Digital Commons Network^™

Somatodendritic Orientation Determines Tdcs-Induced Neuromodulation Of Purkinje Cell Activity In Awake Mice, Carlos A Sánchez-León, Guillermo Sánchez-Garrido Campos, Marta Fernández, Álvaro Sánchez-López, Javier F Medina, Javier Márquez-Ruiz

Faculty, Staff and Students Publications

Transcranial direct-current stimulation (tDCS) of the cerebellum is a promising non-invasive neuromodulatory technique being proposed for the treatment of neurological and neuropsychiatric disorders. However, there is a lack of knowledge about how externally applied currents affect neuronal spiking activity in cerebellar circuits in vivo. We investigated how Cb-tDCS affects the firing rate of Purkinje cells (PC) and non-PC in the mouse cerebellar cortex to understand the underlying mechanisms behind the polarity-dependent modulation of neuronal activity induced by tDCS. Mice (n=9) were prepared for the chronic recording of local field potentials (LFPs) to assess the actual electric field gradient imposed by …

Proteogenomic Characterization Of Non-Functional Pancreatic Neuroendocrine Tumors Unravels Clinically Relevant Subgroups, Shunrong Ji, Lihua Cao, Jing Gao, Yang Du, Zeng Ye, Xin Lou, Fen Liu, Yehan Zhang, Junfeng Xu, Xiaohan Shi, Huan Wang, Penghao Li, Yikai Li, Hongxu Chen, Zhicheng Yang, Suizhi Gao, Wuhu Zhang, Dan Huang, Shujuan Ni, Miaoyan Wei, Fei Wang, Yan Wang, Tian Ding, Desheng Jing, Guixiong Fan, Zhiyun Gong, Renquan Lu, Yi Qin, Jie Chen, Xiaowu Xu, Pei Wang, Bing Zhang, Li Ding, Ana I Robles, Henry Rodriguez, David K Chang, Ralph H Hruban, Dong Gao, Daming Gao, Gang Jin, Hu Zhou, Jianmin Wu, Xianjun Yu

Faculty, Staff and Students Publications

The majority of neuroendocrine neoplasms in pancreas are non-functional pancreatic neuroendocrine tumors (NF-PanNETs), which exhibit a high occurrence of distant metastases with limited therapeutic options. Here, we perform a comprehensive molecular characterization of 108 NF-PanNETs through integrative analysis of genomic, transcriptomic, proteomic, and phosphoproteomic profiles. Proteogenomic analysis provides functional insights into the genomic driver alterations of NF-PanNETs, revealing a potential mediator of MEN1 alterations using Men1-conditional knockout mice. Machine-learning-based modeling uncovers a three-protein signature as an independent prognostic factor, which is validated by an independent external cohort. Proteomic and phosphoproteomic-based stratification identifies four subtypes with distinct molecular characteristics, immune microenvironments, …

Pilot First-In-Human Ccr2 Pet/Ct To Detect Abdominal Aortic Aneurysm Wall Instability, Santiago Elizondo-Benedetto, Deborah Sultan, Ryan Wahidi, Mahdjoub Hamdi, Mohamed S Zaghloul, Shahab Hafezi, Batool Arif, Laura K Mcdonald, Kitty Harrison, Dakkota Thies, Gyu Seong Heo, Hannah Luehmann, Lisa Detering, J Westley Ohman, Zachary J Wanken, Luis A Sanchez, Joseph E Ippolito, Jie Zheng, Robert J Gropler, Richard Laforest, Yongjian Liu, Mohamed A Zayed

2020-Current year OA Pubs

No abstract provided.

Disc Edema Secondary To Sleep Apnea: A Case Report, Jeannette A. Wong-Powell Od

Optometric Clinical Practice

Background: Bilateral optic disc edema is associated with multiple systemic conditions of potentially dire consequences. Idiopathic intracranial hypertension (IIH) is a common culprit and diagnosis of exclusion, which has been observed in multiple patients with obstructive sleep apnea (OSA) and raised questions of a pathophysiological link between the two.

Case Report: A 28-year-old Caucasian male with history of transient ischemic attack-like symptoms presented with bilateral disc edema prompting a multi-disciplinary work up that included imaging, lumbar puncture, laboratory analysis, neuroophthalmological, cardiological, and pulmonary evaluations that ultimately led to a diagnosis of OSA. The case is unique in that it followed …

A Space-Occupying Lesion Manifesting As Unilateral Optic Disc Edema, Len V. Koh Od, Phd, Anna Wells Od, Lindsay Jansen Od

Optometric Clinical Practice

Background: Primary and secondary orbital diseases can arise from different tissues in the periorbital regions as space-occupying lesion leading to ophthalmic symptoms. Therefore, eye care providers are often the first encounter for these patients.

