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Full-Text Articles in Medicine and Health Sciences

Translational Approaches To Understanding Resilience To Alzheimer's Disease., Sarah M Neuner, Maria Telpoukhovskaia, Vilas Menon, Kristen M S O'Connell, Timothy J Hohman, Catherine Kaczorowski May 2022

Translational Approaches To Understanding Resilience To Alzheimer's Disease., Sarah M Neuner, Maria Telpoukhovskaia, Vilas Menon, Kristen M S O'Connell, Timothy J Hohman, Catherine Kaczorowski

Faculty Research 2022

Individuals who maintain cognitive function despite high levels of Alzheimer's disease (AD)-associated pathology are said to be 'resilient' to AD. Identifying mechanisms underlying resilience represents an exciting therapeutic opportunity. Human studies have identified a number of molecular and genetic factors associated with resilience, but the complexity of these cohorts prohibits a complete understanding of which factors are causal or simply correlated with resilience. Genetically and phenotypically diverse mouse models of AD provide new and translationally relevant opportunities to identify and prioritize new resilience mechanisms for further cross-species investigation. This review will discuss insights into resilience gained from both ...


Heterozygous Frameshift Variants In Hnrnpa2b1 Cause Early-Onset Oculopharyngeal Muscular Dystrophy, Hong Joo Kim, Payam Mohassel, Sandra Donkervoort, Lin Guo, Kevin O'Donovan, Maura Coughlin, Xaviere Lornage, Nicola Foulds, Simon R Hammans, A Reghan Foley, Charlotte M Fare, Alice F Ford, Masashi Ogasawara, Aki Sato, Aritoshi Iida, Pinki Munot, Gautam Ambegaonkar, Rahul Phadke, Dominic G O'Donovan, Rebecca Buchert, Mona Grimmel, Ana Töpf, Irina T Zaharieva, Lauren Brady, Ying Hu, Thomas E Lloyd, Andrea Klein, Maja Steinlin, Alice Kuster, Sandra Mercier, Pascale Marcorelles, Yann Péréon, Emmanuelle Fleurence, Adnan Manzur, Sarah Ennis, Rosanna Upstill-Goddard, Luca Bello, Cinzia Bertolin, Elena Pegoraro, Leonardo Salviati, Courtney E French, Andriy Shatillo, F Lucy Raymond, Tobias B Haack, Susana Quijano-Roy, Johann Böhm, Isabelle Nelson, Tanya Stojkovic, Teresinha Evangelista, Volker Straub, Norma B Romero, Jocelyn Laporte, Francesco Muntoni, Ichizo Nishino, Mark A Tarnopolsky, James Shorter, Carsten G Bönnemann, J Paul Taylor Apr 2022

Heterozygous Frameshift Variants In Hnrnpa2b1 Cause Early-Onset Oculopharyngeal Muscular Dystrophy, Hong Joo Kim, Payam Mohassel, Sandra Donkervoort, Lin Guo, Kevin O'Donovan, Maura Coughlin, Xaviere Lornage, Nicola Foulds, Simon R Hammans, A Reghan Foley, Charlotte M Fare, Alice F Ford, Masashi Ogasawara, Aki Sato, Aritoshi Iida, Pinki Munot, Gautam Ambegaonkar, Rahul Phadke, Dominic G O'Donovan, Rebecca Buchert, Mona Grimmel, Ana Töpf, Irina T Zaharieva, Lauren Brady, Ying Hu, Thomas E Lloyd, Andrea Klein, Maja Steinlin, Alice Kuster, Sandra Mercier, Pascale Marcorelles, Yann Péréon, Emmanuelle Fleurence, Adnan Manzur, Sarah Ennis, Rosanna Upstill-Goddard, Luca Bello, Cinzia Bertolin, Elena Pegoraro, Leonardo Salviati, Courtney E French, Andriy Shatillo, F Lucy Raymond, Tobias B Haack, Susana Quijano-Roy, Johann Böhm, Isabelle Nelson, Tanya Stojkovic, Teresinha Evangelista, Volker Straub, Norma B Romero, Jocelyn Laporte, Francesco Muntoni, Ichizo Nishino, Mark A Tarnopolsky, James Shorter, Carsten G Bönnemann, J Paul Taylor

Department of Biochemistry and Molecular Biology Faculty Papers

Missense variants in RNA-binding proteins (RBPs) underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Here, we present ten independent families with a severe, progressive muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD) but of much earlier onset, caused by heterozygous frameshift variants in the RBP hnRNPA2/B1. All disease-causing frameshift mutations abolish the native stop codon and extend the reading frame, creating novel transcripts that escape nonsense-mediated decay and are translated to produce hnRNPA2/B1 protein with the same neomorphic C-terminal sequence. In contrast to previously reported disease-causing missense variants in HNRNPA2B1 ...


A Periplasmic Cinched Protein Is Required For Siderophore Secretion And Virulence Of Mycobacterium Tuberculosis., Lei Zhang, James E Kent, Meredith Whitaker, David C Young, Dominik Herrmann, Alexander E Aleshin, Ying-Hui Ko, Gino Cingolani, Jamil S Saad, D Branch Moody, Francesca M Marassi, Sabine Ehrt, Michael Niederweis Apr 2022

A Periplasmic Cinched Protein Is Required For Siderophore Secretion And Virulence Of Mycobacterium Tuberculosis., Lei Zhang, James E Kent, Meredith Whitaker, David C Young, Dominik Herrmann, Alexander E Aleshin, Ying-Hui Ko, Gino Cingolani, Jamil S Saad, D Branch Moody, Francesca M Marassi, Sabine Ehrt, Michael Niederweis

Department of Biochemistry and Molecular Biology Faculty Papers

Iron is essential for growth of Mycobacterium tuberculosis, the causative agent of tuberculosis. To acquire iron from the host, M. tuberculosis uses the siderophores called mycobactins and carboxymycobactins. Here, we show that the rv0455c gene is essential for M. tuberculosis to grow in low-iron medium and that secretion of both mycobactins and carboxymycobactins is drastically reduced in the rv0455c deletion mutant. Both water-soluble and membrane-anchored Rv0455c are functional in siderophore secretion, supporting an intracellular role. Lack of Rv0455c results in siderophore toxicity, a phenotype observed for other siderophore secretion mutants, and severely impairs replication of M. tuberculosis in mice, demonstrating ...


