Digital Commons Network^™

Swi/Snf Senses Carbon Starvation With A Ph-Sensitive Low-Complexity Sequence, J. Ignacio Gutierrez, Gregory P. Brittingham, Yonca Karadeniz, Kathleen D. Tran, Arnob Dutta, Alex S. Holehouse, Craig L. Peterson, Liam J. Holt

Open Access Publications

It is increasingly appreciated that intracellular pH changes are important biological signals. This motivates the elucidation of molecular mechanisms of pH sensing. We determined that a nucleocytoplasmic pH oscillation was required for the transcriptional response to carbon starvation in

Leveraging Large Multi-Center Cohorts Of Alzheimer Disease Endophenotypes To Understand The Role Of Klotho Heterozygosity On Disease Risk, Muhammad Ali, Yun Ju Sung, Fengxian Wang, Maria V. Fernández, John C. Morris, Anne M. Fagan, Richard J. Perrin, Carlos Cruchaga, Et Al

Open Access Publications

Two genetic variants in strong linkage disequilibrium (rs9536314 and rs9527025) in the Klotho (KL) gene, encoding a transmembrane protein, implicated in longevity and associated with brain resilience during normal aging, were recently shown to be associated with Alzheimer disease (AD) risk in cognitively normal participants who are APOE ε4 carriers. Specifically, the participants heterozygous for this variant (KL-SVHET+) showed lower risk of developing AD. Furthermore, a neuroprotective effect of KL-VSHET+ has been suggested against amyloid burden for cognitively normal participants, potentially mediated via the regulation of redox pathways. However, inconsistent associations and a smaller sample size of existing studies pose …

Coping With Covid-19: Differences In Hope, Resilience, And Mental Well-Being Across U.S. Racial Groups, Carol Graham, Yung Chun, Bartram Hamilton, Stephen Roll, Wilbur Ross, Michal Grinstein-Weiss

Open Access Publications

OBJECTIVES: To explore if the COVID-19 pandemic revealed differences across racial groups in coping, resilience, and optimism, all of which have implications for health and mental well-being.

METHODS: We collect data obtained from four rounds of a national sample of 5,000 US survey respondents in each round from April 2020 to February 2021. Using logistic regression and fixed effects models, we estimate the pandemic impacts on COVID-19 related concerns, social distancing behaviors, and mental health/life satisfaction and optimism for racial/income groups.

RESULTS: Despite extreme income and health disparities before and during the COVID-19 outbreak, Blacks and Hispanics remain more resilient …

An Immuno-Enrichment Free, Validated Quantification Of Tau Protein In Human Csf By Lc-Ms/Ms, Wade Self, Khader Awwad, John Paul Savaryn, Michael Schulz

Open Access Publications

Tau protein is a key target of interest in developing therapeutics for neurodegenerative diseases. Here, we sought to develop a method that quantifies extracellular tau protein concentrations in human cerebrospinal fluid (CSF) without antibody-based enrichment strategies. We demonstrate that the fit-for-purpose validated method in Alzheimer's Disease CSF is limited to quasi quantitative measures of tau surrogate peptides. We also provide evidence that CSF total Tau measures by LC-MS are feasible in the presence of monoclonal therapeutic antibodies in human CSF. Our Tau LC-MS/MS method is a translational bioanalytical tool for assaying target engagement and pharmacodynamics for anti-tau antibody drug development …

Effects Of Slow Deep Breathing On Acute Clinical Pain In Adults: A Systematic Review And Meta-Analysis Of Randomized Controlled Trials, Amira E Joseph, Rajat N Moman, Ross A Barman, Donald J Kleppel, Nathan D Eberhart, Danielle J Gerberi, M Hassan Murad, W Michael Hooten

Open Access Publications

Slow deep breathing (SDB) may help patients with acute pain. The primary aim of this systematic review and meta-analysis is to investigate the effects of SDB on acute pain. Secondary aims include investigating the effects of SDB on acute pain-related physical and emotional functioning. An

What Clonal Hematopoiesis Can Teach Us About Mds, Irenaeus C C Chan, Brian J Wiley, Kelly L Bolton