Case report: A 54-year-old Caucasian male presented as a new patient at the eye clinic with an incidental finding of edema of the left optic disc. After a thorough optometric evaluation, a referral was made to a local ear-nose-throat (ENT) specialist who confirmed a diagnosis of cavernous hemangioma by further neuroimaging. Surgical removal eventuated in resolution of disc edema with restoration of vision.

Conclusion: An insidious …

Large-Scale Multi-Omics Analyses In Hispanic/Latino Populations Identify Genes For Cardiometabolic Traits, Lauren E Petty, Hung-Hsin Chen, Elizabeth G Frankel, Wanying Zhu, Carolina G Downie, Mariaelisa Graff, Phillip Lin, Priya Sharma, Xinruo Zhang, Alyssa C Scartozzi, Rashedeh Roshani, Joshua M Landman, Michael Boehnke, Donald W Bowden, John C Chambers, Anubha Mahajan, Mark I Mccarthy, Maggie C Y Ng, Xueling Sim, Cassandra N Spracklen, Weihua Zhang, Michael Preuss, Erwin P Bottinger, Girish N Nadkarni, Ruth J F Loos, Yii-Der Ida Chen, Jingyi Tan, Eli Ipp, Pauline Genter, Leslie S Emery, Tin Louie, Tamar Sofer, Adrienne M Stilp, Kent D Taylor, Anny H Xiang, Thomas A Buchanan, Kathryn Roll, Chuan Gao, Nicholette D Palmer, Jill M Norris, Lynne E Wagenknecht, Darryl Nousome, Rohit Varma, Roberta Mckean-Cowdin, Xiuqing Guo, Yang Hai, Willa Hsueh, Kevin Sandow, Esteban J Parra, Miguel Cruz, Adan Valladares-Salgado, Niels Wacher-Rodarte, Jerome I Rotter, Mark O Goodarzi, Stephen S Rich, Alain Bertoni, Leslie J Raffel, Jerry L Nadler, Fouad R Kandeel, Ravindranath Duggirala, John Blangero, Donna M Lehman, Ralph A Defronzo, Farook Thameem, Yujie Wang, Sheila Gahagan, Estela Blanco, Raquel Burrows, Alicia Huerta-Chagoya, Jose C Florez, Teresa Tusie-Luna, Clicerio González-Villalpando, Lorena Orozco, Christopher A Haiman, Craig L Hanis, Rebecca Rohde, Eric A Whitsel, Alexander P Reiner, Charles Kooperberg, Yun Li, Qing Duan, Miryoung Lee, Paulina Correa-Burrows, Susan K Fried, Kari E North, Joseph B Mccormick, Susan P Fisher-Hoch, Eric R Gamazon, Andrew P Morris, Josep M Mercader, Heather M Highland, Jennifer E Below

Faculty, Staff and Student Publications

Here, we present a multi-omics study of type 2 diabetes and quantitative blood lipid and lipoprotein traits conducted to date in Hispanic/Latino populations (nmax = 63,184). We conduct a meta-analysis of 16 type 2 diabetes and 19 lipid trait GWAS, identifying 20 genome-wide significant loci for type 2 diabetes, including one novel locus and novel signals at two known loci, based on fine-mapping. We also identify sixty-one genome-wide significant loci across the lipid/lipoprotein traits, including nine novel loci, and novel signals at 19 known loci through fine-mapping. Next, we analyze genetically regulated expression, perform Mendelian randomization, and analyze association with …

