Medicine and Health Sciences Commons^™

Randomized, Double-Blinded, Placebo-Controlled Trial Of Allogeneic Cord Blood T-Regulatory Cells For Treatment Of Covid-19 Ards, Douglas E Gladstone, Franco D'Alessio, Christopher Howard, Mi-Ae Lyu, Jason R Mock, Kevin W Gibbs, Darryl Abrams, Meixian Huang, Ke Zeng, James P Herlihy, Sergio T Castillo, Roland Bassett, Tara Sadeghi, Simrit Parmar, Christopher R Flowers, Siddhartha Mukherjee, David Schoenfeld, Peter F Thall, Arthur S Slutsky

Faculty, Staff and Students Publications

No abstract provided.

Author Correction: Drugnomeai Is An Ensemble Machine-Learning Framework For Predicting Druggability Of Candidate Drug Targets, Arwa Raies, Ewa Tulodziecka, James Stainer, Lawrence Middleton, Ryan S Dhindsa, Pamela Hill, Ola Engkvist, Andrew R Harper, Slavé Petrovski, Dimitrios Vitsios

Faculty, Staff and Students Publications

No abstract provided.

Taking Shape: Intercalation Within The Mammary Terminal End Bud, Kevin Roarty

Faculty, Staff and Students Publications

In this issue of Developmental Cell, Pfannenstein and Macara leverage the experimental versatility of the mammary gland to show that intercalation within the terminal end bud is regulated by the tight junction organizing protein ZO-1 and dynamic actin cytoskeletal rearrangements to propel ductal elongation.

Myc Regulates Csf1 Expression Via Microrna 17/20a To Modulate Tumor-Associated Macrophages In Osteosarcoma, Bikesh K Nirala, Tajhal D Patel, Lyazat Kurenbekova, Ryan Shuck, Atreyi Dasgupta, Nino Rainusso, Cristian Coarfa, Jason T Yustein

Faculty, Staff and Students Publications

Osteosarcoma (OS) is the most common primary bone tumor of childhood. Approximately 20%-30% of OSs carry amplification of chromosome 8q24, which harbors the oncogene c-MYC and correlates with a poor prognosis. To understand the mechanisms that underlie the ability of MYC to alter both the tumor and its surrounding tumor microenvironment (TME), we generated and molecularly characterized an osteoblast-specific Cre-Lox-Stop-Lox-c-MycT58A p53fl/+ knockin genetically engineered mouse model (GEMM). Phenotypically, the Myc-knockin GEMM had rapid tumor development with a high incidence of metastasis. MYC-dependent gene signatures in our murine model demonstrated significant homology to the human hyperactivated MYC OS. We established that …

Roving Methyltransferases Generate A Mosaic Epigenetic Landscape And Influence Evolution In Bacteroides Fragilis Group, Michael J Tisza, Derek D N Smith, Andrew E Clark, Jung-Ho Youn, Pavel P Khil, John P Dekker

Faculty, Staff and Students Publications

Three types of DNA methyl modifications have been detected in bacterial genomes, and mechanistic studies have demonstrated roles for DNA methylation in physiological functions ranging from phage defense to transcriptional control of virulence and host-pathogen interactions. Despite the ubiquity of methyltransferases and the immense variety of possible methylation patterns, epigenomic diversity remains unexplored for most bacterial species. Members of the Bacteroides fragilis group (BFG) reside in the human gastrointestinal tract as key players in symbiotic communities but also can establish anaerobic infections that are increasingly multi-drug resistant. In this work, we utilize long-read sequencing technologies to perform pangenomic (n = …

