediates B-cell development and lymphocyte migration to lymph nodes and is implicated in various inflammatory diseases. However, CD53 is also expressed in highly metabolic tissues, including adipose and liver; yet its function outside the lymphoid compartment is not defined. Here, we show that CD53 demarcates the nutritional and inflammatory status of hepatocytes. High-fat exposure and inflammatory stimuli induced CD53 in vivo in liver and isolated primary hepatocytes. In contrast, restricting hepatocyte glucose flux through hepatocyte glucose transporter 8 deletion or through trehalose treatment blocked CD53 induction …


Autophagy Requirements For Eye Lens Differentiation And Transparency, Lisa Brennan, M Joseph Costello, J Fielding Hejtmancik, A Sue Menko, S Amer Riazuddin, Alan Shiels, Marc Kantorow Feb 2023

Autophagy Requirements For Eye Lens Differentiation And Transparency, Lisa Brennan, M Joseph Costello, J Fielding Hejtmancik, A Sue Menko, S Amer Riazuddin, Alan Shiels, Marc Kantorow

2020-Current year OA Pubs

Recent evidence points to autophagy as an essential cellular requirement for achieving the mature structure, homeostasis, and transparency of the lens. Collective evidence from multiple laboratories using chick, mouse, primate, and human model systems provides evidence that classic autophagy structures, ranging from double-membrane autophagosomes to single-membrane autolysosomes, are found throughout the lens in both undifferentiated lens epithelial cells and maturing lens fiber cells. Recently, key autophagy signaling pathways have been identified to initiate critical steps in the lens differentiation program, including the elimination of organelles to form the core lens organelle-free zone. Other recent studies using ex vivo lens culture …


Modulation Of Trpv4 Protects Against Degeneration Induced By Sustained Loading And Promotes Matrix Synthesis In The Intervertebral Disc, Garrett W D Easson, Alireza Savadipour, Akila Anandarajah, Leanne E Iannucci, Spencer P Lake, Farshid Guilak, Simon Y Tang Feb 2023

Modulation Of Trpv4 Protects Against Degeneration Induced By Sustained Loading And Promotes Matrix Synthesis In The Intervertebral Disc, Garrett W D Easson, Alireza Savadipour, Akila Anandarajah, Leanne E Iannucci, Spencer P Lake, Farshid Guilak, Simon Y Tang

2020-Current year OA Pubs

While it is well known that mechanical signals can either promote or disrupt intervertebral disc (IVD) homeostasis, the molecular mechanisms for transducing mechanical stimuli are not fully understood. The transient receptor potential vanilloid 4 (TRPV4) ion channel activated in isolated IVD cells initiates extracellular matrix (ECM) gene expression, while TRPV4 ablation reduces cytokine production in response to circumferential stretching. However, the role of TRPV4 on ECM maintenance during tissue-level mechanical loading remains unknown. Using an organ culture model, we modulated TRPV4 function over both short- (hours) and long-term (days) and evaluated the IVDs' response. Activating TRPV4 with the agonist GSK101 …


Brainwave: A Flexible Method For Noninvasive Stimulation Of Brain Rhythms Across Species, Matthew K. Attokaren, Nuri Jeong, Lou Blanpain, Abigail L. Paulson, Kristie M. Garza, Ben Borron, Michael Walelign, Jon Willie, Annabelle C. Singer Feb 2023

Brainwave: A Flexible Method For Noninvasive Stimulation Of Brain Rhythms Across Species, Matthew K. Attokaren, Nuri Jeong, Lou Blanpain, Abigail L. Paulson, Kristie M. Garza, Ben Borron, Michael Walelign, Jon Willie, Annabelle C. Singer

2020-Current year OA Pubs

Rhythmic neural activity, which coordinates brain regions and neurons to achieve multiple brain functions, is impaired in many diseases. Despite the therapeutic potential of driving brain rhythms, methods to noninvasively target deep brain regions are limited. Accordingly, we recently introduced a noninvasive stimulation approach using flickering lights and sounds ("flicker"). Flicker drives rhythmic activity in deep and superficial brain regions. Gamma flicker spurs immune function, clears pathogens, and rescues memory performance in mice with amyloid pathology. Here, we present substantial improvements to this approach that is flexible, user-friendly, and generalizable across multiple experimental settings and species. We present novel open-source …


In Vivo Editing Of The Pan-Endothelium By Immunity Evading Simian Adenoviral Vector, Reka Lorincz, Aluet Borrego Alvarez, Christopher J Walkey, Samir A Mendonça, Zhi Hong Lu, Alexa E Martinez, Cecilia Ljungberg, Jason D Heaney, William R Lagor, David T Curiel Feb 2023

In Vivo Editing Of The Pan-Endothelium By Immunity Evading Simian Adenoviral Vector, Reka Lorincz, Aluet Borrego Alvarez, Christopher J Walkey, Samir A Mendonça, Zhi Hong Lu, Alexa E Martinez, Cecilia Ljungberg, Jason D Heaney, William R Lagor, David T Curiel