G Protein-Coupled Receptor Kinase 5 Regulates Thrombin Signaling In Platelets Via Par-1., Kate Downes, Xuefei Zhao, Nicholas S Gleadall, Harriet Mckinney, Carly Kempster, Joana Batista, Patrick L Thomas, Matthew Cooper, James V Michael, Roman Kreuzhuber, Katherine Wedderburn, Kathryn Waller, Bianca Varney, Hippolyte Verdier, Neline Kriek, Sofie E Ashford, Kathleen E Stirrups, Joanne L Dunster, Steven E Mckenzie, Willem H Ouwehand, Jonathan M Gibbins, Jing Yang, William J Astle, Peisong Ma Apr 2022

G Protein-Coupled Receptor Kinase 5 Regulates Thrombin Signaling In Platelets Via Par-1., Kate Downes, Xuefei Zhao, Nicholas S Gleadall, Harriet Mckinney, Carly Kempster, Joana Batista, Patrick L Thomas, Matthew Cooper, James V Michael, Roman Kreuzhuber, Katherine Wedderburn, Kathryn Waller, Bianca Varney, Hippolyte Verdier, Neline Kriek, Sofie E Ashford, Kathleen E Stirrups, Joanne L Dunster, Steven E Mckenzie, Willem H Ouwehand, Jonathan M Gibbins, Jing Yang, William J Astle, Peisong Ma

Cardeza Foundation for Hematologic Research

The interindividual variation in the functional response of platelets to activation by agonists is heritable. Genome-wide association studies (GWASs) of quantitative measures of platelet function have identified fewer than 20 distinctly associated variants, some with unknown mechanisms. Here, we report GWASs of pathway-specific functional responses to agonism by adenosine 5'-diphosphate, a glycoprotein VI-specific collagen mimetic, and thrombin receptor-agonist peptides, each specific to 1 of the G protein-coupled receptors PAR-1 and PAR-4, in subsets of 1562 individuals. We identified an association (P = 2.75 × 10-40) between a common intronic variant, rs10886430, in the G protein-coupled receptor kinase 5 gene (GRK5 ...


A Mouse Model With Widespread Expression Of The C9orf72-Linked Glycine-Arginine Dipeptide Displays Non-Lethal Als/Ftd-Like Phenotypes, Brandie Morris Verdone, Maria Elena Cicardi, Xinmei Wen, Sindhu Sriramoji, Katelyn Russell, Shashirekha S Markandaiah, Brigid K Jensen, Karthik Krishnamurthy, Aaron R. Haeusler, Piera Pasinelli, Davide Trotti Apr 2022

A Mouse Model With Widespread Expression Of The C9orf72-Linked Glycine-Arginine Dipeptide Displays Non-Lethal Als/Ftd-Like Phenotypes, Brandie Morris Verdone, Maria Elena Cicardi, Xinmei Wen, Sindhu Sriramoji, Katelyn Russell, Shashirekha S Markandaiah, Brigid K Jensen, Karthik Krishnamurthy, Aaron R. Haeusler, Piera Pasinelli, Davide Trotti

Department of Neuroscience Faculty Papers

Translation of the hexanucleotide G4C2 expansion associated with C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) produces five different dipeptide repeat protein (DPR) species that can confer toxicity. There is yet much to learn about the contribution of a single DPR to disease pathogenesis. We show here that a short repeat length is sufficient for the DPR poly-GR to confer neurotoxicity in vitro, a phenomenon previously unobserved. This toxicity is also reported in vivo in our novel knock-in mouse model characterized by widespread central nervous system (CNS) expression of the short-length poly-GR. We observe sex-specific chronic ALS/FTD-like phenotypes ...


Patterns Of Crystallin Gene Expression In Differentiation State Specific Regions Of The Embryonic Chicken Lens, Zhiwei Ma, Daniel Chauss, Joshua Disatham, Xiaodong Jiao, Lisa Ann Brennan, A Sue Menko, Marc Kantorow, J Fielding Hejtmancik Apr 2022

Patterns Of Crystallin Gene Expression In Differentiation State Specific Regions Of The Embryonic Chicken Lens, Zhiwei Ma, Daniel Chauss, Joshua Disatham, Xiaodong Jiao, Lisa Ann Brennan, A Sue Menko, Marc Kantorow, J Fielding Hejtmancik

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Purpose: Transition from lens epithelial cells to lens fiber cell is accompanied by numerous changes in gene expression critical for lens transparency. We identify expression patterns of highly prevalent genes including ubiquitous and enzyme crystallins in the embryonic day 13 chicken lens.

Methods: Embryonic day 13 chicken lenses were dissected into central epithelial cell (EC), equatorial epithelial cell (EQ), cortical fiber cell (FP), and nuclear fiber cell (FC) compartments. Total RNA was prepared, subjected to high-throughput unidirectional mRNA sequencing, analyzed, mapped to the chicken genome, and functionally grouped.

Results: A total of 77,097 gene-specific transcripts covering 17,450 genes ...


Efficient Targeted Transgenesis Of Large Donor Dna Into Multiple Mouse Genetic Backgrounds Using Bacteriophage Bxb1 Integrase., Benjamin E. Low, Vishnu Hosur, Simon Lesbirel, Michael V. Wiles Mar 2022

Efficient Targeted Transgenesis Of Large Donor Dna Into Multiple Mouse Genetic Backgrounds Using Bacteriophage Bxb1 Integrase., Benjamin E. Low, Vishnu Hosur, Simon Lesbirel, Michael V. Wiles

Faculty Research 2022

The development of mouse models of human disease and synthetic biology research by targeted transgenesis of large DNA constructs represent a significant genetic engineering hurdle. We developed an efficient, precise, single-copy integration of large transgenes directly into zygotes using multiple mouse genetic backgrounds. We used in vivo Bxb1 mediated recombinase-mediated cassette exchange (RMCE) with a transgene "landing pad" composed of dual heterologous Bxb1 attachment (att) sites in cis, within the Gt(ROSA)26Sor safe harbor locus. RMCE of donor was achieved by microinjection of vector DNA carrying cognate attachment sites flanking the donor transgene with Bxb1-integrase mRNA. This approach achieves ...