Whole Genome Sequencing Analysis Of Body Mass Index Identifies Novel African Ancestry-Specific Risk Allele, Xinruo Zhang, Jennifer A Brody, Mariaelisa Graff, Heather M Highland, Nathalie Chami, Hanfei Xu, Zhe Wang, Kendra R Ferrier, Geetha Chittoor, Navya Shilpa Josyula, Mariah Meyer, Shreyash Gupta, Xihao Li, Zilin Li, Matthew A Allison, Diane M Becker, Lawrence F Bielak, Joshua C Bis, Meher Preethi Boorgula, Donald W Bowden, Jai G Broome, Erin J Buth, Christopher S Carlson, Kyong-Mi Chang, Sameer Chavan, Yen-Feng Chiu, Lee-Ming Chuang, Matthew P Conomos, Dawn L Demeo, Mengmeng Du, Ravindranath Duggirala, Celeste Eng, Alison E Fohner, Barry I Freedman, Melanie E Garrett, Xiuqing Guo, Chris Haiman, Benjamin D Heavner, Bertha Hidalgo, James E Hixson, Yuk-Lam Ho, Brian D Hobbs, Donglei Hu, Qin Hui, Chii-Min Hwu, Rebecca D Jackson, Deepti Jain, Rita R Kalyani, Sharon L R Kardia, Tanika N Kelly, Ethan M Lange, Michael Lenoir, Changwei Li, Loic Le Marchand, Merry-Lynn N Mcdonald, Caitlin P Mchugh, Alanna C Morrison, Take Naseri, Jeffrey O'Connell, Christopher J O'Donnell, Nicholette D Palmer, James S Pankow, James A Perry, Ulrike Peters, Michael H Preuss, D C Rao, Elizabeth A Regan, Sefuiva M Reupena, Dan M Roden, Jose Rodriguez-Santana, Colleen M Sitlani, Jennifer A Smith, Hemant K Tiwari, Ramachandran S Vasan, Zeyuan Wang, Daniel E Weeks, Jennifer Wessel, Kerri L Wiggins, Lynne R Wilkens, Peter W F Wilson, Lisa R Yanek, Zachary T Yoneda, Wei Zhao, Sebastian Zöllner, Donna K Arnett, Allison E Ashley-Koch, Kathleen C Barnes, John Blangero, Eric Boerwinkle, Esteban G Burchard, April P Carson, Daniel I Chasman, Yii-Der Ida Chen, Joanne E Curran, Myriam Fornage, Victor R Gordeuk, Jiang He, Susan R Heckbert, Lifang Hou, Marguerite R Irvin, Charles Kooperberg, Ryan L Minster, Braxton D Mitchell, Mehdi Nouraie, Bruce M Psaty, Laura M Raffield, Alexander P Reiner, Stephen S Rich, Jerome I Rotter, M Benjamin Shoemaker, Nicholas L Smith, Kent D Taylor, Marilyn J Telen, Scott T Weiss, Yingze Zhang, Nancy Heard-Costa, Yan V Sun, Xihong Lin, L Adrienne Cupples, Leslie A Lange, Ching-Ti Liu, Ruth J F Loos, Kari E North, Anne E Justice

Faculty, Staff and Student Publications

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P <  5 × 10

Natural Killer Cells’ Functional Impairment Drives The Immune Escape Of Pre-Malignant Clones In Early-Stage Myelodysplastic Syndromes, Juan Jose Rodriguez-Sevilla, Irene Ganan-Gomez, Bijender Kumar, Natthakan Thongon, Feiyang Ma, Kelly S Chien, Yi J Kim, Hui Yang, Sanam Loghavi, Roselyn Tan, Vera Adema, Zongrui Li, Tomoyuki Tanaka, Hidetaka Uryu, Rashmi Kanagal-Shamanna, Gheath Al-Atrash, Rafael Bejar, Pinaki Prosad Banerjee, Sophia Lynn Cha, Guillermo Montalban-Bravo, Max Dougherty, Maria Claudina Fernandez Laurita, Noelle Wheeler, Baosen Jia, Eirini P Papapetrou, Franco Izzo, Daniela E Dueñas, Salome Mcallen, Yiqian Gu, Gabriele Todisco, Francesca Ficara, Matteo Giovanni Della Porta, Abhinav Jain, Koichi Takahashi, Karen Clise-Dwyer, Stephanie Halene, Maria Teresa Sabrina Bertilaccio, Guillermo Garcia-Manero, May Daher, Simona Colla

Faculty, Staff and Student Publications

Dissecting the preneoplastic disease states' biological mechanisms that precede tumorigenesis can lead to interventions that can slow down disease progression and/or mitigate disease-related comorbidities. Myelodysplastic syndromes (MDS) cannot be cured by currently available pharmacological therapies, which fail to eradicate aberrant hematopoietic stem cells (HSCs), most of which are mutated by the time of diagnosis. Here, we sought to elucidate how MDS HSCs evade immune surveillance and expand in patients with clonal cytopenias of undetermined significance (CCUS), the pre-malignant stage of MDS. We used multi-omic single-cell approaches and functional in vitro studies to show that immune escape at disease initiation is …

Do Patients Want Their Spirituality Addressed During Their Hospital Journey; A Cross-Sectional Study At A Tertiary Care Center In Lebanon, Mohammad Assaf, Ali Ahmad, Hanine Atwi, Joseph Habib, Magda Haj, Reham Yehia, Amal C Rahi, Marianne Majdalani

Faculty, Staff and Student Publications

Background: Spirituality (including religiosity) is a powerful concept in Middle Eastern populations for members of all religious affiliations. This study aims to assess the desire of cancer and critically ill adult inpatients to be asked about their spiritual history, the impact their religious and spiritual beliefs have on their medical decisions, and if such beliefs help them cope with their illnesses.