2020-Current year OA Pubs

Biological applications deriving from the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 site-specific nuclease system continue to impact and accelerate gene therapy strategies. Safe and effective in vivo co-delivery of the CRISPR/Cas9 system to target somatic cells is essential in the clinical therapeutic context. Both non-viral and viral vector systems have been applied for this delivery matter. Despite elegant proof-of-principle studies, available vector technologies still face challenges that restrict the application of CRISPR/Cas9-facilitated gene therapy. Of note, the mandated co-delivery of the gene-editing components must be accomplished in the potential presence of pre-formed anti-vector immunity. Additionally, methods must be sought …


Machine Learning Approximations To Predict Epigenetic Age Acceleration In Stroke Patients, Isabel Fernández-Pérez, Joan Jiménez-Balado, Uxue Lazcano, Eva Giralt-Steinhauer, Lucía Rey Álvarez, Elisa Cuadrado-Godia, Ana Rodríguez-Campello, Adrià Macias-Gómez, Antoni Suárez-Pérez, Anna Revert-Barberá, Isabel Estragués-Gázquez, Carolina Soriano-Tarraga, Jaume Roquer, Angel Ois, Jordi Jiménez-Conde Feb 2023

Machine Learning Approximations To Predict Epigenetic Age Acceleration In Stroke Patients, Isabel Fernández-Pérez, Joan Jiménez-Balado, Uxue Lazcano, Eva Giralt-Steinhauer, Lucía Rey Álvarez, Elisa Cuadrado-Godia, Ana Rodríguez-Campello, Adrià Macias-Gómez, Antoni Suárez-Pérez, Anna Revert-Barberá, Isabel Estragués-Gázquez, Carolina Soriano-Tarraga, Jaume Roquer, Angel Ois, Jordi Jiménez-Conde

2020-Current year OA Pubs

Age acceleration (Age-A) is a useful tool that is able to predict a broad range of health outcomes. It is necessary to determine DNA methylation levels to estimate it, and it is known that Age-A is influenced by environmental, lifestyle, and vascular risk factors (VRF). The aim of this study is to estimate the contribution of these easily measurable factors to Age-A in patients with cerebrovascular disease (CVD), using different machine learning (ML) approximations, and try to find a more accessible model able to predict Age-A. We studied a CVD cohort of 952 patients with information about VRF, lifestyle habits, …


The Hepatic Mitochondrial Pyruvate Carrier As A Regulator Of Systemic Metabolism And A Therapeutic Target For Treating Metabolic Disease, Kyle S Mccommis, Brian N Finck Jan 2023

The Hepatic Mitochondrial Pyruvate Carrier As A Regulator Of Systemic Metabolism And A Therapeutic Target For Treating Metabolic Disease, Kyle S Mccommis, Brian N Finck

2020-Current year OA Pubs

Pyruvate sits at an important metabolic crossroads of intermediary metabolism. As a product of glycolysis in the cytosol, it must be transported into the mitochondrial matrix for the energy stored in this nutrient to be fully harnessed to generate ATP or to become the building block of new biomolecules. Given the requirement for mitochondrial import, it is not surprising that the mitochondrial pyruvate carrier (MPC) has emerged as a target for therapeutic intervention in a variety of diseases characterized by altered mitochondrial and intermediary metabolism. In this review, we focus on the role of the MPC and related metabolic pathways …


Effect Of Histology On Stereotactic Body Radiotherapy For Non-Small Cell Lung Cancer Oligometastatic Pulmonary Lesions, Alexander J. Allen, Dominic A. Labella, Roman O. Kowalchuk, Michael R. Waters, Charles R. Kersh Jan 2023

Effect Of Histology On Stereotactic Body Radiotherapy For Non-Small Cell Lung Cancer Oligometastatic Pulmonary Lesions, Alexander J. Allen, Dominic A. Labella, Roman O. Kowalchuk, Michael R. Waters, Charles R. Kersh

2020-Current year OA Pubs

BACKGROUND: Stereotactic body radiotherapy (SBRT) is commonly used to provide targeted treatment to metastatic lung disease. Investigation is needed to understand the influence of histology on treatment outcomes. We report how tumor histology affects local control (LC) in a cohort of patients with non-small cell lung cancer (NSCLC) receiving SBRT for oligometastatic and recurrent pulmonary lesions.

METHODS: Patients who received SBRT to recurrent or oligometastatic NSCLC pulmonary lesions from 2015-2019 at our institution were included in this retrospective cohort study. Minimum follow-up was 2 months. Kaplan-Meier (KM) analysis was performed to assess local progression-free survival (LPFS). Local failure cumulative incidence …


Exploration Of The Nuclear Proteomes In The Ciliate Oxytricha Trifallax, Michael W Lu, Leslie Y Beh, V Talya Yerlici, Wenwen Fang, Katarzyna Kulej, Benjamin A Garcia, Laura F Landweber Jan 2023

Exploration Of The Nuclear Proteomes In The Ciliate Oxytricha Trifallax, Michael W Lu, Leslie Y Beh, V Talya Yerlici, Wenwen Fang, Katarzyna Kulej, Benjamin A Garcia, Laura F Landweber