Measuring The Effect Of Newborn Screening On Survival After Haematopoietic Cell Transplantation For Severe Combined Immunodeficiency: A 36-Year Longitudinal Study From The Primary Immune Deficiency Treatment Consortium, Monica S Thakar, Brent R Logan, Jennifer M Puck, Elizabeth A Dunn, Rebecca H Buckley, Morton J Cowan, Richard J O'Reilly, Neena Kapoor, Lisa Forbes Satter, Sung-Yun Pai, Jennifer Heimall, Sharat Chandra, Christen L Ebens, Deepak Chellapandian, Olatundun Williams, Lauri M Burroughs, Blachy Davila Saldana, Ahmad Rayes, Lisa M Madden, Shanmuganathan Chandrakasan, Jeffrey J Bednarski, Kenneth B Desantes, Geoffrey D E Cuvelier, Pierre Teira, Alfred P Gillio, Hesham Eissa, Alan P Knutsen, Frederick D Goldman, Victor M Aquino, Evan B Shereck, Theodore B Moore, Emi H Caywood, Mark T Vander Lugt, Jacob Rozmus, Larisa Broglie, Lolie C Yu, Ami J Shah, Jeffrey R Andolina, Xuerong Liu, Roberta E Parrott, Jasmeen Dara, Susan Prockop, Caridad A Martinez, Malika Kapadia, Soma C Jyonouchi, Kathleen E Sullivan, Jack J Bleesing, Sonali Chaudhury, Aleksandra Petrovic, Michael D Keller, Troy C Quigg, Suhag Parikh, Shalini Shenoy, Christine Seroogy, Tamar Rubin, Hélène Decaluwe, John M Routes, Troy R Torgerson, Jennifer W Leiding, Michael A Pulsipher, Donald B Kohn, Linda M Griffith, Elie Haddad, Christopher C Dvorak, Luigi D Notarangelo

Faculty, Staff and Students Publications

Background: Severe combined immunodeficiency (SCID) is fatal unless durable adaptive immunity is established, most commonly through allogeneic haematopoietic cell transplantation (HCT). The Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades, focusing on the effects of population-based newborn screening for SCID that was initiated in 2008 and expanded during 2010-18.

Methods: We analysed transplantation-related data from children with SCID treated at 34 PIDTC sites in the USA and Canada, using the calendar time intervals 1982-89, 1990-99, 2000-09, and 2010-18. Categorical variables were compared by χ2 test and continuous outcomes by …

Vitamin B2 Enables Regulation Of Fasting Glucose Availability, Peter M Masschelin, Pradip Saha, Scott A Ochsner, Aaron R Cox, Kang Ho Kim, Jessica B Felix, Robert Sharp, Xin Li, Lin Tan, Jun Hyoung Park, Liping Wang, Vasanta Putluri, Philip L Lorenzi, Alli M Nuotio-Antar, Zheng Sun, Benny Abraham Kaipparettu, Nagireddy Putluri, David D Moore, Scott A Summers, Neil J Mckenna, Sean M Hartig

Faculty, Staff and Students Publications

Flavin adenine dinucleotide (FAD) interacts with flavoproteins to mediate oxidation-reduction reactions required for cellular energy demands. Not surprisingly, mutations that alter FAD binding to flavoproteins cause rare inborn errors of metabolism (IEMs) that disrupt liver function and render fasting intolerance, hepatic steatosis, and lipodystrophy. In our study, depleting FAD pools in mice with a vitamin B2-deficient diet (B2D) caused phenotypes associated with organic acidemias and other IEMs, including reduced body weight, hypoglycemia, and fatty liver disease. Integrated discovery approaches revealed B2D tempered fasting activation of target genes for the nuclear receptor PPARα, including those required for gluconeogenesis. We also found …

Membrane Translocation Process Revealed By In Situ Structures Of Type Ii Secretion System Secretins, Zhili Yu, Yaoming Wu, Muyuan Chen, Tong Huo, Wei Zheng, Steven J Ludtke, Xiaodong Shi, Zhao Wang

Faculty, Staff and Students Publications

The GspD secretin is the outer membrane channel of the bacterial type II secretion system (T2SS) which secrets diverse toxins that cause severe diseases such as diarrhea and cholera. GspD needs to translocate from the inner to the outer membrane to exert its function, and this process is an essential step for T2SS to assemble. Here, we investigate two types of secretins discovered so far in Escherichia coli, GspDα, and GspDβ. By electron cryotomography subtomogram averaging, we determine in situ structures of key intermediate states of GspDα and GspDβ in the translocation process, with resolution ranging from 9 Å …