Open Access Publications

Clonal hematopoiesis (CH), defined as the clonal expansion of mutated hematopoietic stem and progenitor cells (HSPCs), is a common aging process. CH is a risk factor for the development of hematologic malignancies, most commonly myeloid neoplasms (MNs) including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasm (MPN). Recent work has elucidated how the development and cellular fitness of CH is shaped by aging, environmental exposures, and the germline (inherited) genetic background of an individual. This in turn has provided valuable insights into the pathogenesis of MNs including MDS. Here, in this review, we discuss the genetic origins of …

High-Dimensional Analysis Reveals Distinct Endotypes In Patients With Idiopathic Inflammatory Myopathies, Erin M Wilfong, Todd Bartkowiak, Katherine N Vowell, Camille S Westlake, Jonathan M Irish, Peggy L Kendall, Leslie J Crofford, Rachel H Bonami

Open Access Publications

The idiopathic inflammatory myopathies (IIM) are a rare clinically heterogeneous group of conditions affecting the skin, muscle, joint, and lung in various combinations. While myositis specific autoantibodies are well described, we postulate that broader immune endotypes exist in IIM spanning B cell, T cell, and monocyte compartments. This study aims to identify immune endotypes through detailed immunophenotyping of peripheral blood mononuclear cells (PBMCs) in IIM patients compared to healthy controls. We collected PBMCs from 17 patients with a clinical diagnosis of inflammatory myositis and characterized the B, T, and myeloid cell subsets using mass cytometry by time of flight (CyTOF). …

Pleiotropic Effects Of Simvastatin And Losartan In Preclinical Models Of Post-Traumatic Elbow Contracture, Michael A David, Alex J Reiter, Chelsey L Dunham, Ryan M Castile, James A Abraham, Leanne E Iannucci, Ishani D Shah, Necat Havlioglu, Aaron M Chamberlain, Spencer P Lake

Open Access Publications

Elbow trauma can lead to post-traumatic joint contracture (PTJC), which is characterized by loss of motion associated with capsule/ligament fibrosis and cartilage damage. Unfortunately, current therapies are often unsuccessful or cause complications. This study aimed to determine the effects of prophylactically administered simvastatin (SV) and losartan (LS) in two preclinical models of elbow PTJC: an

Externalizing Personality Characteristics Define Clinically Relevant Subgroups Of Alcohol Use Disorder, Ildikó Kovács, Bernadett I Gál, Zsolt Horváth, Ildikó Demeter, Sándor Rózsa, Zoltán Janka, Róbert Urbán, Zsolt Demetrovics, Bálint Andó

Open Access Publications

AIMS: Higher levels of externalizing characteristics, i.e. impulsivity, novelty seeking and aggression, could contribute to the development, progression and severity of alcohol use disorder (AUD). The present study aims to explore whether these externalizing characteristics together have a potential group-forming role in AUD using latent profile analysis (LPA).

METHODS: Externalizing characteristics of 102 AUD patients were analyzed using LPA to explore the group-forming role of externalizing symptoms; groups were compared in terms of demographic and alcohol-related variables, indices of psychopathological, depressive and anxiety symptom severity.

RESULTS: LPA revealed and supported a two-group model based on externalizing symptoms. The group with …

Perceived Physical Fatigability Predicts All-Cause Mortality In Older Adults, Nancy W. Glynn, Theresa Gmelin, Sharon W. Renner, Yujia Susanna Qiao, Robert M. Boudreau, Mary F. Feitosa, Mary K. Wojczynski, Stephanie Cosentino, Stacy L. Andersen, Kaare Christensen, Anne B. Newman

Open Access Publications

BACKGROUND: Perceived physical fatigability is highly prevalent in older adults and associated with mobility decline and other health consequences. We examined the prognostic value of perceived physical fatigability as an independent predictor of risk of death among older adults.

