Digital Commons Network^™

Gene Regulation And Speciation In A Migratory Divide Between Songbirds, Matthew I M Louder, Hannah Justen, Abigail A Kimmitt, Koedi S Lawley, Leslie M Turner, J David Dickman, Kira E Delmore

Faculty, Staff and Students Publications

Behavioral variation abounds in nature. This variation is important for adaptation and speciation, but its molecular basis remains elusive. Here, we use a hybrid zone between two subspecies of songbirds that differ in migration - an ecologically important and taxonomically widespread behavior---to gain insight into this topic. We measure gene expression in five brain regions. Differential expression between migratory states was dominated by circadian genes in all brain regions. The remaining patterns were largely brain-region specific. For example, expression differences between the subspecies that interact with migratory state likely help maintain reproductive isolation in this system and were documented in …

Clonal Hematopoiesis And Incident Heart Failure With Preserved Ejection Fraction, Art Schuermans, Michael C Honigberg, Laura M Raffield, Bing Yu, Mary B Roberts, Charles Kooperberg, Pinkal Desai, April P Carson, Amil M Shah, Christie M Ballantyne, Alexander G Bick, Pradeep Natarajan, Joann E Manson, Eric A Whitsel, Charles B Eaton, Alexander P Reiner

Faculty, Staff and Student Publications

IMPORTANCE: Clonal hematopoiesis of indeterminate potential (CHIP), the age-related clonal expansion of hematopoietic stem cells with leukemogenic acquired genetic variants, is associated with incident heart failure (HF).

OBJECTIVE: To evaluate the associations of CHIP and key gene-specific CHIP subtypes with incident HF with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF).

DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study included participants from 2 racially diverse prospective cohort studies with uniform HF subtype adjudication: the Jackson Heart Study (JHS) and Women's Health Initiative (WHI). JHS participants were enrolled during 2000 to 2004 and followed up through 2016. WHI participants were …

Novel Techniques In Imaging Congenital Heart Disease: Jacc Scientific Statement, Ritu Sachdeva, Aimee K Armstrong, Rima Arnaout, Lars Grosse-Wortmann, B Kelly Han, Luc Mertens, Ryan A Moore, Laura J Olivieri, Anitha Parthiban, Andrew J Powell

Faculty, Staff and Students Publications

Recent years have witnessed exponential growth in cardiac imaging technologies, allowing better visualization of complex cardiac anatomy and improved assessment of physiology. These advances have become increasingly important as more complex surgical and catheter-based procedures are evolving to address the needs of a growing congenital heart disease population. This state-of-the-art review presents advances in echocardiography, cardiac magnetic resonance, cardiac computed tomography, invasive angiography, 3-dimensional modeling, and digital twin technology. The paper also highlights the integration of artificial intelligence with imaging technology. While some techniques are in their infancy and need further refinement, others have found their way into clinical workflow …

Injectable Hydrogel Electrodes As Conduction Highways To Restore Native Pacing, Gabriel J Rodriguez-Rivera, Allison Post, Mathews John, Skylar Buchan, Drew Bernard, Mehdi Razavi, Elizabeth Cosgriff-Hernandez

Faculty, Staff and Students Publications

There is an urgent clinical need for a treatment regimen that addresses the underlying pathophysiology of ventricular arrhythmias, the leading cause of sudden cardiac death. The current report describes the design of an injectable hydrogel electrode and successful deployment in a pig model with access far more refined than any current pacing modalities allow. In addition to successful cardiac capture and pacing, analysis of surface ECG tracings and three-dimensional electroanatomic mapping revealed a QRS morphology comparable to native sinus rhythm, strongly suggesting the hydrogel electrode captures the deep septal bundle branches and Purkinje fibers. In an ablation model, electroanatomic mapping …

Breathe, Renee J Flores

Faculty and Staff Publications

This is a personal essay about breasts. It focuses on my experiences as a young girl, moving through adolescence to a history of breast cancer in my family, including my mother's breast cancer diagnosis. As a physician, patient, and wife, I reflect on the choices that I have to make and what this means for my identity as a woman and mother.