Methods: A questionnaire consisting of demographics and spirituality questions was developed and administered to 100 patients in a cross-sectional study. We performed psychometric analysis of the questionnaire through reliability and validity testing including construct validity using PCA with a …

Whole Genome Sequencing Analysis Of Body Mass Index Identifies Novel African Ancestry-Specific Risk Allele, Xinruo Zhang, D C Rao, Et Al.

2020-Current year OA Pubs

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P <  5 × 10

Behavioral And Psychological Symptoms Of Dementia And Alzheimer's Disease Progression In Down Syndrome, Melissa R Jenkins, Beau M Ances, Et Al.

2020-Current year OA Pubs

BACKGROUND: Adults with Down syndrome (DS) have a 90% lifetime risk for Alzheimer's disease (AD), with neurobiological pathology present decades prior to dementia onset. The profile and timing of cognitive decline in DS is well-documented. However, there is a small body of research on whether Behavioral and Psychological Symptoms of Dementia (BPSD) occur early on in the progression of AD in DS and are associated with early AD pathology (i.e., amyloid-beta [Aβ] and neurofibrillary tau tangles [NFT]).

METHODS: Data were analyzed from 337 adults with DS (M = 45.13 years, SD = 9.53 years) enrolled in a large cohort study. …

Lipoprotein(A) And Risk Of Incident Atherosclerotic Cardiovascular Disease: Impact Of High-Sensitivity C-Reactive Protein And Risk Variability Among Human Clinical Subgroups, Ron C Hoogeveen, Margaret R Diffenderfer, Elise Lim, Ching-Ti Liu, Hiroaki Ikezaki, Weihua Guan, Michael Y Tsai, Christie M Ballantyne

Faculty, Staff and Students Publications

No abstract provided.

Her2-Selective Tyrosine Kinase Inhibitor, Zongertinib (Bi 1810631), In Patients With Advanced/Metastatic Solid Tumors With Her2 Alterations: A Phase Ia Dose-Escalation Study, John V Heymach, Frans Opdam, Minal Barve, Hai-Yan Tu, Yi-Long Wu, David Berz, Lukas Schröter, Yanick Botilde, Behbood Sadrolhefazi, Josep Serra, Kiyotaka Yoh, Noboru Yamamoto

Faculty, Staff and Student Publications

Purpose: Human epidermal growth factor receptor 2 (HER2) alterations occur in many solid cancers, including non-small cell lung cancer (NSCLC). Beamion LUNG-1 (ClinicalTrials.gov identifier: NCT04886804) is assessing the safety/efficacy of zongertinib (BI 1810631), a novel HER2-selective tyrosine kinase inhibitor that spares epidermal growth factor receptor, in patients with HER2-altered solid tumors.

Materials and methods: Beamion LUNG-1 is an ongoing multicenter, multicohort phase Ia/Ib trial. Phase Ia assessed zongertinib administered twice a day (15-150 mg) or once daily (60-360 mg) in pretreated patients with various tumors, including NSCLC. Primary end points were maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs); …

An Open-Label Study Evaluating The Safety And Efficacy Of Amo-01 For The Treatment Of Seizures In Phelan-Mcdermid Syndrome, Tess Levy, J Lloyd Holder, Joseph P Horrigan, Michael F Snape, Alison Mcmorn, Christina Layton, Hailey Silver, Kate Friedman, Hannah Grosman, Slayton Underwood, Danielle Halpern, Jessica Zweifach, Paige M Siper, Alexander Kolevzon

Duncan NRI Faculty and Staff Publications

Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene. Approximately 25% of individuals with PMS have epilepsy. Treatment of epilepsy in PMS may require multiple anticonvulsants, and in a minority of cases, seizures remain poorly controlled. Converging lines of evidence in different experimental models indicate that the Ras-ERK pathway is implicated in the pathophysiology of seizure generation and neurobehavioral symptoms in PMS. The goal of this study was to evaluate the safety, tolerability, and efficacy in treating seizures in adults and adolescents with PMS using AMO-01, a Ras-ERK pathway inhibitor. A single 6-hour intravenous infusion …