Mechanisms Of Mitochondrial Promoter Recognition In Humans And Other Mammalian Species, Angelica Zamudio-Ochoa, Yaroslav I Morozov, Azadeh Sarfallah, Michael Anikin, Dmitry Temiakov Mar 2022

Mechanisms Of Mitochondrial Promoter Recognition In Humans And Other Mammalian Species, Angelica Zamudio-Ochoa, Yaroslav I Morozov, Azadeh Sarfallah, Michael Anikin, Dmitry Temiakov

Department of Biochemistry and Molecular Biology Faculty Papers

Recognition of mammalian mitochondrial promoters requires the concerted action of mitochondrial RNA polymerase (mtRNAP) and transcription initiation factors TFAM and TFB2M. In this work, we found that transcript slippage results in heterogeneity of the human mitochondrial transcripts in vivo and in vitro. This allowed us to correctly interpret the RNAseq data, identify the bona fide transcription start sites (TSS), and assign mitochondrial promoters for > 50% of mammalian species and some other vertebrates. The divergent structure of the mammalian promoters reveals previously unappreciated aspects of mtDNA evolution. The correct assignment of TSS also enabled us to establish the precise register of ...


Uncontrolled Mitochondrial Calcium Uptake Underlies The Pathogenesis Of Neurodegeneration In Micu1-Deficient Mice And Patients, Raghavendra Singh, Adam Bartok, Melanie Paillard, Ashley L. Tyburski, Melanie B Elliott, György Hajnóczky Mar 2022

Uncontrolled Mitochondrial Calcium Uptake Underlies The Pathogenesis Of Neurodegeneration In Micu1-Deficient Mice And Patients, Raghavendra Singh, Adam Bartok, Melanie Paillard, Ashley L. Tyburski, Melanie B Elliott, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Dysregulation of mitochondrial Ca2+ homeostasis has been linked to neurodegenerative diseases. Mitochondrial Ca2+ uptake is mediated via the calcium uniporter complex that is primarily regulated by MICU1, a Ca2+-sensing gatekeeper. Recently, human patients with MICU1 loss-of-function mutations were diagnosed with neuromuscular and cognitive impairments. While studies in patient-derived cells revealed altered mitochondrial calcium signaling, the neuronal pathogenesis was difficult to study. To fill this void, we created a neuron-specific MICU1-KO mouse model. These animals show progressive, abnormal motor and cognitive phenotypes likely caused by the degeneration of motor neurons in the spinal cord and the cortex. We found increased ...


Transcriptional Control Of Retinal Ganglion Cell Death After Axonal Injury., Stephanie B Syc-Mazurek, Hongtian Stanley Yang, Olivia J Marola, Gareth R Howell, Richard T Libby Mar 2022

Transcriptional Control Of Retinal Ganglion Cell Death After Axonal Injury., Stephanie B Syc-Mazurek, Hongtian Stanley Yang, Olivia J Marola, Gareth R Howell, Richard T Libby

Faculty Research 2022

Injury to the axons of retinal ganglion cells (RGCs) is a key pathological event in glaucomatous neurodegeneration. The transcription factors JUN (the target of the c-Jun N-terminal kinases, JNKs) and DDIT3/CHOP (a mediator of the endoplasmic reticulum stress response) have been shown to control the majority of proapoptotic signaling after mechanical axonal injury in RGCs and in other models of neurodegeneration. The downstream transcriptional networks controlled by JUN and DDIT3, which are critical for RGC death, however, are not well defined. To determine these networks, RNA was isolated from the retinas of wild-type mice and mice deficient in Jun ...


Adult Mouse Fibroblasts Retain Organ-Specific Transcriptomic Identity., Elvira Forte, Mirana Ramialison, Hieu T Nim, Madison Mara, Jacky Y Li, Rachel Cohn, Sandra Daigle, Sarah Boyd, Edouard G Stanley, Andrew G Elefanty, J Travis Hinson, Mauro W Costa, Nadia Rosenthal, Milena B Furtado Mar 2022

Adult Mouse Fibroblasts Retain Organ-Specific Transcriptomic Identity., Elvira Forte, Mirana Ramialison, Hieu T Nim, Madison Mara, Jacky Y Li, Rachel Cohn, Sandra Daigle, Sarah Boyd, Edouard G Stanley, Andrew G Elefanty, J Travis Hinson, Mauro W Costa, Nadia Rosenthal, Milena B Furtado

Faculty Research 2022

Organ fibroblasts are essential components of homeostatic and diseased tissues. They participate in sculpting the extracellular matrix, sensing the microenvironment, and communicating with other resident cells. Recent studies have revealed transcriptomic heterogeneity among fibroblasts within and between organs. To dissect the basis of interorgan heterogeneity, we compare the gene expression of murine fibroblasts from different tissues (tail, skin, lung, liver, heart, kidney, and gonads) and show that they display distinct positional and organ-specific transcriptome signatures that reflect their embryonic origins. We demonstrate that expression of genes typically attributed to the surrounding parenchyma by fibroblasts is established in embryonic development and ...


Key Factors For Improving Rigor And Reproducibility: Guidelines, Peer Reviews, And Journal Technical Reviews, Hong S. Lu, Alan Daugherty Mar 2022

Key Factors For Improving Rigor And Reproducibility: Guidelines, Peer Reviews, And Journal Technical Reviews, Hong S. Lu, Alan Daugherty

Saha Cardiovascular Research Center Faculty Publications

To respond to the NIH's policy for rigor and reproducibility in preclinical research, many journals have implemented guidelines and checklists to guide authors in improving the rigor and reproducibility of their research. Transparency in developing detailed prospective experimental designs and providing raw data are essential premises of rigor and reproducibility. Standard peer reviews and journal-specific technical and statistical reviews are critical factors for enhancing rigor and reproducibility. This brief review also shares some experience from Arteriosclerosis, Thrombosis, and Vascular Biology, an American Heart Association journal, that has implemented several mechanisms to enhance rigor and reproducibility for preclinical research.