Targeting Gbm With An Oncolytic Picornavirus Svv-001 Alone And In Combination With Fractionated Radiation In A Novel Panel Of Orthotopic Pdx Models, Huiyuan Zhang, Yuchen Du, Lin Qi, Sophie Xiao, Frank K Braun, Mari Kogiso, Yulun Huang, Frank Huang, Aalaa Abdallah, Milagros Suarez, Sekar Karthick, Nabil M Ahmed, Vita S Salsman, Patricia A Baxter, Jack M Su, Daniel J Brat, Paul L Hellenbeck, Wan-Yee Teo, Akash J Patel, Xiao-Nan Li

Faculty, Staff and Students Publications

BACKGROUND: Animal models representing different molecular subtypes of glioblastoma multiforme (GBM) is desired for developing new therapies. SVV-001 is an oncolytic virus selectively targeting cancer cells. It's capacity of passing through the blood brain barrier makes is an attractive novel approach for GBM.

MATERIALS AND METHODS: 23 patient tumor samples were implanted into the brains of NOD/SCID mice (1 × 105 cells/mouse). Tumor histology, gene expression (RNAseq), and growth rate of the developed patient-derived orthotopic xenograft (PDOX) models were compared with the originating patient tumors during serial subtransplantations. Anti-tumor activities of SVV-001 were examined in vivo; and therapeutic efficacy validated …

Adjuvanted Fusion Protein Vaccine Induces Durable Immunity To Onchocerca Volvulus In Mice And Non-Human Primates, Nathan M Ryan, Jessica A Hess, Erica J Robertson, Nancy Tricoche, Cheri Turner, Jenn Davis, Nikolai Petrovsky, Melissa Ferguson, William J Rinaldi, Valerie M Wong, Ayako Shimada, Bin Zhan, Maria Elena Bottazzi, Benjamin L Makepeace, Sean A Gray, Darrick Carter, Sara Lustigman, David Abraham

Faculty, Staff and Students Publications

Onchocerciasis remains a debilitating neglected tropical disease. Due to the many challenges of current control methods, an effective vaccine against the causative agent Onchocerca volvulus is urgently needed. Mice and cynomolgus macaque non-human primates (NHPs) were immunized with a vaccine consisting of a fusion of two O. volvulus protein antigens, Ov-103 and Ov-RAL-2 (Ov-FUS-1), and three different adjuvants: Advax-CpG, alum, and AlT4. All vaccine formulations induced high antigen-specific IgG titers in both mice and NHPs. Challenging mice with O. volvulus L3 contained within subcutaneous diffusion chambers demonstrated that Ov-FUS-1/Advax-CpG-immunized animals developed protective immunity, durable for …

Anti-Scg3 Gene Therapy To Treat Choroidal Neovascularization In Mice, Chengchi Huang, Liyang Ji, Avinash Kaur, Hong Tian, Prabuddha Waduge, Keith A Webster, Wei Li

Faculty, Staff and Students Publications

Neovascular age-related macular degeneration (nAMD) with choroidal neovascularization (CNV) is a leading cause of blindness in the elderly in developed countries. The disease is currently treated with anti-angiogenic biologics, including aflibercept, against vascular endothelial growth factor (VEGF) but with limited efficacy, treatment resistance and requirement for frequent intravitreal injections. Although anti-VEGF gene therapy may provide sustained therapy that obviates multiple injections, the efficacy and side effects related to VEGF pathway targeting remain, and alternative strategies to block angiogenesis independently of VEGF are needed. We recently reported that secretogranin III (Scg3) induces only pathological angiogenesis through VEGF-independent pathways, and Scg3-neutralizing antibodies …

Evaluating The Generalizability Of Predictive Classifiers Built From Desi Imaging Lipid Data Across Mass Spectrometry Platformsjournal Of The American Society For Mass Spectrometry, Rachel J Dehoog, Monica Lin, Gregory Roman, Roy Martin, James Suliburk, Livia S Eberlin

Faculty, Staff and Students Publications

In this study, we evaluate the generalizability of predictive classifiers built from DESI lipid data for thyroid fine needle aspiration (FNA) biopsy analysis and classification using two high-performance mass spectrometers (time-of-flight and orbitrap) suited with different DESI imaging sources operated by different users. The molecular profiles obtained from thyroid samples with the different platforms presented similar trends, although specific differences in ion abundances were observed. When using a previously published statistical model built to discriminate thyroid cancer from benign thyroid tissues to predict on a new independent data set obtained, agreement for 24 of the 30 samples across the imaging …