Unveiling The Complex World Of Extracellular Vesicles: Novel Characterization Techniques And Manufacturing Considerations, James J Lai, John J Hill, Casey Y Huang, Gino C Lee, Karol W Mai, Maggie Y Shen, Simon K Wang

Faculty, Staff and Student Publications

Extracellular vesicles (EVs) function as potent mediators of intercellular communication for many in vivo processes, contributing to both health and disease related conditions. Given their biological origins and diverse functionality from correspondingly unique "cargo" compositions, both endogenous and modified EVs are garnering attention as promising therapeutic modalities and vehicles for targeted therapeutic delivery applications. Their diversity in composition, however, has revealed a significant need for more comprehensive analytical-based characterization methods, and manufacturing processes that are consistent and scalable. In this review, we explore the dynamic landscape of EV research and development efforts, ranging from novel isolation approaches, to their analytical …

Xuebijing Improves Intestinal Microcirculation Dysfunction In Septic Rats By Regulating The Vegf-A/Pi3k/Akt Signaling Pathway, A-Ling Tang, Yan Li, Li-Chao Sun, Xiao-Yu Liu, Nan Gao, Sheng-Tao Yan, Guo-Qiang Zhang

Faculty, Staff and Student Publications

BACKGROUND: This study aims to explore whether Xuebijing (XBJ) can improve intestinal microcirculation dysfunction in sepsis and its mechanism.

METHODS: A rat model of sepsis was established by cecal ligation and puncture (CLP). A total of 30 male SD rats were divided into four groups: sham group, CLP group, XBJ + axitinib group, and XBJ group. XBJ was intraperitoneally injected 2 h before CLP. Hemodynamic data (blood pressure and heart rate) were recorded. The intestinal microcirculation data of the rats were analyzed via microcirculation imaging. Enzyme-linked immunosorbent assay (ELISA) kits were used to detect the serum levels of interleukin-6 (IL-6), …

Protein-Centric Omics Analysis Reveals Circulating Complements Linked To Non-Viral Liver Diseases As Potential Therapeutic Targets, Yingzhou Shi, Hang Dong, Shiwei Sun, Xiaoqin Wu, Jiansong Fang, Jianbo Zhao, Junming Han, Zongyue Li, Huixiao Wu, Luna Liu, Wanhong Wu, Yang Tian, Guandou Yuan, Xiude Fan, Chao Xu

Faculty, Staff and Student Publications

BACKGROUND/AIMS: To evaluate the causal correlation between complement components and non-viral liver diseases and their potential use as druggable targets.

METHODS: We conducted Mendelian randomization (MR) to assess the causal role of circulating complements in the risk of non-viral liver diseases. A complement-centric protein interaction network was constructed to explore biological functions and identify potential therapeutic options.

RESULTS: In the MR analysis, genetically predicted levels of complement C1q C chain (C1QC) were positively associated with the risk of autoimmune hepatitis (odds ratio 1.125, 95% confidence interval 1.018-1.244), while complement factor H-related protein 5 (CFHR5) was positively associated with the risk …

Feasible Diet And Circadian Interventions Reduce In Vivo Progression Of Flt3-Itd-Positive Acute Myeloid Leukemia, Megan Rodriguez, Baharan Fekry, Brianna Murphy, Mary Figueroa, Tiewei Cheng, Margaret Raber, Lisa Wartenberg, Donna Bell, Lisa Triche, Karla Crawford, Huaxian Ma, Kendra Allton, Ruwaida Ahmed, Jaime Tran, Christine Ranieri, Marina Konopleva, Michelle Barton, Cesar Nunez, Kristin Eckel-Mahan, Joya Chandra

Faculty, Staff and Student Publications

BACKGROUND: Acute myeloid leukemia (AML) with an internal tandem duplication in the fms-like tyrosine kinase receptor 3 gene (FLT3-ITD) is associated with poor survival, and few studies have examined the impact of modifiable behaviors, such as nutrient quality and timing, in this subset of acute leukemia.

METHODS: The influence of diet composition (low-sucrose and/or low-fat diets) and timing of diet were tested in tandem with anthracycline treatment in orthotopic xenograft mouse models. A pilot clinical study to test receptivity of pediatric leukemia patients to macronutrient matched foods was conducted. A role for the circadian protein, BMAL1 (brain and muscle ARNT-like …

Developing Medical Genetics In A Low-Income Country: Unveiling The Journey Of The Pakistani Society Of Medical Genetics And Genomics (Psmg), Aisha Furqan, Syed A Ahmed, Rizwan Naeem, Myla Ashfaq

Faculty, Staff and Student Publications

No abstract provided.