The Europdx Data Portal: An Open Platform For Patient-Derived Cancer Xenograft Data Sharing And Visualization., Zdenka Dudová, Nathalie Conte, Jeremy Mason, Dalibor Stuchlík, Radim Peša, Csaba Halmagyi, Zinaida Perova, Abayomi Mosaku, Ross Thorne, Alex Follette, Ľuboslav Pivarč, Radim Šašinka, Muhammad Usman, Steven Neuhauser, Dale A. Begley, Debra M Krupke, Massimiliano Frassà, Alessandro Fiori, Riccardo Corsi, Luca Vezzadini, Claudio Isella, Andrea Bertotti, Carol J Bult, Helen Parkinson, Enzo Medico, Terrence Meehan, Aleš Křenek Feb 2022

The Europdx Data Portal: An Open Platform For Patient-Derived Cancer Xenograft Data Sharing And Visualization., Zdenka Dudová, Nathalie Conte, Jeremy Mason, Dalibor Stuchlík, Radim Peša, Csaba Halmagyi, Zinaida Perova, Abayomi Mosaku, Ross Thorne, Alex Follette, Ľuboslav Pivarč, Radim Šašinka, Muhammad Usman, Steven Neuhauser, Dale A. Begley, Debra M Krupke, Massimiliano Frassà, Alessandro Fiori, Riccardo Corsi, Luca Vezzadini, Claudio Isella, Andrea Bertotti, Carol J Bult, Helen Parkinson, Enzo Medico, Terrence Meehan, Aleš Křenek

Faculty Research 2022

BACKGROUND: Patient-derived xenografts (PDX) mice models play an important role in preclinical trials and personalized medicine. Sharing data on the models is highly valuable for numerous reasons - ethical, economical, research cross validation etc. The EurOPDX Consortium was established 8 years ago to share such information and avoid duplicating efforts in developing new PDX mice models and unify approaches to support preclinical research. EurOPDX Data Portal is the unified data sharing platform adopted by the Consortium.

MAIN BODY: In this paper we describe the main features of the EurOPDX Data Portal ( https://dataportal.europdx.eu/ ), its architecture and possible utilization by ...


Similarly Efficacious Anti-Malarial Drugs Sj733 And Pyronaridine Differ In Their Ability To Remove Circulating Parasites In Mice, Arya Sheelanair, Aleksandra S. Romanczuk, Rosemary A. Aogo, Rohit Nemai Haldar, Lianne I. M. Lansink, Deborah Cromer, Yandira G. Salinas, R. Kiplin Guy, James S. Mccarthy, Miles P. Davenport, Ashraful Haque, David S. Khoury Feb 2022

Similarly Efficacious Anti-Malarial Drugs Sj733 And Pyronaridine Differ In Their Ability To Remove Circulating Parasites In Mice, Arya Sheelanair, Aleksandra S. Romanczuk, Rosemary A. Aogo, Rohit Nemai Haldar, Lianne I. M. Lansink, Deborah Cromer, Yandira G. Salinas, R. Kiplin Guy, James S. Mccarthy, Miles P. Davenport, Ashraful Haque, David S. Khoury

Pharmaceutical Sciences Faculty Publications

BACKGROUND: Artemisinin-based combination therapy (ACT) has been a mainstay for malaria prevention and treatment. However, emergence of drug resistance has incentivised development of new drugs. Defining the kinetics with which circulating parasitized red blood cells (pRBC) are lost after drug treatment, referred to as the "parasite clearance curve", has been critical for assessing drug efficacy; yet underlying mechanisms remain partly unresolved. The clearance curve may be shaped both by the rate at which drugs kill parasites, and the rate at which drug-affected parasites are removed from circulation.

METHODS: In this context, two anti-malarials, SJ733, and an ACT partner drug, pyronaridine ...


Treatment Preferences For Pharmacological Versus Psychological Interventions Among Primary Care Providers In Nepal: Mixed Methods Analysis Of A Pilot Cluster Randomized Controlled Trial., Anvita Bhardwaj, Dristy Gurung, Sauharda Rai, Bonnie N Kaiser, Cori L Cafaro, Kathleen J Sikkema, Crick Lund, Nagendra P Luitel, Brandon A. Kohrt Feb 2022

Treatment Preferences For Pharmacological Versus Psychological Interventions Among Primary Care Providers In Nepal: Mixed Methods Analysis Of A Pilot Cluster Randomized Controlled Trial., Anvita Bhardwaj, Dristy Gurung, Sauharda Rai, Bonnie N Kaiser, Cori L Cafaro, Kathleen J Sikkema, Crick Lund, Nagendra P Luitel, Brandon A. Kohrt

Psychiatry and Behavioral Sciences Faculty Publications

There is increasing evidence supporting the effectiveness of psychological interventions in low- and middle-income countries. However, primary care providers (PCPs) may prefer treating patients with medication. A secondary exploratory analysis of a pilot cluster randomized controlled trial was conducted to evaluate psychological vs. pharmacological treatment preferences among PCPs. Thirty-four health facilities, including 205 PCPs, participated in the study, with PCPs in 17 facilities assigned to a standard version of the mental health Gap Action Programme (mhGAP) training delivered by mental health specialists. PCPs in the other 17 facilities received mhGAP instruction delivered by specialists and people with lived experience of ...


Noncoding-Rna-Based Therapeutics With An Emphasis On Prostatic Carcinoma-Progress And Challenges., Victor E. Nava, Pin-Yu Perera, Nirbhay Kumar, Maneesh Jain Feb 2022

Noncoding-Rna-Based Therapeutics With An Emphasis On Prostatic Carcinoma-Progress And Challenges., Victor E. Nava, Pin-Yu Perera, Nirbhay Kumar, Maneesh Jain

Pathology Faculty Publications

Noncoding RNAs (ncRNAs) defy the central dogma by representing a family of RNA molecules that are not translated into protein but can convey information encoded in their DNA. Elucidating the exact function of ncRNA has been a focus of discovery in the last decade and remains challenging. Nevertheless, the importance of understanding ncRNA is apparent since these molecules regulate gene expression at the transcriptional and post-transcriptional level exerting pleiotropic effects critical in development, oncogenesis, and immunity. NcRNAs have been referred to as "the dark matter of the nucleus", and unraveling their role in physiologic and pathologic processes will provide vast ...