Tiam1 Coordinates Synaptic Structural And Functional Plasticity Underpinning The Pathophysiology Of Neuropathic Pain, Lingyong Li, Qin Ru, Yungang Lu, Xing Fang, Guanxing Chen, Ali Bin Saifullah, Changqun Yao, Kimberley F Tolias

Faculty, Staff and Students Publications

Neuropathic pain is a common, debilitating chronic pain condition caused by damage or a disease affecting the somatosensory nervous system. Understanding the pathophysiological mechanisms underlying neuropathic pain is critical for developing new therapeutic strategies to treat chronic pain effectively. Tiam1 is a Rac1 guanine nucleotide exchange factor (GEF) that promotes dendritic and synaptic growth during hippocampal development by inducing actin cytoskeletal remodeling. Here, using multiple neuropathic pain animal models, we show that Tiam1 coordinates synaptic structural and functional plasticity in the spinal dorsal horn via actin cytoskeleton reorganization and synaptic NMDAR stabilization and that these actions are essential for the …

A Comprehensive Analysis Of Lung Cancer Highlighting Epidemiological Factors And Psychiatric Comorbidities From The All Of Us Research Program, Vikram R Shaw, Jinyoung Byun, Rowland W Pettit, Younghun Han, David A Hsiou, Luke A Nordstrom, Christopher I Amos

Faculty, Staff and Students Publications

Lung cancer is the leading cause of cancer-related mortality in the United States. Investigating epidemiological and clinical parameters can contribute to an improved understanding of disease development and management. In this cross-sectional, case-control study, we used the All of Us database to compare healthcare access, family history, smoking-related behaviors, and psychiatric comorbidities in light smoking controls, matched smoking controls, and primary and secondary lung cancer patients. We found a decreased odds of primary lung cancer patients versus matched smoking controls reporting inability to afford follow-up or specialist care. Additionally, we found a significantly increased odds of secondary lung cancer patients …

Circadian Disruption And Colorectal Cancer Incidence In Black Women, Lauren E Barber, Trang Vopham, Laura F White, Hemant K Roy, Julie R Palmer, Kimberly A Bertrand

Faculty, Staff and Students Publications

BACKGROUND: Animal and experimental studies suggest circadian disruption increases colorectal cancer risk, but evidence in humans is limited. We examined night shift work, chronotype, and residential position within a time zone, proxies for circadian disruption, in relation to colorectal cancer risk.

METHODS: Participants in the Black Women's Health Study, a prospective cohort of 59,000 Black American women established in 1995, reported history of night shift work and chronotype on follow-up questionnaires. Residential position within a time zone was estimated using participant addresses at each questionnaire cycle. Number of colorectal cancer cases and follow-up duration varied by analysis depending on timing …

Dynamic Functional Thalamocortical Dysconnectivity In Schizophrenia Correlates To Antipsychotics Response, Mi Yang, Liju Liu, Hongmei Cui, Chijun Deng, Weisen Xiong, Guocheng Zhao, Shulin Du, Thomas R Kosten, Huafu Chen, Zezhi Li, Xiangyang Zhang

Faculty, Staff and Students Publications

Although many studies have showed abnormal thalamocortical networks in patients with schizophrenia (SCZ), the dynamic functional thalamocortical connectivity of individuals with SCZ and the effect of antipsychotics on this connectivity have not been investigated. Drug-naïve first-episode individuals with SCZ and healthy controls were recruited. Patients were treated with risperidone for 12 weeks. Resting-state functional magnetic resonance imaging was acquired at baseline and week 12. We identified six functional thalamic subdivisions. The sliding window strategy was used to determine the dynamic functional connectivity (dFC) of each functional thalamic subdivision. Individuals with SCZ displayed decreased or increased dFC variance in different thalamic …

Association Between Historical Neighborhood Redlining And Cardiovascular Outcomes Among Us Veterans With Atherosclerotic Cardiovascular Diseases, Salil V Deo, Issam Motairek, Khurram Nasir, Amgad Mentias, Yakov Elgudin, Salim S Virani, Sanjay Rajagopalan, Sadeer Al-Kindi

Faculty, Staff and Students Publications

Importance: In the 1930s, the government-sponsored Home Owners' Loan Corporation (HOLC) established maps of US neighborhoods that identified mortgage risk (grade A [green] characterizing lowest-risk neighborhoods in the US through mechanisms that transcend traditional risk factors to grade D [red] characterizing highest risk). This practice led to disinvestments and segregation in neighborhoods considered redlined. Very few studies have targeted whether there is an association between redlining and cardiovascular disease.