METHODS: Participants (N = 2 906), mean age 73.5 [SD, 10.4] years, 54.2% women, 99.7% white enrolled in the Long Life Family Study, were assessed at Visit 2 (2014-2017) with 2.7 [SD, 1.0] years follow-up. The Pittsburgh Fatigability Scale (PFS), a 10-item, self-administered validated questionnaire (score range 0-50, higher = greater fatigability) measured perceived physical fatigability at Visit 2. Deaths post-Visit …

Amigo1 Promotes Axon Growth And Territory Matching In The Retina, Florentina Soto, Ning Shen, Daniel Kerschensteiner

Open Access Publications

Dendrite and axon arbor sizes are critical to neuronal function and vary widely between different neuron types. The relative dendrite and axon sizes of synaptic partners control signal convergence and divergence in neural circuits. The developmental mechanisms that determine cell-type-specific dendrite and axon size and match synaptic partners' arbor territories remain obscure. Here, we discover that retinal horizontal cells express the leucine-rich repeat domain cell adhesion molecule AMIGO1. Horizontal cells provide pathway-specific feedback to photoreceptors-horizontal cell axons to rods and horizontal cell dendrites to cones. AMIGO1 selectively expands the size of horizontal cell axons. When

Economic Choices Under Simultaneous Or Sequential Offers Rely On The Same Neural Circuit, Weikang Shi, Sébastien Ballesta, Camillo Padoa-Schioppa

Open Access Publications

A series of studies in which monkeys chose between two juices offered in variable amounts identified in the orbitofrontal cortex (OFC) different groups of neurons encoding the value of individual options (offer value), the binary choice outcome (chosen juice), and the chosen value. These variables capture both the input and the output of the choice process, suggesting that the cell groups identified in OFC constitute the building blocks of a decision circuit. Several lines of evidence support this hypothesis. However, in previous experiments offers were presented simultaneously, raising the question of whether current notions generalize to when goods are presented …

Oncogenic Gq/11 Signaling Acutely Drives And Chronically Sustains Metabolic Reprogramming In Uveal Melanoma, Michael D Onken, Sarah E Noda, Kevin M Kaltenbronn, Cheryl Frankfater, Carol M Makepeace, Nikki Fettig, Kisha D Piggott, Philip L Custer, Joseph E Ippolito, Kendall J Blumer

Open Access Publications

Metabolic reprogramming has been shown to occur in uveal melanoma (UM), the most common intraocular tumor in adults. Mechanisms driving metabolic reprogramming in UM are poorly understood. Elucidation of these mechanisms could inform development of new therapeutic strategies for metastatic UM, which has poor prognosis because existing therapies are ineffective. Here, we determined whether metabolic reprogramming is driven by constitutively active mutant α-subunits of the heterotrimeric G proteins Gq or G11 (Gq/11), the oncogenic drivers in ∼90% of UM patients. Using PET-computed tomography imaging, microphysiometry, and GC/MS, we found that inhibition of oncogenic Gq/11 with the small molecule FR900359 (FR) …

Family History Of Breast Cancer And Mammographic Breast Density In Premenopausal Women, Yunan Han, Justin Xavier Moore, Graham A. Colditz, Adetunji T. Toriola

Open Access Publications

Importance: Family history of breast cancer (FHBC) and mammographic breast density are independent risk factors for breast cancer, but the association of FHBC and mammographic breast density in premenopausal women is not well understood.

Objectives: To investigate the association of FHBC and mammographic breast density in premenopausal women using both quantitative and qualitative measurements.

Design, Setting, and Participants: This single-center cohort study examined 2 retrospective cohorts: a discovery set of 375 premenopausal women and a validation set of 14 040 premenopausal women. Data from women in the discovery set was collected between December 2015 and October 2016, whereas data from …

A Case Of Gorham-Stout Disease Of The Skull Base Treated With Intensity Modulated Radiation Therapy, Amit Roy, Neal Andruska, Randall Brenneman, Jacob Hogan, Hilary L P Orlowski, Patrik Pipkorn, Mackenzie D Daly

Open Access Publications

No abstract provided.

Contralateral Limb Specificity For Movement Preparation In The Parietal Reach Region, Eric Mooshagian, Eric A. Yttri, Arthur D. Loewy, Lawrence H. Snyder

Open Access Publications

The canonical view of motor control is that distal musculature is controlled primarily by the contralateral cerebral hemisphere; unilateral brain lesions typically affect contralateral but not ipsilateral musculature. Contralateral-only limb deficits following a unilateral lesion suggest but do not prove that control is strictly contralateral: the loss of a contribution of the lesioned hemisphere to the control of the ipsilesional limb could be masked by the intact contralateral drive from the nonlesioned hemisphere. To distinguish between these possibilities, we serially inactivated the parietal reach region, comprising the posterior portion of medial intraparietal area, the anterior portion of V6a, and portions …

Analysis And Classification Of Postcatheterization Femoral Arteriovenous Fistulas Based On Color Doppler Examinations, William D Middleton, Kathryn A Robinson

Open Access Publications

OBJECTIVE: To analyze and classify arterial supply and venous drainage of postcatheterization femoral arteriovenous fistulas (AVFs).