The Human Brainstem's Red Nucleus Was Upgraded To Support Goal-Directed Action, Samuel R Krimmel, Timothy O Laumann, Roselyne J Chauvin, Tamara Hershey, Jarod L Roland, Joshua S Shimony, Jon T Willie, Scott A Norris, Scott Marek, Andrew N Van, Anxu Wang, Julia Monk, Kristen M Scheidter, Forrest I Whiting, Nadeshka Ramirez-Perez, Athanasia Metoki, Noah J Baden, Benjamin P Kay, Hadas Nahman-Averbuch, Abraham Z Snyder, Marcus E Raichle, Evan M Gordon, Nico U F Dosenbach, Et Al.

2020-Current year OA Pubs

The red nucleus, a large brainstem structure, coordinates limb movement for locomotion in quadrupedal animals. In humans, its pattern of anatomical connectivity differs from that of quadrupeds, suggesting a different purpose. Here, we apply our most advanced resting-state functional connectivity based precision functional mapping in highly sampled individuals (n = 5), resting-state functional connectivity in large group-averaged datasets (combined n ~ 45,000), and task based analysis of reward, motor, and action related contrasts from group-averaged datasets (n > 1000) and meta-analyses (n > 14,000 studies) to precisely examine red nucleus function. Notably, red nucleus functional connectivity with motor-effector networks (somatomotor hand, foot, …

Sociodemographic Differences In Logins And Engagement With The Electronic Health Coach Messaging Feature Of A Mobile App To Support Opioid And Stimulant Use Recovery: Results From A 1-Month Observational Study, Lindsey M Filiatreau, Hannah Szlyk, Alex T Ramsey, Erin Kasson, Xiao Li, Zhuoran Zhang, Patricia Cavazos-Rehg

2020-Current year OA Pubs

BACKGROUND: Mobile health apps can serve as a critical tool in supporting the overall health of uninsured and underinsured individuals and groups who have been historically marginalized by the medical community and may be hesitant to seek health care. However, data on uptake and engagement with specific app features (eg, in-app messaging) are often lacking, limiting our ability to understand nuanced patterns of app use.

OBJECTIVE: This study aims to characterize sociodemographic differences in uptake and engagement with a smartphone app (uMAT-R) to support recovery efforts in a sample of individuals with opioid and stimulant use disorders in the Greater …

Early Nintedanib Deployment In Covid-19 Interstitial Lung Disease (Endcov-I): Study Protocol Of A Randomised, Double-Blind, Placebo-Controlled Trial, Valeria Santibanez, Aditi Mathur, Jigna Zatakia, Nicole Ng, Michele Cohen, Emilia Bagiella, Stacey-Ann Brown, Ivan O Rosas, Nina M Patel, Amy Olson, Peide Li, Maria Padilla

Faculty, Staff and Students Publications

Introduction: In December 2019, the novel SARS-CoV-2 triggered a global pneumonia outbreak, leading to millions of deaths worldwide. A subset of survivors faces increased morbidity and mortality, particularly due to subacute lung injury evolving to chronic fibrosing interstitial lung disease. While nintedanib, a tyrosine-kinase inhibitor, shows promise in treating progressive fibrotic lung disease, limited randomised trial data exists for post-COVID-19-induced lung injury. We hypothesise that treatment with nintedanib may attenuate advancement to the fibrotic stages, offering a potential avenue for improving outcomes in this specific patient subset.

Methods and analysis: We describe the design of a multicentre, randomised, double-blind, placebo-controlled …

Effects Of Metformin Use On Aneurysmal Subarachnoid Hemorrhage Outcomes, Angel Bueno, Andrea Becerril-Gaitan, Collins Mokua, Kristina Ramirez-Garcia, Justin Nguyen, Faris Shaker, Tien Nguyen, Antonio Dono, Spiros Blackburn, Peng Roc Chen, Mark Dannenbaum, H Alex Choi, Arthur L Day, Jacques J Morcos, Ching-Jen Chen

Faculty, Staff and Student Publications

Background: Metformin is widely prescribed and has neuroprotective effects in animals, but its impact on brain injury after aneurysmal subarachnoid hemorrhage (aSAH) in humans is unclear.