Objective: To evaluate whether redlining is associated with adverse cardiovascular outcomes in US veterans.

Design, setting, and participants: In this longitudinal cohort study, US veterans were followed up (January 1, 2016, …

Circular Rna As Therapeutic Targets In Atherosclerosis: Are We Running In Circles?, Jeffrey Triska, Christo Mathew, Yang Zhao, Yuqing E Chen, Yochai Birnbaum

Faculty, Staff and Students Publications

Much attention has been paid lately to harnessing the diagnostic and therapeutic potential of non-coding circular ribonucleic acids (circRNAs) and micro-RNAs (miRNAs) for the prevention and treatment of cardiovascular diseases. The genetic environment that contributes to atherosclerosis pathophysiology is immensely complex. Any potential therapeutic application of circRNAs must be assessed for risks, benefits, and off-target effects in both the short and long term. A search of the online PubMed database for publications related to circRNA and atherosclerosis from 2016 to 2022 was conducted. These studies were reviewed for their design, including methods for developing atherosclerosis and the effects of the …

Radiological-Histopathological Discordance In Patients Transplanted For Hcc And Its Impact On Post-Transplant Outcomes, Islam B Mohamed, Mohamed Saleh Ismail, Ahmed El Sabagh, Ahmed M Afifi Abdelwahab, Efstathia Polychronopoulou, Yong-Fang Kuo, Manal Hassan, John A Goss, Fasiha Kanwal, Prasun K Jalal

Faculty, Staff and Students Publications

BACKGROUND AND AIMS: Contrast-enhanced cross-sectional imaging is the cornerstone in the diagnosis, staging, and management of HCC, including eligibility for liver transplantation (LT). Radiological-histopathological discordance may lead to improper staging and may impact patient outcomes. We aimed to assess the radiological-histopathological discordance at the time of LT in HCC patients and its impact on the post-LT outcomes.

METHODS: We analyzed further the effect of 6-month waiting policy on the discordance. Using United Network for Organ Sharing-Organ Procurement and Transplantation Network (UNOS-OPTN) database, we examined the discordance between pre-LT imaging and explant histopathology for all adult HCC patients who received liver …

Current Programs And Incentives To Overcome Rural Physician Shortages In The United States: A Narrative Review, Kelley Arredondo, Hilary N Touchett, Sundas Khan, Matthew Vincenti, Bradley V Watts

Faculty, Staff and Students Publications

Access to healthcare continues to be a top priority and prominent challenge in rural communities, with 20% of the total U.S. population living in rural areas while only 10% of physicians practice in rural areas. In response to physician shortages, a variety of programs and incentives have been implemented to recruit and retain physicians in rural areas; however, less is known about the types and structures of incentives that are offered in rural areas and how that compares to physician shortages. The purpose of our study is to conduct a narrative review of the literature to identify and compare current …

External Validation Of A Novel Electronic Risk Score For Cancer-Associated Thrombosis In A Comprehensive Cancer Center, Ang Li, Giordana De Las Pozas, Clark R Andersen, Chijioke C Nze, Katy M Toale, Emily M Milner, Nathanael R Fillmore, Elizabeth Yu Chiao, Cristhiam Rojas Hernandez, Michael H Kroll, Kelly W Merriman, Christopher R Flowers

Faculty, Staff and Students Publications

Venous thromboembolism (VTE) is a significant complication for cancer patients undergoing systemic therapy. We performed an independent external validation for a recently derived and validated a novel electronic health record (EHR) VTE risk score in a comprehensive cancer center. Adult patients with incident cancer diagnoses were identified from MD Anderson Cancer Center Tumor Registry 1/2017-1/2021. Baseline covariates extracted at the time of first-line systemic therapy included demographics, cancer site/histology, stage, treatment, complete blood count, body mass index, recent prolonged hospitalization, and history of VTE or paralysis. VTE was ascertained using an institution-specific natural language processing radiology algorithm (positive predictive value …