Human Equilibrative Nucleoside Transporter 1: Novel Biomarker And Prognostic Indicator For Patients With Gemcitabine-Treated Pancreatic Cancer, Jianchun Xiao, Fangyu Zhao, Wenhao Luo, Gang Yang, Yicheng Wang, Jiangdong Qiu, Yueze Liu, Lei You, Lianfang Zheng, Taiping Zhang

Faculty, Staff and Student Publications

AIM: This article aimed to find appropriate pancreatic cancer (PC) patients to treat with Gemcitabine with better survival outcomes by detecting hENT1 levels.

METHODS: We collected surgical pathological tissues from PC patients who received radical surgery in our hospital from September 2004 to December 2014. A total of 375 PC tissues and paired adjacent nontumor tissues were employed for the construction of 4 tissue microarrays (TMAs). The quality of the 4 TMAs was examined by HE staining. We performed immunohistochemistry analysis to evaluate hENT1 expression in the TMAs. Moreover, we detected hENT1 expression level and proved the role of hENT1 …

Mouse Models Of Chronic Lymphocytic Leukemia And Richter Transformation: What We Have Learnt And What We Are Missing, Maria Teresa Sabrina Bertilaccio, Shih-Shih Chen

Faculty, Staff and Student Publications

Although the chronic lymphocytic leukemia (CLL) treatment landscape has changed dramatically, unmet clinical needs are emerging, as CLL in many patients does not respond, becomes resistant to treatment, relapses during treatment, or transforms into Richter. In the majority of cases, transformation evolves the original leukemia clone into a diffuse large B-cell lymphoma (DLBCL). Richter transformation (RT) represents a dreadful clinical challenge with limited therapeutic opportunities and scarce preclinical tools. CLL cells are well known to highly depend on survival signals provided by the tumor microenvironment (TME). These signals enhance the frequency of immunosuppressive cells with protumor function, including regulatory CD4

A Relay Velocity Model Infers Cell-Dependent Rna Velocity, Shengyu Li, Pengzhi Zhang, Weiqing Chen, Lingqun Ye, Kristopher W Brannan, Nhat-Tu Le, Jun-Ichi Abe, John P Cooke, Guangyu Wang

Faculty, Staff and Student Publications

RNA velocity provides an approach for inferring cellular state transitions from single-cell RNA sequencing (scRNA-seq) data. Conventional RNA velocity models infer universal kinetics from all cells in an scRNA-seq experiment, resulting in unpredictable performance in experiments with multi-stage and/or multi-lineage transition of cell states where the assumption of the same kinetic rates for all cells no longer holds. Here we present cellDancer, a scalable deep neural network that locally infers velocity for each cell from its neighbors and then relays a series of local velocities to provide single-cell resolution inference of velocity kinetics. In the simulation benchmark, cellDancer shows robust …

Fc Gamma Receptors Promote Antibody-Induced Lilrb4 Internalization And Immune Regulation Of Monocytic Aml, Joshua W Morse, Xun Gui, Mi Deng, Ryan Huang, Xiaohua Ye, Peng Zhao, Xuejun Fan, Wei Xiong, Chengcheng Zhang, Ningyan Zhang, Zhiqiang An

Faculty, Staff and Student Publications

The immune checkpoint leukocyte immunoglobulin-like receptor B4 (LILRB4) is found specifically on the cell surface of acute monocytic leukemia (monocytic AML), an aggressive and common subtype of AML. We have developed a humanized monoclonal IgG1 LILRB4-blocking antibody (h128-3), which improved immune regulation but reduced cell surface expression of LILRB4 in monocytic AML models by 40–60%. Interestingly, most of this effect was neutralized by mutation of the Fc region of the antibody (h128-3/N297A), which prevents interaction with Fc gamma receptors (FcγRs). This suggested that there is FcγR-dependent antigenic modulation underlying h128-3’s effects, a mechanism known to alter the function of antibodies …

Neuromuscular Polytrauma Pain Is Resolved By Macrophage Cox-2 Nanoimmunomodulation, Ibdanelo Cortez, Caitlyn M Gaffney, Riddhi Vichare, Caitlin V Crelli, Lu Liu, Eric Lee, Jules Edralin, James M Nichols, Hoang Vu Pham, Syed Mehdi, Jelena M Janjic, Andrew J Shepherd