Methods: This single-center retrospective review assessed patients with aSAH from 2009 to 2023, categorizing them based on pre-admission metformin use. The primary outcome was delayed cerebral ischemia (DCI), while secondary outcomes included in-hospital mortality, rebleeding, angiographic cerebral vasospasm (CVS), and favorable modified Rankin Scale (mRS) scores at discharge and the 3-month follow-up. Outcomes were analyzed using logistic regression. Sensitivity analysis was performed after excluding patients receiving comfort care.

Results: A total of 900 patients …

Heterozygous Hereditary Vitamin D-Dependent Rickets Type 2a (Vddr2a) In A Patient Presenting With Pseudoarthrosis, Risa Goldberg, Gunjan Umarji, Serge Jabbour

Division of Endocrinology, Diabetes and Metabolic Diseases Faculty Papers

This case report is centered on an atypical presentation of Hereditary Vitamin D-dependent Rickets 2A (VDDR2A), a rare disorder caused by defects in the gene encoding the vitamin D receptor (VDR). While this disorder is primarily autosomal recessive in inheritance, this case demonstrates that a single heterozygous variant in the VDR gene could be linked to both phenotypic and laboratory manifestations of this condition. To understand the pathogenesis of this condition, one must know the typical roles of vitamin D, calcium, and parathyroid hormone (PTH) in maintaining homeostasis in the body. This case report focuses on the underlying pathogenesis of …

Impact Of Perioperative Organ Injury On Morbidity And Mortality In 28 Million Surgical Patients, Felix Kork, Yafen Liang, Adit A Ginde, Xiaoyi Yuan, Rolf Rossaint, Hongfang Liu, Alex S Evers, Holger K Eltzschig

2020-Current year OA Pubs

Perioperative organ injury contributes to morbidity and mortality of surgical patients. This cohort study included all elective and emergent surgeries in Germany over 4 years to address the impact of perioperative organ injuries on outcomes. We analyzed 28,350,953 cases. In-hospital mortality was 1.4% (n = 393,157), and 4.4% of cases (n = 1,245,898) experienced perioperative organ injury. Perioperative organ injury was associated with 9-fold higher odds of death and prolonged hospital stay by 11.2 days. Acute kidney injury had the highest incidence (2.0%) and was associated with 25.0% mortality. While delirium had the second highest incidence (1.5%), it was associated …

Co-Designing A Web-Based And Tablet App To Evaluate Clinical Outcomes Of Early Psychosis Service Users In A Learning Health Care Network: User-Centered Design Workshop And Pilot Study, Kathleen E Burch, Adam B Wilcox, Et Al.

2020-Current year OA Pubs

BACKGROUND: The Early Psychosis Intervention Network of California project, a learning health care network of California early psychosis intervention (EPI) programs, prioritized incorporation of community partner feedback while designing its eHealth app, Beehive. Though eHealth apps can support learning health care network data collection aims, low user acceptance or adoption can pose barriers to successful implementation. Adopting user-centered design (UCD) approaches, such as incorporation of user feedback, prototyping, iterative design, and continuous evaluation, can mitigate these potential barriers.

OBJECTIVE: We aimed to use UCD during development of a data collection and data visualization web-based and tablet app, Beehive, to promote …

An Unsupervised Map Of Excitatory Neuron Dendritic Morphology In The Mouse Visual Cortex, Marissa A Weis, Stelios Papadopoulos, Laura Hansel, Timo Lüddecke, Brendan Celii, Paul G Fahey, Eric Y Wang, J Alexander Bae, Agnes L Bodor, Derrick Brittain, Joann Buchanan, Daniel J Bumbarger, Manuel A Castro, Forrest Collman, Nuno Maçarico Da Costa, Sven Dorkenwald, Leila Elabbady, Akhilesh Halageri, Zhen Jia, Chris Jordan, Dan Kapner, Nico Kemnitz, Sam Kinn, Kisuk Lee, Kai Li, Ran Lu, Thomas Macrina, Gayathri Mahalingam, Eric Mitchell, Shanka Subhra Mondal, Shang Mu, Barak Nehoran, Sergiy Popovych, R Clay Reid, Casey M Schneider-Mizell, H Sebastian Seung, William Silversmith, Marc Takeno, Russel Torres, Nicholas L Turner, William Wong, Jingpeng Wu, Wenjing Yin, Szi-Chieh Yu, Jacob Reimer, Philipp Berens, Andreas S Tolias, Alexander S Ecker

Faculty, Staff and Students Publications

Neurons in the neocortex exhibit astonishing morphological diversity, which is critical for properly wiring neural circuits and giving neurons their functional properties. However, the organizational principles underlying this morphological diversity remain an open question. Here, we took a data-driven approach using graph-based machine learning methods to obtain a low-dimensional morphological "bar code" describing more than 30,000 excitatory neurons in mouse visual areas V1, AL, and RL that were reconstructed from the millimeter scale MICrONS serial-section electron microscopy volume. Contrary to previous classifications into discrete morphological types (m-types), our data-driven approach suggests that the morphological landscape of cortical excitatory neurons is …

Gramd1b Is A Regulator Of Lipid Homeostasis, Autophagic Flux And Phosphorylated Tau, Diana Acosta Ingram, Jacob Marsh, Celeste M Karch, Et Al.