Aloin Isoforms (A And B) Selectively Inhibits Proteolytic And Deubiquitinating Activity Of Papain Like Protease (Plpro) Of Sars-Cov-2 In Vitro., Devin S M Lewis, Joanna Ho, Savannah Wills, Anasha Kawall, Avini Sharma, Krishna Chavada, Maximilian C C J C Ebert, Stefania Evoli, Ajay Singh, Srujana Rayalam, Vicky Mody, Shashidharamurthy Taval Feb 2022

Aloin Isoforms (A And B) Selectively Inhibits Proteolytic And Deubiquitinating Activity Of Papain Like Protease (Plpro) Of Sars-Cov-2 In Vitro., Devin S M Lewis, Joanna Ho, Savannah Wills, Anasha Kawall, Avini Sharma, Krishna Chavada, Maximilian C C J C Ebert, Stefania Evoli, Ajay Singh, Srujana Rayalam, Vicky Mody, Shashidharamurthy Taval

PCOM Scholarly Papers

The most common host entry point of human adapted coronaviruses (CoV) including SARS-CoV-2 is through the initial colonization in the nostril and mouth region which is responsible for spread of the infection. Most recent studies suggest that the commercially available oral and nasal rinse products are effective in inhibiting the viral replication. However, the anti-viral mechanism of the active ingredients present in the oral rinses have not been studied. In the present study, we have assessed in vitro enzymatic inhibitory activity of active ingredients in the oral mouth rinse products: aloin A and B, chlorhexidine, eucalyptol, hexetidine, menthol, triclosan, methyl ...


Parasite Dynamics In Untreated Horses Through One Calendar Year, Ashley E. Steuer, Haley P. Anderson, Taylor Shepherd, Morgan Clark, Jessica A. Scare, Holli S. Gravatte, Martin K. Nielsen Feb 2022

Parasite Dynamics In Untreated Horses Through One Calendar Year, Ashley E. Steuer, Haley P. Anderson, Taylor Shepherd, Morgan Clark, Jessica A. Scare, Holli S. Gravatte, Martin K. Nielsen

Veterinary Science Faculty Publications

BACKGROUND: Horses are host to a plethora of parasites. Knowledge of the seasonality of parasite egg shedding and transmission is important for constructing parasite control programs. However, studies describing these patterns are sparse, and have largely been conducted only in the United Kingdom. This study evaluated strongylid egg shedding patterns and transmission dynamics of Strongylus vulgaris in naturally infected and untreated mares and foals through one calendar year in Kentucky, USA. The study also investigated the existence of a peri-parturient rise (PPR) in strongylid egg counts in foaling mares and collected information about Strongyloides westeri and Parascaris spp. in the ...


Selective Elimination Of Pluripotent Stem Cells By Pikfyve Specific Inhibitors., Arup R Chakraborty, Alex Vassilev, Sushil K Jaiswal, Constandina E O'Connell, John F Ahrens, Barbara S Mallon, Martin Pera, Melvin L Depamphilis Feb 2022

Selective Elimination Of Pluripotent Stem Cells By Pikfyve Specific Inhibitors., Arup R Chakraborty, Alex Vassilev, Sushil K Jaiswal, Constandina E O'Connell, John F Ahrens, Barbara S Mallon, Martin Pera, Melvin L Depamphilis

Faculty Research 2022

Inhibition of PIKfyve phosphoinositide kinase selectively kills autophagy-dependent cancer cells by disrupting lysosome homeostasis. Here, we show that PIKfyve inhibitors can also selectively eliminate pluripotent embryonal carcinoma cells (ECCs), embryonic stem cells, and induced pluripotent stem cells under conditions where differentiated cells remain viable. PIKfyve inhibitors prevented lysosome fission, induced autophagosome accumulation, and reduced cell proliferation in both pluripotent and differentiated cells, but they induced death only in pluripotent cells. The ability of PIKfyve inhibitors to distinguish between pluripotent and differentiated cells was confirmed with xenografts derived from ECCs. Pretreatment of ECCs with the PIKfyve specific inhibitor WX8 suppressed their ...


Retraction Note: Obesity-Induced Adipokine Imbalance Impairs Mouse Pulmonary Vascular Endothelial Function And Primes The Lung For Injury, Dilip Shah, Freddy Romero, Michelle Duong, Nadan Wang, Bishnuhari Paudyal, Benjamin T Suratt, Caleb B Kallen, Jianxin Sun, Ying Zhu, Kenneth Walsh, Ross Summer Feb 2022

Retraction Note: Obesity-Induced Adipokine Imbalance Impairs Mouse Pulmonary Vascular Endothelial Function And Primes The Lung For Injury, Dilip Shah, Freddy Romero, Michelle Duong, Nadan Wang, Bishnuhari Paudyal, Benjamin T Suratt, Caleb B Kallen, Jianxin Sun, Ying Zhu, Kenneth Walsh, Ross Summer

Center for Translational Medicine Faculty Papers

The Authors have retracted this Article. Afer publication of this Article, concerns have been raised about irregularities in the western blot data. In particular, the following bands appear to be duplicated: – Fig. 1e HFD/p-Src lane 1 and 3; – Fig. 4c NCD/Ve-cadherin lane 1 and 3 – Fig. 5e HFD+APN/ICAM-1 lane 1 and 2 – Fig. 5f HFD/beta-catenin lane 2 and HFD+APN/beta-catenin lane 1 – Fig. S1d HFD/beta-catenin all lanes – Fig. S4c NCD/beta-catenin lane 1 and 3. Additionally, the beta-catenin subpanel in Fig. 5f was subsequently reused in another study [1] and described as showing ...