Faculty, Staff and Student Publications

Soft tissue injuries often involve muscle and peripheral nerves and are qualitatively distinct from single-tissue injuries. Prior research suggests that damaged innervation compromises wound healing. To test this in a traumatic injury context, we developed a novel mouse model of nerve and lower limb polytrauma, which features greater pain hypersensitivity and more sustained macrophage infiltration than either injury in isolation. We also show that macrophages are crucial mediators of pain hypersensitivity in this model by delivering macrophage-targeted nanoemulsions laden with the cyclooxygenase-2 (COX-2) inhibitor celecoxib. This treatment was more effective in males than females, and more effective when delivered 3 …

Candidate Circulating Microrna Biomarkers In Dogs With Chronic Pancreatitis, Susan K Armstrong, Robert W Hunter, Wilna Oosthyuzen, Maciej Parys, Adam G Gow, Silke Salavati Schmitz, James W Dear, Richard J Mellanby

Faculty, Staff and Student Publications

BACKGROUND: Pancreatitis is an important cause of disease and death in dogs. Available circulating biomarkers are not sufficiently sensitive and specific for a definitive diagnosis.

HYPOTHESIS: Circulating microRNAs would be differentially expressed in dogs with chronic pancreatitis and could have potential as diagnostic biomarkers.

ANIMALS: Healthy controls (n = 19) and dogs with naturally occurring pancreatitis (n = 17).

METHODS: A retrospective case-control study. Dogs with pancreatitis were included if they satisfied diagnostic criteria for pancreatitis as adjudicated by 3 experts. MicroRNA was extracted from stored serum samples and sequenced. Reads were mapped to mature microRNA sequences in the canine, …

Phospholipid Metabolic Adaptation Promotes Survival Of Idh2 Mutant Acute Myeloid Leukemia Cells, Tatsuya Morishima, Koichi Takahashi, Desmond Wai Loon Chin, Yuxin Wang, Kenji Tokunaga, Yuichiro Arima, Masao Matsuoka, Toshio Suda, Hitoshi Takizawa

Faculty, Staff and Student Publications

Genetic mutations in the isocitrate dehydrogenase (IDH) gene that result in a pathological enzymatic activity to produce oncometabolite have been detected in acute myeloid leukemia (AML) patients. While specific inhibitors that target mutant IDH enzymes and normalize intracellular oncometabolite level have been developed, refractoriness and resistance has been reported. Since acquisition of pathological enzymatic activity is accompanied by the abrogation of the crucial WT IDH enzymatic activity in IDH mutant cells, aberrant metabolism in IDH mutant cells can potentially persist even after the normalization of intracellular oncometabolite level. Comparisons of isogenic AML cell lines with and without IDH2 gene mutations …

Targeting The Renin-Angiotensin System (Ras) For Neuropsychiatric Disorders, Aline Silva De Miranda, Danielle S Macedo, Natalia P Rocha, Antonio L Teixeira

Faculty, Staff and Student Publications

BACKGROUND: Neuropsychiatric disorders, such as mood disorders, schizophrenia, and Alzheimer's disease (AD) and related dementias, are associated to significant morbidity and mortality worldwide. The pathophysiological mechanisms of neuropsychiatric disorders remain to be fully elucidated, which has hampered the development of effective therapies. The Renin Angiotensin System (RAS) is classically viewed as a key regulator of cardiovascular and renal homeostasis. The discovery that RAS components are expressed in the brain pointed out a potential role for this system in central nervous system (CNS) pathologies. The understanding of RAS involvement in the pathogenesis of neuropsychiatric disorders may contribute to identifying novel therapeutic …

G-Quadruplex Dna And Rna In Cellular Senescence, Rocio Diaz Escarcega, Paul Marshall, Andrey S Tsvetkov

Faculty, Staff and Student Publications

Normal cells divide, are damaged, and are repaired across their lifetime. As cells age, they enter cellular senescence, characterized by a permanent state of cell-cycle arrest triggered by various stressors. The molecular mechanisms that regulate senescent phenotypes have been actively investigated over the last several decades; however, one area that has been neglected is how G-quadruplex (G4) DNA and RNA (G4-DNA and G4-RNA) mediate senescence. These non-canonical four-stranded DNA and RNA structures regulate most normative DNA and RNA-dependent processes, such as transcription, replication, and translation, as well as pathogenic mechanisms, including genomic instability and abnormal stress granule function. This review …