METHODS: A review of extremity Doppler reports identified 77 femoral AVFs in 75 patients. Doppler exams were reviewed retrospectively. Fistulas were classified as above or below the common femoral artery bifurcation and subclassified based on the location of arterial inflow and venous outflow.

RESULTS: Arterial inflow originated above the femoral bifurcation in 32 cases. The communication was between the common femoral artery and the superficial circumflex iliac vein in 25 of 32 cases and between a branch of the common femoral or external iliac …

White Matter Microstructure Associations To Amyloid Burden In Adults With Down Syndrome, Austin M Bazydlo, Beau Ances, Et Al

Open Access Publications

INTRODUCTION: Individuals with Down syndrome (DS) are at an increased risk of developing Alzheimer's Disease (AD). One of the early underlying mechanisms in AD pathology is the accumulation of amyloid protein plaques, which are deposited in extracellular gray matter and signify the first stage in the cascade of neurodegenerative events. AD-related neurodegeneration is also evidenced as microstructural changes in white matter. In this work, we explored the correlation of white matter microstructure with amyloid load to assess amyloid-related neurodegeneration in a cohort of adults with DS.

METHODS: In this study of 96 adults with DS, the relation of white matter …

Increased Connectivity Among Sensory And Motor Regions During Visual And Audiovisual Speech Perception, Jonathan E. Peelle, Brent Spehar, Michael S. Jones, Sarah Mcconkey, Joel Myerson, Sandra Hale, Mitchell S. Sommers, Nancy Tye-Murray

Open Access Publications

In everyday conversation, we usually process the talker's face as well as the sound of the talker's voice. Access to visual speech information is particularly useful when the auditory signal is degraded. Here, we used fMRI to monitor brain activity while adult humans (

Assessment Of A Plasma Amyloid Probability Score To Estimate Amyloid Positron Emission Tomography Findings Among Adults With Cognitive Impairment, Yan Hu, Barry A. Siegel, David M. Holtzman, Et Al

Open Access Publications

Importance: The diagnostic evaluation for Alzheimer disease may be improved by a blood-based diagnostic test identifying presence of brain amyloid plaque pathology.

Objective: To determine the clinical performance associated with a diagnostic algorithm incorporating plasma amyloid-β (Aβ) 42:40 ratio, patient age, and apoE proteotype to identify brain amyloid status.

Design, Setting, and Participants: This cohort study includes analysis from 2 independent cross-sectional cohort studies: the discovery cohort of the Plasma Test for Amyloidosis Risk Screening (PARIS) study, a prospective add-on to the Imaging Dementia-Evidence for Amyloid Scanning study, including 249 patients from 2018 to 2019, and MissionAD, a dataset of …

Quantifying Rural Disparity In Healthcare Utilization In The United States: Analysis Of A Large Midwestern Healthcare System, Akua Nuako, Jingxia Liu, Giang Pham, Nina Smock, Aimee James, Timothy Baker, Laura Bierut, Graham Colditz, Li-Shiun Chen

Open Access Publications

PURPOSE: The objective of this study is to identify how predisposing characteristics, enabling factors, and health needs are jointly and individually associated with epidemiological patterns of outpatient healthcare utilization for patients who already interact and engage with a large healthcare system.

METHODS: We retrospectively analyzed electronic medical record data from 1,423,166 outpatient clinic visits from 474,674 patients in a large healthcare system from June 2018-March 2019. We evaluated patients who exclusively visited rural clinics versus patients who exclusively visited urban clinics using Chi-square tests and the generalized estimating equation Poisson regression methodology. The outcome was healthcare use defined by the …

Perspectives And Experiences With Covid-19 Vaccines In People With Ms, John R Ciotti, Dana C Perantie, Brandon P Moss, Kathryn C Fitzgerald, Jeffrey A Cohen, Ellen M Mowry, Robert T Naismith, Salim Chahin

Open Access Publications

Background: People with MS may have unique perspectives on COVID-19 vaccines due to their condition and/or medications.