Chromosome-Level Genome Of Schistosoma Haematobium Underpins Genome-Wide Explorations Of Molecular Variation., Andreas J Stroehlein, Pasi K Korhonen, V Vern Lee, Stuart A Ralph, Margaret Mentink-Kane, Hong You, Donald P Mcmanus, Louis-Albert Tchuem Tchuenté, J Russell Stothard, Parwinder Kaur, Olga Dudchenko, Erez Lieberman Aiden, Bicheng Yang, Huanming Yang, Aidan M Emery, Bonnie L Webster, Paul J. Brindley, David Rollinson, Bill C H Chang, Robin B Gasser, Neil D Young Feb 2022

Chromosome-Level Genome Of Schistosoma Haematobium Underpins Genome-Wide Explorations Of Molecular Variation., Andreas J Stroehlein, Pasi K Korhonen, V Vern Lee, Stuart A Ralph, Margaret Mentink-Kane, Hong You, Donald P Mcmanus, Louis-Albert Tchuem Tchuenté, J Russell Stothard, Parwinder Kaur, Olga Dudchenko, Erez Lieberman Aiden, Bicheng Yang, Huanming Yang, Aidan M Emery, Bonnie L Webster, Paul J. Brindley, David Rollinson, Bill C H Chang, Robin B Gasser, Neil D Young

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Urogenital schistosomiasis is caused by the blood fluke Schistosoma haematobium and is one of the most neglected tropical diseases worldwide, afflicting > 100 million people. It is characterised by granulomata, fibrosis and calcification in urogenital tissues, and can lead to increased susceptibility to HIV/AIDS and squamous cell carcinoma of the bladder. To complement available treatment programs and break the transmission of disease, sound knowledge and understanding of the biology and ecology of S. haematobium is required. Hybridisation/introgression events and molecular variation among members of the S. haematobium-group might effect important biological and/or disease traits as well as the ...


Genetic Interaction Between Mfrp And Adipor1 Mutations Affect Retinal Disease Phenotypes, Navdeep Gogna, Sonia Weatherly, Fuxin Zhao, Gayle B. Collin, Jai Pinkney, Lisa Stone, Juergen K. Naggert, Gregory W. Carter, Patsy M. Nishina Jan 2022

Genetic Interaction Between Mfrp And Adipor1 Mutations Affect Retinal Disease Phenotypes, Navdeep Gogna, Sonia Weatherly, Fuxin Zhao, Gayle B. Collin, Jai Pinkney, Lisa Stone, Juergen K. Naggert, Gregory W. Carter, Patsy M. Nishina

Faculty Research 2022

Adipor1tm1Dgen and Mfrprd6 mutant mice share similar eye disease characteristics. Previously, studies established a functional relationship of ADIPOR1 and MFRP proteins in maintaining retinal lipidome homeostasis and visual function. However, the independent and/or interactive contribution of both genes to similar disease phenotypes, including fundus spots, decreased axial length, and photoreceptor degeneration has yet to be examined. We performed a gene-interaction study where homozygous Adipor1tm1Dgen and Mfrprd6 mice were bred together and the resulting doubly heterozygous F1 offspring were intercrossed to produce 210 F2 progeny. Four-month-old mice from all nine genotypic combinations obtained in the F2 ...


The Earth Biogenome Project 2020: Starting The Clock., Harris A Lewin, Stephen Richards, Erez Lieberman Aiden, Miguel L Allende, John M Archibald, Miklós Bálint, Katharine B Barker, Bridget Baumgartner, Katherine Belov, Giorgio Bertorelle, Mark L Blaxter, Jing Cai, Nicolette D Caperello, Keith Carlson, Juan Carlos Castilla-Rubio, Shu-Miaw Chaw, Lei Chen, Anna K Childers, Jonathan A Coddington, Dalia A Conde, Montserrat Corominas, Keith A. Crandall, Andrew J Crawford, Federica Dipalma, Richard Durbin, Thankgod E Ebenezer, Scott V Edwards, Olivier Fedrigo, Paul Flicek, Giulio Formenti, Richard A Gibbs, M Thomas P Gilbert, Melissa M. Goldstein, Jennifer Marshall Graves, Henry T Greely, Igor V Grigoriev, Kevin J Hackett, Neil Hall, David Haussler, Kristofer M Helgen, Carolyn J Hogg, Sachiko Isobe, Kjetill Sigurd Jakobsen, Axel Janke, Erich D Jarvis, Warren E Johnson, Steven J M Jones, Elinor K Karlsson, Paul J Kersey, Jin-Hyoung Kim, W John Kress, Shigehiro Kuraku, Mara K N Lawniczak, James H Leebens-Mack, Xueyan Li, Kerstin Lindblad-Toh, Xin Liu, Jose V Lopez, Tomas Marques-Bonet, Sophie Mazard, Jonna A K Mazet, Camila J Mazzoni, Eugene W Myers, Rachel J O'Neill, Sadye Paez, Hyun Park, Gene E Robinson, Cristina Roquet, Oliver A Ryder, Jamal S M Sabir, H Bradley Shaffer, Timothy M Shank, Jacob S Sherkow, Pamela S Soltis, Boping Tang, Leho Tedersoo, Marcela Uliano-Silva, Kun Wang, Xiaofeng Wei, Regina Wetzer, Julia L Wilson, Xun Xu, Huanming Yang, Anne D Yoder, Guojie Zhang Jan 2022

The Earth Biogenome Project 2020: Starting The Clock., Harris A Lewin, Stephen Richards, Erez Lieberman Aiden, Miguel L Allende, John M Archibald, Miklós Bálint, Katharine B Barker, Bridget Baumgartner, Katherine Belov, Giorgio Bertorelle, Mark L Blaxter, Jing Cai, Nicolette D Caperello, Keith Carlson, Juan Carlos Castilla-Rubio, Shu-Miaw Chaw, Lei Chen, Anna K Childers, Jonathan A Coddington, Dalia A Conde, Montserrat Corominas, Keith A. Crandall, Andrew J Crawford, Federica Dipalma, Richard Durbin, Thankgod E Ebenezer, Scott V Edwards, Olivier Fedrigo, Paul Flicek, Giulio Formenti, Richard A Gibbs, M Thomas P Gilbert, Melissa M. Goldstein, Jennifer Marshall Graves, Henry T Greely, Igor V Grigoriev, Kevin J Hackett, Neil Hall, David Haussler, Kristofer M Helgen, Carolyn J Hogg, Sachiko Isobe, Kjetill Sigurd Jakobsen, Axel Janke, Erich D Jarvis, Warren E Johnson, Steven J M Jones, Elinor K Karlsson, Paul J Kersey, Jin-Hyoung Kim, W John Kress, Shigehiro Kuraku, Mara K N Lawniczak, James H Leebens-Mack, Xueyan Li, Kerstin Lindblad-Toh, Xin Liu, Jose V Lopez, Tomas Marques-Bonet, Sophie Mazard, Jonna A K Mazet, Camila J Mazzoni, Eugene W Myers, Rachel J O'Neill, Sadye Paez, Hyun Park, Gene E Robinson, Cristina Roquet, Oliver A Ryder, Jamal S M Sabir, H Bradley Shaffer, Timothy M Shank, Jacob S Sherkow, Pamela S Soltis, Boping Tang, Leho Tedersoo, Marcela Uliano-Silva, Kun Wang, Xiaofeng Wei, Regina Wetzer, Julia L Wilson, Xun Xu, Huanming Yang, Anne D Yoder, Guojie Zhang

Health Policy and Management Faculty Publications

No abstract provided.