2020-Current year OA Pubs

Lipid dyshomeostasis and tau pathology are present in frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). However, the relationship between lipid dyshomeostasis and tau pathology remains unclear. We report that GRAM Domain Containing 1B (GRAMD1B), a nonvesicular cholesterol transporter, is increased in excitatory neurons of human neural organoids (HNOs) with the MAPT R406W mutation. Human FTLD, AD cases, and PS19 tau mice also have increased GRAMD1B expression. We show that overexpression of GRAMD1B increases levels of free cholesterol, lipid droplets, and impairs autophagy flux. Modulating GRAMD1B in iPSC-derived neurons also alters key autophagy-related components such as PI3K, phospho-AKT, and p62, …

The Medial Olivocochlear Efferent Pathway Potentiates Cochlear Amplification In Response To Hearing Loss, Patricia M Quiñones, Michelle Pei, Hemant Srivastava, Ariadna Cobo-Cuan, Marcela A Morán, Bong Jik Kim, Clayton B Walker, Michael J Serafino, Frank Macias-Escriva, Juemei Wang, James B Dewey, Brian E Applegate, Matthew J Mcginley, John S Oghalai

Faculty, Staff and Students Publications

The mammalian cochlea receives efferent feedback from the brain. Many functions for this feedback have been hypothesized, including on short timescales, such as mediating attentional states, and long timescales, such as buffering acoustic trauma. Testing these hypotheses has been impeded by an inability to make direct measurements of efferent effects in awake animals. Here, we assessed the role of the medial olivocochlear (MOC) efferent nerve fibers on cochlear amplification by measuring organ of Corti vibratory responses to sound in both sexes of awake and anesthetized mice. We studied long-term effects by genetically ablating the efferents and/or afferents. Cochlear amplification increased …

Cell Type-Specific Multi-Omics Analysis Of Cocaine Use Disorder In The Human Caudate Nucleus, Lea Zillich, Annasara Artioli, Veronika Pohořalá, Eric Zillich, Laura Stertz, Hanna Belschner, Ammar Jabali, Josef Frank, Fabian Streit, Diana Avetyan, Maja P Völker, Svenja Müller, Anita C Hansson, Thomas D Meyer, Marcella Rietschel, Julia Ladewig, Rainer Spanagel, Ana M M Oliveira, Consuelo Walss-Bass, Rick E Bernardi, Philipp Koch, Stephanie H Witt

Faculty, Staff and Student Publications

Structural and functional alterations in the brain's reward circuitry are present in cocaine use disorder (CocUD), but their molecular underpinnings remain unclear. To investigate these mechanisms, we performed single-nuclei multiome profiling on postmortem caudate nucleus tissue from six individuals with CocUD and eight controls. We profiled 30,030 nuclei, identifying 13 cell types including D1- and D2-medium spiny neurons (MSNs) and glial cells. We observed 1485 differentially regulated genes and 10,342 differentially accessible peaks, with alterations in MSNs and astrocytes related to neurotransmitter activity and synapse organization. Gene regulatory network analysis identified transcription factors including ZEB1 as exhibiting distinct CocUD-specific subclusters, …

Impact Of Perioperative Organ Injury On Morbidity And Mortality In 28 Million Surgical Patients, Felix Kork, Yafen Liang, Adit A Ginde, Xiaoyi Yuan, Rolf Rossaint, Hongfang Liu, Alex S Evers, Holger K Eltzschig

Faculty, Staff and Student Publications

Perioperative organ injury contributes to morbidity and mortality of surgical patients. This cohort study included all elective and emergent surgeries in Germany over 4 years to address the impact of perioperative organ injuries on outcomes. We analyzed 28,350,953 cases. In-hospital mortality was 1.4% (n = 393,157), and 4.4% of cases (n = 1,245,898) experienced perioperative organ injury. Perioperative organ injury was associated with 9-fold higher odds of death and prolonged hospital stay by 11.2 days. Acute kidney injury had the highest incidence (2.0%) and was associated with 25.0% mortality. While delirium had the second highest incidence (1.5%), it was associated …