Clic1-Mediated Autophagy Confers Resistance To Ddp In Gastric Cancer, Zhen-Liang Nong, Kun Zhao, Ye Wang, Zhu Yu, Cong-Jun Wang, Jun-Qiang Chen

Faculty, Staff and Student Publications

Gastric cancer has been a constant concern to researchers as one of the most common malignant tumors worldwide. The treatment options for gastric cancer include surgery, chemotherapy and traditional Chinese medicine. Chemotherapy is an effective treatment for patients with advanced gastric cancer. Cisplatin (DDP) has been approved as a critical chemotherapy drug to treat various kinds of solid tumors. Although DDP is an effective chemotherapeutic agent, many patients develop drug resistance during treatment, which has become a severe problem in clinical chemotherapy. This study aims to investigate the mechanism of DDP resistance in gastric cancer. The results show that intracellular …

A Novel Assessment Of Whole-Mount Gleason Grading In Prostate Cancer To Identify Candidates For Radical Prostatectomy: A Machine Learning-Based Multiomics Study, Jing Ning, Clemens P Spielvogel, David Haberl, Karolina Trachtova, Stefan Stoiber, Sazan Rasul, Vojtech Bystry, Gabriel Wasinger, Pascal Baltzer, Elisabeth Gurnhofer, Gerald Timelthaler, Michaela Schlederer, Laszlo Papp, Helga Schachner, Thomas Helbich, Markus Hartenbach, Bernhard Grubmüller, Shahrokh F Shariat, Marcus Hacker, Alexander Haug, Lukas Kenner

Faculty, Staff and Student Publications

Purpose: This study aims to assess whole-mount Gleason grading (GG) in prostate cancer (PCa) accurately using a multiomics machine learning (ML) model and to compare its performance with biopsy-proven GG (bxGG) assessment.

Materials and Methods: A total of 146 patients with PCa recruited in a pilot study of a prospective clinical trial (NCT02659527) were retrospectively included in the side study, all of whom underwent ⁶⁸Ga-PSMA-11 integrated positron emission tomography (PET) / magnetic resonance (MR) before radical prostatectomy (RP) between May 2014 and April 2020. To establish a multiomics ML model, we quantified PET radiomics features, pathway-level genomics …

Toxicity In The Era Of Immune Checkpoint Inhibitor Therapy, Synat Keam, Naimah Turner, Fernanda G Kugeratski, Rene Rico, Jocelynn Colunga-Minutti, Rayansh Poojary, Sayan Alekseev, Anisha B Patel, Yuanteng Jeff Li, Ajay Sheshadri, Monica E Loghin, Karin Woodman, Ashley E Aaroe, Sarah Hamidi, Priyanka Chandrasekhar Iyer, Nicolas L Palaskas, Yinghong Wang, Roza Nurieva

Faculty, Staff and Student Publications

Immune checkpoint inhibitors (ICIs) reinvigorate anti-tumor immune responses by disrupting co-inhibitory immune checkpoint molecules such as programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4). Although ICIs have had unprecedented success and have become the standard of care for many cancers, they are often accompanied by off-target inflammation that can occur in any organ system. These immune related adverse events (irAEs) often require steroid use and/or cessation of ICI therapy, which can both lead to cancer progression. Although irAEs are common, the detailed molecular and immune mechanisms underlying their development are still elusive. To further our understanding …

A Pthrp Gradient Drives Mandibular Condylar Chondrogenesis Via Runx2, C Tsutsumi-Arai, Y Arai, A Tran, M Salinas, Y Nakai, S Orikasa, W Ono, N Ono

Faculty, Staff and Student Publications

The mandibular condylar cartilage (MCC) is an essential component of the temporomandibular joint, which orchestrates the vertical growth of the mandibular ramus through endochondral ossification with distinctive modes of cell differentiation. Parathyroid hormone–related protein (PTHrP) is a master regulator of chondrogenesis; in the long bone epiphyseal growth plate, PTHrP expressed by resting zone chondrocytes promotes chondrocyte proliferation in the adjacent layer. However, how PTHrP regulates chondrogenesis in the MCC remains largely unclear. In this study, we used a Pthrp-mCherry knock-in reporter strain to map the localization of PTHrP+ cells in the MCC and define the function of PTHrP in the …