Candidemia In Patients With Cardiovascular Implantable Electronic Devices: Uncertainty In Management Based On Current International Guidelines, Supavit Chesdachai, Larry M Baddour, M Rizwan Sohail, Bharath Raj Palraj, Malini Madhavan, Hussam Tabaja, Madiha Fida, Douglas W Challener, Daniel C Desimone

Faculty, Staff and Students Publications

BACKGROUND: In contrast to bloodstream infection due to a variety of bacteria in patients with cardiovascular implantable electronic devices (CIED), there are limited data regarding candidemia and risk of CIED infection.

METHODS: All patients with candidemia and a CIED at Mayo Clinic Rochester between 2012 and 2019 were reviewed. Cardiovascular implantable electronic device infection was defined by (1) clinical signs of pocket site infection or (2) echocardiographic evidence of lead vegetations.

RESULTS: A total of 23 patients with candidemia had underlying CIED; 9 (39.1%) cases were community onset. None of the patients had pocket site infection. The duration between CIED …

Designing A Local Policy To Reduce Hiv In Mexico City, Mayar Al Mohajer

Faculty, Staff and Students Publications

The Joint United Nations Program on human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) (Joint United Nations Program on HIV/AIDS, UNAIDS) has recommended 90-90-90 goals to increase the number of patients who are aware of their status, on antiretroviral therapy, and have undetectable viral loads. Mexico City has made several achievements to aid in prevention, early diagnosis, and treatment; however, the incidence of HIV has not decreased over the past decade. This article reviews global initiatives that were successful in achieving some or all these metrics and provide a road map for Mexico to reach the desired goals.

Artist's Statement: Foreground/Background, Tahira Scholle

Faculty, Staff and Students Publications

No abstract provided.

Association Of Chronic Pancreatitis Pain Features With Physical, Mental, And Social Health, Dhiraj Yadav, Robert L Askew, Tonya Palermo, Liang Li, Dana K Andersen, Minxing Chen, William E Fisher, Evan L Fogel, Christopher E Forsmark, Phil A Hart, Mohamed O Othman, Stephen J Pandol, Walter G Park, Mark D Topazian, Stephen K Van Den Eeden, Santhi Swaroop Vege, Yunlong Yang, Jose Serrano, Darwin L Conwell, Consortium For The Study Of Chronic Pancreatitis, Diabetes, Pancreatic Cancer (Cpdpc)

Faculty, Staff and Students Publications

BACKGROUND AND AIMS: Pain is a cardinal symptom of chronic pancreatitis (CP). Using Patient-Reported Outcomes Measurement Information System (PROMIS) measures, we characterized physical and mental health and symptom profiles of a well-defined cohort of individuals with CP and compared them with control subjects. Among patients with CP, we also examined associations between pain (intensity, temporal nature) and PROMIS symptom profiles and the prevalence of clinically significant psychological comorbidities.

METHODS: We analyzed baseline data in 488 CP patients and 254 control subjects enrolled in PROCEED (Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies), an ongoing longitudinal cohort study. Participants …

The Predictive Performance Of Contemporary Guideline Recommendations For Helicobacter Pylori Testing In A United States Population, Theresa Nguyen Wenker, Frederick B Peng, Ikenna Emelogu, Niharika Mallepally, Fasiha Kanwal, Hashem B El-Serag, Mimi C Tan

Faculty, Staff and Students Publications

BACKGROUND: The Houston Consensus Conference and American College of Gastroenterology (ACG) have recommended Helicobacter pylori screening in United States populations with specific risk factors. However, the performance of these guidelines in clinical practice is not known.