Langerhans Cells And Cdc1s Play Redundant Roles In Mrna-Lnp Induced Protective Anti-Influenza And Anti-Sars-Cov-2 Immune Responses, Sonia Ndeupen, Aurélie Bouteau, Christopher Herbst, Zhen Qin, Sonya Jacobsen, Nicholas E Powers, Zachary Hutchins, Drishya Kurup, Leila Zabihi Diba, Megan Watson, Holly Ramage, Botond Z. Igyártó Jan 2022

Langerhans Cells And Cdc1s Play Redundant Roles In Mrna-Lnp Induced Protective Anti-Influenza And Anti-Sars-Cov-2 Immune Responses, Sonia Ndeupen, Aurélie Bouteau, Christopher Herbst, Zhen Qin, Sonya Jacobsen, Nicholas E Powers, Zachary Hutchins, Drishya Kurup, Leila Zabihi Diba, Megan Watson, Holly Ramage, Botond Z. Igyártó

Department of Microbiology and Immunology Faculty Papers

Nucleoside modified mRNA combined with Acuitas Therapeutics' lipid nanoparticles (LNPs) has been shown to support robust humoral immune responses in many preclinical animal vaccine studies and later in humans with the SARS-CoV-2 vaccination. We recently showed that this platform is highly inflammatory due to the LNPs' ionizable lipid component. The inflammatory property is key to support the development of potent humoral immune responses. However, the mechanism by which this platform drives T follicular helper (Tfh) cells and humoral immune responses remains unknown. Here we show that lack of Langerhans cells or cDC1s neither significantly affected the induction of PR8 HA ...


“Why Should The Fish Feel Safe? I Don’T Feel Safe!”: An Audit Of Pet Ownership Within An Nhs Service For Adults With Severe Mental Illness, With Lessons For Service Improvement, Abigail Alfrey, Steve Church, Niki Christodoulou, Emma Harding Jan 2022

“Why Should The Fish Feel Safe? I Don’T Feel Safe!”: An Audit Of Pet Ownership Within An Nhs Service For Adults With Severe Mental Illness, With Lessons For Service Improvement, Abigail Alfrey, Steve Church, Niki Christodoulou, Emma Harding

People and Animals: The International Journal of Research and Practice

Background—Several studies have identified that pets can promote mental health, wellness, and recovery. However, little is known about the impact of pet ownership upon those with a severe mental illness (SMI), or whether mental health services are offering sufficient support that is specific to the needs of pet-owning service users. Aims—To identify the proportion of pet owners among an urban, U.K.-based community psychosis service; and to elicit service users’ views on pet ownership, to better understand and support this population’s particular needs. Method—The proportion of pet owners among this sample (n = 212) was compared ...


Common Genetic Variants Contribute To Risk Of Transposition Of The Great Arteries., Doris Škorić-Milosavljević, Rafik Tadros, Fernanda M Bosada, Federico Tessadori, Jan Hendrik Van Weerd, Odilia I Woudstra, Fleur V Y Tjong, Najim Lahrouchi, Fanny Bajolle, Heather J Cordell, A J Agopian, Gillian M Blue, Daniela Q C M Barge-Schaapveld, Marc Gewillig, Christoph Preuss, Elisabeth M Lodder, Phil Barnett, Aho Ilgun, Leander Beekman, Karel Van Duijvenboden, Regina Bokenkamp, Martina Müller-Nurasyid, Hubert W Vliegen, Thelma C Konings, Joost P Van Melle, Arie P J Van Dijk, Roland R J Van Kimmenade, Jolien W Roos-Hesselink, Gertjan T Sieswerda, Folkert Meijboom, Hashim Abdul-Khaliq, Felix Berger, Sven Dittrich, Marc-Phillip Hitz, Julia Moosmann, Frank-Thomas Riede, Stephan Schubert, Pilar Galan, Mark Lathrop, Hans M Munter, Ammar Al-Chalabi, Christopher E Shaw, Pamela J Shaw, Karen E Morrison, Jan H Veldink, Leonard H Van Den Berg, Sylvia Evans, Marcelo A Nobrega, Ivy Aneas, Milena Radivojkov-Blagojević, Thomas Meitinger, Erwin Oechslin, Tapas Mondal, Lynn Bergin, John F Smythe, Luis Altamirano-Diaz, Jane Lougheed, Berto J Bouma, Marie-A Chaix, Jennie Kline, Anne S Bassett, Gregor Andelfinger, Roel L F Van Der Palen, Patrice Bouvagnet, Sally-Ann B Clur, Jeroen Breckpot, Wilhelmina S Kerstjens-Frederikse, David S Winlaw, Ulrike M M Bauer, Seema Mital, Elizabeth Goldmuntz, Bernard Keavney, Damien Bonnet, Barbara J Mulder, Michael W T Tanck, Jeroen Bakkers, Vincent M Christoffels, Cornelis J Boogerd, Alex V Postma, Connie R Bezzina Jan 2022