Independent Regulation Of Piezo1 Activity By Principal And Intercalated Cells Of The Collecting Duct, Kyrylo Pyrshev, Anna Atamanchuk-Stavniichuk, Mariya Kordysh, Oleg Zaika, Viktor N Tomilin, Oleh Pochynyuk

Faculty, Staff and Student Publications

The renal collecting duct is continuously exposed to a wide spectrum of fluid flow rates and osmotic gradients. Expression of a mechanoactivated Piezo1 channel is the most prominent in the collecting duct. However, the status and regulation of Piezo1 in functionally distinct principal and intercalated cells (PCs and ICs) of the collecting duct remain to be determined. We used pharmacological Piezo1 activation to quantify Piezo1-mediated [Ca2+]i influx and single-channel activity separately in PCs and ICs of freshly isolated collecting ducts with fluorescence imaging and electrophysiological tools. We also employed a variety of systemic treatments to examine their consequences on Piezo1 …

Rare Genomic Copy Number Variants Implicate New Candidate Genes For Bicuspid Aortic Valve, Steven G Carlisle, Hasan Albasha, Hector I Michelena, Anna Sabate-Rotes, Lisa Bianco, Julie De Backer, Laura Muiño Mosquera, Anji T Yetman, Malenka M Bissell, Maria Grazia Andreassi, Ilenia Foffa, Dawn S Hui, Anthony Caffarelli, Yuli Y Kim, Dongchuan Guo, Rodolfo Citro, Margot De Marco, Justin T Tretter, Kim L Mcbride, Dianna M Milewicz, Simon C Body, Siddharth K Prakash, Ebav Investigators, Bavcon Investigators

Faculty, Staff and Student Publications

Bicuspid aortic valve (BAV), the most common congenital heart defect, is a major cause of aortic valve disease requiring valve interventions and thoracic aortic aneurysms predisposing to acute aortic dissections. The spectrum of BAV ranges from early onset valve and aortic complications (EBAV) to sporadic late onset disease. Rare genomic copy number variants (CNVs) have previously been implicated in the development of BAV and thoracic aortic aneurysms. We determined the frequency and gene content of rare CNVs in EBAV probands (n = 272) using genome-wide SNP microarray analysis and three complementary CNV detection algorithms (cnvPartition, PennCNV, and QuantiSNP). Unselected control …

The Immunobiology Of Myelodysplastic Neoplasms: A Mini-Review, Shruthi Kannan, Rolando A Vedia, Jeffrey J Molldrem

Faculty, Staff and Student Publications

This mini review summarizes the immunobiology of myelodysplastic syndromes, specifically focusing on the interactions between immune cells, cytokines, and dysplastic cells within the tumor microenvironment in the bone marrow. We elucidate in detail how immune dysregulation and evasion influence the initiation and progression of myelodysplastic syndromes, as well as resistance to therapy and progression to AML. In addition, we highlight a range of therapeutic strategies, including the most recent breakthroughs and experimental therapies for treating MDS. Finally, we address the existing knowledge gaps in the understanding of the immunobiology of MDS and propose future research directions, promising advancements toward enhancing …

Nasal Bots Carry Relevant Titers Of Cwd Prions In Naturally Infected White-Tailed Deer, Paulina Soto, Francisca Bravo-Risi, Carlos Kramm, Nazaret Gamez, Rebeca Benavente, Denise L Bonilla, J Hunter Reed, Mitch Lockwood, Terry R Spraker, Tracy Nichols, Rodrigo Morales

Faculty, Staff and Student Publications

Chronic wasting disease (CWD) is a prion disease affecting farmed and free-ranging cervids. CWD is rapidly expanding across North America and its mechanisms of transmission are not completely understood. Considering that cervids are commonly afflicted by nasal bot flies, we tested the potential of these parasites to transmit CWD. Parasites collected from naturally infected white-tailed deer were evaluated for their prion content using the protein misfolding cyclic amplification (PMCA) technology and bioassays. Here, we describe PMCA seeding activity in nasal bot larvae collected from naturally infected, nonclinical deer. These parasites efficiently infect CWD-susceptible mice in ways suggestive of high infectivity …