METHODS: We identified consecutive patients undergoing upper endoscopy with gastric biopsies for any indication in a safety-net hospital in Houston, TX during January 2015-December 2016. We tested the association between the presence of H pylori (histopathology, stool antigen, urea breath test, immunoglobulin G serology, or prior treatment) and H pylori risk factors using logistic regression models, reported as odds ratios and 95% confidence intervals …

Targeting Aav Vectors To The Central Nervous System By Engineering Capsid-Receptor Interactions That Enable Crossing Of The Blood-Brain Barrier, Qin Huang, Albert T Chen, Ken Y Chan, Hikari Sorensen, Andrew J Barry, Bahar Azari, Qingxia Zheng, Thomas Beddow, Binhui Zhao, Isabelle G Tobey, Cynthia Moncada-Reid, Fatma-Elzahraa Eid, Christopher J Walkey, M Cecilia Ljungberg, William R Lagor, Jason D Heaney, Yujia A Chan, Benjamin E Deverman

Faculty, Staff and Students Publications

Viruses have evolved the ability to bind and enter cells through interactions with a wide variety of cell macromolecules. We engineered peptide-modified adeno-associated virus (AAV) capsids that transduce the brain through the introduction of de novo interactions with 2 proteins expressed on the mouse blood-brain barrier (BBB), LY6A or LY6C1. The in vivo tropisms of these capsids are predictable as they are dependent on the cell- and strain-specific expression of their target protein. This approach generated hundreds of capsids with dramatically enhanced central nervous system (CNS) tropisms within a single round of screening in vitro and secondary validation in vivo …

Covet: A Covariation-Evolutionary Trace Method That Identifies Protein Structure-Function Modules, Daniel M Konecki, Spencer Hamrick, Chen Wang, Melina A Agosto, Theodore G Wensel, Olivier Lichtarge

Faculty, Staff and Students Publications

Measuring the relative effect that any two sequence positions have on each other may improve protein design or help better interpret coding variants. Current approaches use statistics and machine learning but rarely consider phylogenetic divergences which, as shown by Evolutionary Trace studies, provide insight into the functional impact of sequence perturbations. Here, we reframe covariation analyses in the Evolutionary Trace framework to measure the relative tolerance to perturbation of each residue pair during evolution. This approach (CovET) systematically accounts for phylogenetic divergences: at each divergence event, we penalize covariation patterns that belie evolutionary coupling. We find that while CovET approximates …

Pdcl2 Is Essential For Sperm Acrosome Formation And Male Fertility In Mice, Yoshitaka Fujihara, Kiyonori Kobayashi, Ferheen Abbasi, Tsutomu Endo, Zhifeng Yu, Masahito Ikawa, Martin M Matzuk

Faculty, Staff and Students Publications

BACKGROUND: Each year, infertility affects 15% of couples worldwide, with 50% of cases attributed to men. Globozoospermia is an uncommon cause of male factor infertility, characterized by defects in sperm acrosome formation, leading to round-headed spermatozoa.

OBJECTIVE: We generated Pdcl2 knockout mice to investigate the essential roles of PDCL2 in mammalian reproduction.

MATERIALS AND METHODS: We used reverse transcription-polymerase chain reaction to demonstrate that PDCL2 was expressed exclusively in the male reproductive tract in mice and humans. We created Pdcl2 knockout mice using the CRISPR-Cas9 system and analyzed their fertility. Pdcl2 null spermatozoa underwent further evaluation using computer-assisted sperm analysis, …

Remote Neuronal Activity Drives Glioma Progression Through Sema4f, Emmet Huang-Hobbs, Yi-Ting Cheng, Yeunjung Ko, Estefania Luna-Figueroa, Brittney Lozzi, Kathryn R Taylor, Malcolm Mcdonald, Peihao He, Hsiao-Chi Chen, Yuhui Yang, Ehson Maleki, Zhung-Fu Lee, Sanjana Murali, Michael R Williamson, Dongjoo Choi, Rachel Curry, James Bayley, Junsung Woo, Ali Jalali, Michelle Monje, Jeffrey L Noebels, Akdes Serin Harmanci, Ganesh Rao, Benjamin Deneen

Faculty, Staff and Students Publications

The tumor microenvironment (TME) plays an essential role in malignancy and neurons have emerged as a key component of the TME that promotes tumorigenesis across a host of cancers1,2. Recent studies on glioblastoma (GBM) highlight bi-directional signaling between tumors and neurons that propagates a vicious cycle of proliferation, synaptic integration, and brain hyperactivity3-8; however, the identity of neuronal subtypes and tumor subpopulations driving this phenomenon are incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumors promote progression and widespread infiltration. Using this platform …