2020-Current year OA Pubs

Nuclear dimorphism is a fundamental feature of ciliated protozoa, which have separate somatic and germline genomes in two distinct organelles within a single cell. The transcriptionally active somatic genome, contained within the physically larger macronucleus, is both structurally and functionally different from the silent germline genome housed in the smaller micronucleus. This difference in genome architecture is particularly exaggerated in


Drug Specificity And Affinity Are Encoded In The Probability Of Cryptic Pocket Opening In Myosin Motor Domains, Artur Meller, Jeffrey M Lotthammer, Louis G Smith, Borna Novak, Lindsey A Lee, Catherine C Kuhn, Lina Greenberg, Leslie A Leinwand, Michael J Greenberg, Gregory R Bowman Jan 2023

Drug Specificity And Affinity Are Encoded In The Probability Of Cryptic Pocket Opening In Myosin Motor Domains, Artur Meller, Jeffrey M Lotthammer, Louis G Smith, Borna Novak, Lindsey A Lee, Catherine C Kuhn, Lina Greenberg, Leslie A Leinwand, Michael J Greenberg, Gregory R Bowman

2020-Current year OA Pubs

The design of compounds that can discriminate between closely related target proteins remains a central challenge in drug discovery. Specific therapeutics targeting the highly conserved myosin motor family are urgently needed as mutations in at least six of its members cause numerous diseases. Allosteric modulators, like the myosin-II inhibitor blebbistatin, are a promising means to achieve specificity. However, it remains unclear why blebbistatin inhibits myosin-II motors with different potencies given that it binds at a highly conserved pocket that is always closed in blebbistatin-free experimental structures. We hypothesized that the probability of pocket opening is an important determinant of the …


Gold Nanoparticle-Enhanced X-Ray Microtomography Of The Rodent Reveals Region-Specific Cerebrospinal Fluid Circulation In The Brain, Shelei Pan, Peter H Yang, Dakota Defreitas, Sruthi Ramagiri, Peter O Bayguinov, Carl D Hacker, Abraham Z Snyder, Jackson Wilborn, Hengbo Huang, Gretchen M Koller, Dhvanii K Raval, Grace L Halupnik, Sanja Sviben, Rui Tang, Gabriel Haller, James D Quirk, James A J Fitzpatrick, Prabagaran Esakky, Jennifer M Strahle, Et Al. Jan 2023

Gold Nanoparticle-Enhanced X-Ray Microtomography Of The Rodent Reveals Region-Specific Cerebrospinal Fluid Circulation In The Brain, Shelei Pan, Peter H Yang, Dakota Defreitas, Sruthi Ramagiri, Peter O Bayguinov, Carl D Hacker, Abraham Z Snyder, Jackson Wilborn, Hengbo Huang, Gretchen M Koller, Dhvanii K Raval, Grace L Halupnik, Sanja Sviben, Rui Tang, Gabriel Haller, James D Quirk, James A J Fitzpatrick, Prabagaran Esakky, Jennifer M Strahle, Et Al.

2020-Current year OA Pubs

Cerebrospinal fluid (CSF) is essential for the development and function of the central nervous system (CNS). However, the brain and its interstitium have largely been thought of as a single entity through which CSF circulates, and it is not known whether specific cell populations within the CNS preferentially interact with the CSF. Here, we develop a technique for CSF tracking, gold nanoparticle-enhanced X-ray microtomography, to achieve micrometer-scale resolution visualization of CSF circulation patterns during development. Using this method and subsequent histological analysis in rodents, we identify previously uncharacterized CSF pathways from the subarachnoid space (particularly the basal cisterns) that mediate …


A Broad Characterization Of Glycogen Storage Disease Iv Patients: A Clinical, Genetic, And Histopathological Study, Matheus Vernet Machado Bressan Wilke, Bibiana Mello De Oliveira, Rodrigo Tzovenos Starosta, Marwan Shinawi, Liang Lu, Mai He, Yamin Ma, Janis Stoll, Carolina Fischinger Moura De Souza, Ana Cecilia Menezes De Siqueira, Sandra Maria Gonçalves Vieira, Carlos Thadeu Cerski, Lilia Farret Refosco, Ida Vanessa Doederlein Schwartz Jan 2023

A Broad Characterization Of Glycogen Storage Disease Iv Patients: A Clinical, Genetic, And Histopathological Study, Matheus Vernet Machado Bressan Wilke, Bibiana Mello De Oliveira, Rodrigo Tzovenos Starosta, Marwan Shinawi, Liang Lu, Mai He, Yamin Ma, Janis Stoll, Carolina Fischinger Moura De Souza, Ana Cecilia Menezes De Siqueira, Sandra Maria Gonçalves Vieira, Carlos Thadeu Cerski, Lilia Farret Refosco, Ida Vanessa Doederlein Schwartz

2020-Current year OA Pubs

Glycogen storage disease type IV (GSD IV) is an ultra-rare autosomal recessive disease caused by variants in the