Ketogenic Diet In Treating Sepsis-Related Acquired Weakness: Is It Friend Or Foe?, Yanmei Miao, Leiyu Xie, Shaolin Chen, Xiaoming Zhang, Wenjie Liu, Peng Xie

Faculty, Staff and Students Publications

Background: Sepsis is the body's extreme response to an infection leading to organ dysfunction. Sepsis-related acquired weakness (SAW), a critical illness closely related to metabolic disorders, is characterized by generalized sepsis-induced skeletal muscle weakness, mainly manifesting as symmetrical atrophy of respiratory and limb muscles. Muscle accounts for 40% of the body's total mass and is one of the major sites of glucose and energy absorption. Diet affects skeletal muscle metabolism, which further impacts physiology and signaling pathways. The ketogenic diet (KD) is a high-fat, low-carbohydrate diet that has shown benefits in patients with a variety of neuromuscular disorders. Patients with …

Comparative Exploration Of Mammalian Deafness Gene Homologues In The Drosophila Auditory Organ Shows Genetic Correlation Between Insect And Vertebrate Hearing, Daniel C Sutton, Jonathan C Andrews, Dylan M Dolezal, Ye Jin Park, Hongjie Li, Daniel F Eberl, Shinya Yamamoto, Andrew K Groves

Faculty, Staff and Students Publications

Johnston's organ, the Drosophila auditory organ, is anatomically very different from the mammalian organ of Corti. However, recent evidence indicates significant cellular and molecular similarities exist between vertebrate and invertebrate hearing, suggesting that Drosophila may be a useful platform to determine the function of the many mammalian deafness genes whose underlying biological mechanisms are poorly characterized. Our goal was a comprehensive screen of all known orthologues of mammalian deafness genes in the fruit fly to better understand conservation of hearing mechanisms between the insect and the fly and ultimately gain insight into human hereditary deafness. We used bioinformatic comparisons to …

Identification Of Constrained Sequence Elements Across 239 Primate Genomes, Lukas F K Kuderna, Jacob C Ulirsch, Sabrina Rashid, Mohamed Ameen, Laksshman Sundaram, Glenn Hickey, Anthony J Cox, Hong Gao, Arvind Kumar, Francois Aguet, Matthew J Christmas, Hiram Clawson, Maximilian Haeussler, Mareike C Janiak, Martin Kuhlwilm, Joseph D Orkin, Thomas Bataillon, Shivakumara Manu, Alejandro Valenzuela, Juraj Bergman, Marjolaine Rouselle, Felipe Ennes Silva, Lidia Agueda, Julie Blanc, Marta Gut, Dorien De Vries, Ian Goodhead, R Alan Harris, Muthuswamy Raveendran, Axel Jensen, Idriss S Chuma, Julie E Horvath, Christina Hvilsom, David Juan, Peter Frandsen, Joshua G Schraiber, Fabiano R De Melo, Fabrício Bertuol, Hazel Byrne, Iracilda Sampaio, Izeni Farias, João Valsecchi, Malu Messias, Maria N F Da Silva, Mihir Trivedi, Rogerio Rossi, Tomas Hrbek, Nicole Andriaholinirina, Clément J Rabarivola, Alphonse Zaramody, Clifford J Jolly, Jane Phillips-Conroy, Gregory Wilkerson, Christian Abee, Joe H Simmons, Eduardo Fernandez-Duque, Sree Kanthaswamy, Fekadu Shiferaw, Dongdong Wu, Long Zhou, Yong Shao, Guojie Zhang, Julius D Keyyu, Sascha Knauf, Minh D Le, Esther Lizano, Stefan Merker, Arcadi Navarro, Tilo Nadler, Chiea Chuen Khor, Jessica Lee, Patrick Tan, Weng Khong Lim, Andrew C Kitchener, Dietmar Zinner, Ivo Gut, Amanda D Melin, Katerina Guschanski, Mikkel Heide Schierup, Robin M D Beck, Ioannis Karakikes, Kevin C Wang, Govindhaswamy Umapathy, Christian Roos, Jean P Boubli, Adam Siepel, Anshul Kundaje, Benedict Paten, Kerstin Lindblad-Toh, Jeffrey Rogers, Tomas Marques Bonet, Kyle Kai-How Farh

Faculty, Staff and Students Publications

Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3–9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of …