Objective: Assess perspectives and experiences with COVID-19 vaccination, and quantify variables impacting COVID-19 vaccine willingness in people with MS.

Methods: A survey captured demographics, MS characteristics, and COVID-19 infection and exposures data; opinions on COVID-19 vaccine safety, side effects, and efficacy; and experiences following vaccination. Chi-square tests and a logistic regression model were used to denote between-group differences and variables predicting vaccine willingness, respectively.

Results: Most (87.8%) of the 237 participants were willing to receive the vaccine. Fifteen percent held or delayed a …

Patients With Serious Injection Drug Use-Related Infections Who Experience Patient-Directed Discharges On Oral Antibiotics Have High Rates Of Antibiotic Adherence But Require Multidisciplinary Outpatient Support For Retention In Care, Sophia Lewis, Stephen Y. Liang, Evan S. Schwarz, David B. Liss, Rachel P. Winograd, Nathanial S. Nolan, Michael J. Durkin, Laura R. Marks

Open Access Publications

Background: Persons who inject drugs (PWID) are frequently admitted for serious injection-related infections (SIRIs). Outcomes and adherence to oral antibiotics for PWID with patient-directed discharge (PDD) remain understudied.

Methods: We conducted a prospective multicenter bundled quality improvement project of PWID with SIRI at 3 hospitals in Missouri. All PWID with SIRI were offered multidisciplinary care while inpatient, including the option of addiction medicine consultation and medications for opioid use disorder (MOUD). All patients were offered oral antibiotics in the event of a PDD either at discharge or immediately after discharge through an infectious diseases telemedicine clinic. Additional support services included …

Multicenter, Prospective Validation Of A Phenotypic Algorithm To Guide Carbapenemase Testing In Carbapenem-Resistant Pseudomonas Aeruginosa Using The Erace-Pa Global Surveillance Program, Christian M. Gill, Carey-Ann D. Burnham, Et Al

Open Access Publications

Background: Carbapenemase-producing, carbapenem-resistant

Methods: CRPA isolates were collected during the Enhancing Rational Antimicrobials for

Results: A total of 807 CRPA were assessed, and 464 isolates met the algorithm criteria described above. Overall, testing was reduced by 43% compared with testing all CRPA. Carbapenemase-positive isolates missed by the algorithm were largely driven by Guiana extended spectrum (GES). Addition of the criterion of imipenem- or meropenem-resistant plus ceftolozane/tazobactam-nonsusceptible decreased the number of CP-CRPA missed by the algorithm (21 vs 40 isolates, respectively), reducing number of isolates tested by 39%.

Conclusions: Application of the initial algorithm (imipenem- or meropenem-resistant plus ceftazidime-nonsusceptible plus cefepime-nonsusceptible) …

A Prospective, Multicenter Trial Of A Long-Term Bioabsorbable Mesh With Sepra Technology In Cohort Of Challenging Laparoscopic Ventral Or Incisional Hernia Repairs (Atlas Trial), William W Hope, Jeffrey A Blatnik, Et Al

Open Access Publications

Background: This prospective, multicenter, single-arm, open-label study evaluated P4HB-ST mesh in laparoscopic ventral or incisional hernia repair (LVIHR) in patients with Class I (clean) wounds at high risk for Surgical Site Occurrence (SSO).

Methods: Primary endpoint was SSO requiring intervention <45 days. Secondary endpoints included: surgical procedure time, length of stay, SSO >45 days, hernia recurrence, device-related adverse events, reoperation, and Quality of Life at 1, 3, 6, 12, 18, and 24-months.