Common Genetic Variants Contribute To Risk Of Transposition Of The Great Arteries., Doris Škorić-Milosavljević, Rafik Tadros, Fernanda M Bosada, Federico Tessadori, Jan Hendrik Van Weerd, Odilia I Woudstra, Fleur V Y Tjong, Najim Lahrouchi, Fanny Bajolle, Heather J Cordell, A J Agopian, Gillian M Blue, Daniela Q C M Barge-Schaapveld, Marc Gewillig, Christoph Preuss, Elisabeth M Lodder, Phil Barnett, Aho Ilgun, Leander Beekman, Karel Van Duijvenboden, Regina Bokenkamp, Martina Müller-Nurasyid, Hubert W Vliegen, Thelma C Konings, Joost P Van Melle, Arie P J Van Dijk, Roland R J Van Kimmenade, Jolien W Roos-Hesselink, Gertjan T Sieswerda, Folkert Meijboom, Hashim Abdul-Khaliq, Felix Berger, Sven Dittrich, Marc-Phillip Hitz, Julia Moosmann, Frank-Thomas Riede, Stephan Schubert, Pilar Galan, Mark Lathrop, Hans M Munter, Ammar Al-Chalabi, Christopher E Shaw, Pamela J Shaw, Karen E Morrison, Jan H Veldink, Leonard H Van Den Berg, Sylvia Evans, Marcelo A Nobrega, Ivy Aneas, Milena Radivojkov-Blagojević, Thomas Meitinger, Erwin Oechslin, Tapas Mondal, Lynn Bergin, John F Smythe, Luis Altamirano-Diaz, Jane Lougheed, Berto J Bouma, Marie-A Chaix, Jennie Kline, Anne S Bassett, Gregor Andelfinger, Roel L F Van Der Palen, Patrice Bouvagnet, Sally-Ann B Clur, Jeroen Breckpot, Wilhelmina S Kerstjens-Frederikse, David S Winlaw, Ulrike M M Bauer, Seema Mital, Elizabeth Goldmuntz, Bernard Keavney, Damien Bonnet, Barbara J Mulder, Michael W T Tanck, Jeroen Bakkers, Vincent M Christoffels, Cornelis J Boogerd, Alex V Postma, Connie R Bezzina

Faculty Research 2022

RATIONALE: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored.

OBJECTIVE: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA.

METHODS AND RESULTS: We conducted a genome-wide association study in an international set of 1 ...


Clinical Utility Of Anti-Mullerian Hormone In Pediatrics, Roopa Kanakatti Shankar, Tazim Dowlut-Mcelroy, Andrew Dauber, Veronica Gomez-Lobo Jan 2022

Clinical Utility Of Anti-Mullerian Hormone In Pediatrics, Roopa Kanakatti Shankar, Tazim Dowlut-Mcelroy, Andrew Dauber, Veronica Gomez-Lobo

Pediatrics Faculty Publications

CONTEXT: Anti-Mullerian hormone (AMH) was originally described in the context of sexual differentiation in the male fetus but has gained prominence now as a marker of ovarian reserve and fertility in females. In this mini-review, we offer an updated synopsis on AMH and its clinical utility in pediatric patients.

DESIGN AND RESULTS: A systematic search was undertaken for studies related to the physiology of AMH, normative data, and clinical role in pediatrics. In males, AMH, secreted by Sertoli cells, is found at high levels prenatally and throughout childhood and declines with progression through puberty to overlap with levels in females ...


Generation And Application Of Inducible Chimeric Rna, Yichen Luo, Liang Du, Zhimeng Yao, Fan Liu, Kai Li, Feifei Li, Jianlin Zhu, Robert P Coppes, Dianzheng Zhang, Yunlong Pan, Shegan Gao, Hao Zhang Jan 2022

Generation And Application Of Inducible Chimeric Rna, Yichen Luo, Liang Du, Zhimeng Yao, Fan Liu, Kai Li, Feifei Li, Jianlin Zhu, Robert P Coppes, Dianzheng Zhang, Yunlong Pan, Shegan Gao, Hao Zhang

PCOM Scholarly Papers

Chimeric RNAs (chiRNAs) play many previously unrecognized roles in different diseases including cancer. They can not only be used as biomarkers for diagnosis and prognosis of various diseases but also serve as potential therapeutic targets. In order to better understand the roles of chiRNAs in pathogenesis, we inserted human sequences into mouse genome and established a knockin mouse model of the tamoxifen-inducible expression of ASTN2-PAPPA antisense chimeric RNA (A-PaschiRNA). Mice carrying the A-PaschiRNA knockin gene do not display any apparent abnormalities in growth, fertility, histological, hematopoietic, and biochemical indices. Using this model, we dissected the role of A-P ...


Stride-Level Analysis Of Mouse Open Field Behavior Using Deep-Learning-Based Pose Estimation., Keith Sheppard, Justin Gardin, Gautam S Sabnis, Asaf Peer, Megan Darrell, Sean P Deats, Brian Q Geuther, Cathleen Lutz, Vivek Kumar Jan 2022

Stride-Level Analysis Of Mouse Open Field Behavior Using Deep-Learning-Based Pose Estimation., Keith Sheppard, Justin Gardin, Gautam S Sabnis, Asaf Peer, Megan Darrell, Sean P Deats, Brian Q Geuther, Cathleen Lutz, Vivek Kumar

Faculty Research 2022

Gait and posture are often perturbed in many neurological, neuromuscular, and neuropsychiatric conditions. Rodents provide a tractable model for elucidating disease mechanisms and interventions. Here, we develop a neural-network-based assay that adopts the commonly used open field apparatus for mouse gait and posture analysis. We quantitate both with high precision across 62 strains of mice. We characterize four mutants with known gait deficits and demonstrate that multiple autism spectrum disorder (ASD) models show gait and posture deficits, implying this is a general feature of ASD. Mouse gait and posture measures are highly heritable and fall into three distinct classes. We ...


Cutaneous Squamous Cell Carcinoma Staging May Influence Management In Users: A Survey Study., Vishal A. Patel, Catherine Mccullum, Andrew D. Sparks, Chrysalyne D Schmults, Sarah T Arron, Anokhi Jambusaria-Pahlajani Jan 2022

Cutaneous Squamous Cell Carcinoma Staging May Influence Management In Users: A Survey Study., Vishal A. Patel, Catherine Mccullum, Andrew D. Sparks, Chrysalyne D Schmults, Sarah T Arron, Anokhi Jambusaria-Pahlajani

Dermatology Faculty Publications

PURPOSE: This study aims to determine whether there is consensus regarding staging and management of cutaneous squamous cell carcinoma (CSCC) across the various specialties that manage this disease.

MATERIALS AND METHODS: A survey regarding CSCC high-risk features, staging, and management was created and emailed to cutaneous oncology experts including dermatology, head and neck surgery/surgical oncology, radiation oncology, and medical oncology.

RESULTS: One hundred fifty-six (46%) of 357 invited physicians completed the survey. Depth of invasion (92%), perineural invasion (99%), histologic differentiation (85%), and patient immunosuppression (90%) achieved consensus (>80%) as high-risk features of CSCC. Dermatologists were more likely to ...