Differential Antibody Response To Ebv Proteome Following Ebvst Immunotherapy In Ebv-Associated Lymphomas, Yomani D Sarathkumara, Nathan W Van Bibber, Zhiwei Liu, Helen E Heslop, Rayne H Rouce, Anna E Coghill, Cliona M Rooney, Carla Proietti, Denise L Doolan

Faculty, Staff and Students Publications

Epstein-Barr virus (EBV) is associated with a diverse range of lymphomas. EBV-specific T-cell (EBVST) infusions have shown promise in safety and clinical effectiveness in treating EBV-associated lymphomas; however, not all patients respond to T-cell immunotherapies. To identify EBV antigen–specific antibody responses associated with clinical outcomes, we comprehensively characterized antibody responses to the complete EBV proteome using a custom protein microarray in 56 patients with EBV-associated lymphoma who received EBVST infusions in phase 1 clinical trials. Responders (nonprogressors) and nonresponders (progressors) had distinct antibody profiles against EBV. Twenty-five immunoglobulin G (IgG) antibodies were significantly elevated in higher levels in nonresponders than …

Phase 2 Trial Of Ibrutinib And Nivolumab In Patients With Relapsed Cns Lymphomas, Dai Chihara, Raphael E Steiner, Ranjit Nair, Lei Feng, Sairah Ahmed, Paolo Strati, Luis Malpica, Donna P Griffith, Shivon A Mathew, Wirt Montinez, Gita Masand, Felipe Samaniego, Maria A Rodriguez, Fredrick B Hagemeister, Luis E Fayad, Swaminathan P Iyer, Loretta J Nastoupil, Sattva S Neelapu, Christopher R Flowers, Jason R Westin

Faculty, Staff and Student Publications

Treatment options are limited for both relapsed/refractory primary and secondary central nervous system (CNS) lymphoma and the prognosis remains poor. Previous studies have shown the activity of Bruton tyrosine kinase inhibitors and programmed death-1-targeted therapies in CNS lymphoma, and studies suggested potential synergy. Therefore, we conducted a phase 2 trial that combined ibrutinib with nivolumab for patients with relapsed/refractory CNS lymphoma. Patients received 560 mg oral ibrutinib daily with 240 mg IV nivolumab every 14 days (28 days per cycle). Patients who had partial or complete response after 6 cycles of treatment could continue therapy for up to 2 years …

Identifying The Human Olfactory And Chemosignaling Neural Networks Using Event Related Fmri And Graph Theory, Saideh Ferdowsi, Tom Foulsham, Alireza Rahmani, Dimitri Ognibene, Luca Citi, Wen Li

Faculty, Staff and Student Publications

This study aims to characterize and compare the functional neural networks associated with different olfactory stimuli, including air, non-social odours, and human body odours. We introduce a novel processing pipeline based on event-related functional magnetic resonance imaging (fMRI) and graph theory for network identification. To ensure the stability and small worldness of the characterized networks, we conduct statistical validations, network modularity assessments, and robustness measurement against local attacks. The key hypothesis is that human body odours (so-called social odours) and non-social odours engage distinct neural networks, particularly in regions responsible for social processing. We found that the posterior medial orbitofrontal …

Gpat4 Sustains Endoplasmic Reticulum Homeostasis In Endocardial Cells And Safeguards Heart Development, Tianyang Zhao, Kuipei Jin, Xiaodong Wang, Xiong Su, Youjun Wang, Mingming Gao, Wen Luo, Hongyuan Yang, Zhongzhou Yang

Faculty, Staff and Student Publications

The endocardium plays a pivotal role in governing myocardial development, and understanding the intrinsic regulatory insights will help apprehend pathological cardiomyopathy. Glycerol-3-phosphate acyltransferase 4 (GPAT4) is an endoplasmic reticulum (ER) membrane anchored protein. While the role of GPAT4 in glycerophospholipid biosynthesis is well established, its function in the ER is less explored. Here, we generate Gpat4 global and tissue-specific knockout mice and identify the essential role of GPAT4 in endocardial development. Deficiency of GPAT4 provokes endocardial ER stress response and enhances ER-mitochondrial (ER-mito) communications, leading to mitochondrial DNA (mtDNA) escape. As a result, the cGAS-STING pathway is triggered to stimulate …