Results: 120 patients (52.5% male), mean age of 55.0 ± 14.9 years, and BMI of 33.2 ± 4.5 kg/m

Conclusion: P4HB-ST mesh demonstrated low rates of SSO and device-related complications, with improved quality of life scores, and reoperation rate comparable …

Essential Functions Of Mll1 And Mll2 In Retinal Development And Cone Cell Maintenance, Chi Sun, Xiaodong Zhang, Philip A Ruzycki, Shiming Chen

Open Access Publications

MLL1 (KMT2A) and MLL2 (KMT2B) are homologous members of the mixed-lineage leukemia (MLL) family of histone methyltransferases involved in epigenomic transcriptional regulation. Their sequence variants have been associated with neurological and psychological disorders, but little is known about their roles and mechanism of action in CNS development. Using mouse retina as a model, we previously reported MLL1's role in retinal neurogenesis and horizontal cell maintenance. Here we determine roles of MLL2 and MLL1/MLL2 together in retinal development using conditional knockout (CKO) mice. Deleting

Homeostatic Interferon-Lambda Response To Bacterial Microbiota Stimulates Preemptive Antiviral Defense Within Discrete Pockets Of Intestinal Epithelium, Jacob A. Van Winkle, Stefan T. Peterson, Elizabeth A. Kennedy, Michael J. Wheadon, Harshad Ingle, Chandni Desai, Rachel Rodgers, David A. Constant, Austin P. Wright, Lena Li, Maxim N. Artyomov, Sanghyun Lee, Megan T. Baldridge, Timothy J. Nice

Open Access Publications

Interferon-lambda (IFN-λ) protects intestinal epithelial cells (IECs) from enteric viruses by inducing expression of antiviral IFN-stimulated genes (ISGs). Here, we find that bacterial microbiota stimulate a homeostatic ISG signature in the intestine of specific pathogen-free mice. This homeostatic ISG expression is restricted to IECs, depends on IEC-intrinsic expression of IFN-λ receptor (

Assessing The Relationship Of Patient Reported Outcome Measures With Functional Status In Dysferlinopathy: A Rasch Analysis Approach, Anna G Mayhew, Catherine Siener, Alan Pestronk, Et Al

Open Access Publications

Dysferlinopathy is a muscular dystrophy with a highly variable functional disease progression in which the relationship of function to some patient reported outcome measures (PROMs) has not been previously reported. This analysis aims to identify the suitability of PROMs and their association with motor performance.Two-hundred and four patients with dysferlinopathy were identified in the Jain Foundation's Clinical Outcome Study in Dysferlinopathy from 14 sites in 8 countries. All patients completed the following PROMs: Individualized Neuromuscular Quality of Life Questionnaire (INQoL), International Physical Activity Questionnaire (IPAQ), and activity limitations for patients with upper and/or lower limb impairments (ACTIVLIMs). In addition, nonambulant …

It's Getting Complicated-A Fresh Look At P53-Mdm2-Arf Triangle In Tumorigenesis And Cancer Therapy, Che-Pei Kung, Jason D Weber

Open Access Publications

Anti-tumorigenic mechanisms mediated by the tumor suppressor p53, upon oncogenic stresses, are our bodies' greatest weapons to battle against cancer onset and development. Consequently, factors that possess significant p53-regulating activities have been subjects of serious interest from the cancer research community. Among them, MDM2 and ARF are considered the most influential p53 regulators due to their abilities to inhibit and activate p53 functions, respectively. MDM2 inhibits p53 by promoting ubiquitination and proteasome-mediated degradation of p53, while ARF activates p53 by physically interacting with MDM2 to block its access to p53. This conventional understanding of p53-MDM2-ARF functional triangle have guided the …

A Novel Computer Adaptive Word List Memory Test Optimized For Remote Assessment: Psychometric Properties And Associations With Neurodegenerative Biomarkers In Older Women Without Dementia, Nikki H Stricker, John L Stricker, Aimee J Karstens, Jennifer R Geske, Julie A Fields, Jason Hassenstab, Christopher G Schwarz, Nirubol Tosakulwong, Heather J Wiste, Clifford R Jack, Kejal Kantarci, Michelle M Mielke

Open Access Publications

Introduction: This study established the psychometric properties and preliminary validity of the Stricker Learning Span (SLS), a novel computer adaptive word list memory test designed for remote assessment and optimized for smartphone use.

Methods: Women enrolled in the Mayo Clinic Specialized Center of Research Excellence (SCORE) were recruited via e-mail or phone to complete two remote cognitive testing sessions. Convergent validity was assessed through correlation with previously administered in-person neuropsychological tests (n = 96, ages 55-79) and criterion validity through associations with magnetic resonance imaging measures of neurodegeneration sensitive to Alzheimer's disease (n = 47).

Results: SLS performance significantly correlated …