Medicine and Health Sciences Commons^™

Identification Of The Adult Hematopoietic Liver As The Primary Reservoir For The Recruitment Of Pro-Regenerative Macrophages Required For Salamander Limb Regeneration., Ryan J Debuque, Andrew J Hart, Gabriela H Johnson, Nadia Rosenthal, James W Godwin

Faculty Research 2021

The lack of scar-free healing and regeneration in many adult human tissues imposes severe limitations on the recovery of function after injury. In stark contrast, salamanders can functionally repair a range of clinically relevant tissues throughout adult life. The impressive ability to regenerate whole limbs after amputation, or regenerate following cardiac injury, is critically dependent on the recruitment of (myeloid) macrophage white blood cells to the site of injury. Amputation in the absence of macrophages results in regeneration failure and scar tissue induction. Identifying the exact hematopoietic source or reservoir of myeloid cells supporting regeneration is a necessary step in …

Does Subthalamic Deep Brain Stimulation Impact Asymmetry And Dyscoordination Of Gait In Parkinson’S Disease?, Deepak K. Ravi, Christian R. Baumann, Elena Bernasconi, Michelle Gwerder, Niklas K. Ignasiak, Mechtild Uhl, Lennart Stieglitz, William R. Taylor, Navrag B. Singh

Physical Therapy Faculty Articles and Research

Background. Subthalamic deep brain stimulation (STN-DBS) is an effective treatment for selected Parkinson’s disease (PD) patients. Gait characteristics are often altered after surgery, but quantitative therapeutic effects are poorly described. Objective. The goal of this study was to systematically investigate modifications in asymmetry and dyscoordination of gait 6 months postoperatively in patients with PD and compare the outcomes with preoperative baseline and to asymptomatic controls without PD. Methods. A convenience sample of thirty-two patients with PD (19 with postural instability and gait disorder (PIGD) type and 13 with tremor dominant disease) and 51 asymptomatic controls participated. Parkinson patients …

Super-Enhancer-Based Identification Of A Batf3/Il-2r-Module Reveals Vulnerabilities In Anaplastic Large Cell Lymphoma, Huan-Chang Liang, Mariantonia Costanza, Nicole Prutsch, Mark W. Zimmerman, Elisabeth Gurnhofer, Ivonne A. Montes-Mojarro, Brian J. Abraham, Nina Prokoph, Stefan Stoiber, Shahid Pervez

Department of Pathology and Laboratory Medicine

Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and …

Recognition And Screening For Chagas Disease In The Usa, Rachel Marcus, Andres F. Henao-Martinez, Melissa Nolan Ph.D., Mph, Elizabeth Livingston, Stephen A. Klotz, Robert H. Gilman, Monica Miranda-Schaeubinger, Sheba Meymandi

Faculty Publications

Chagas disease (CD), caused by the protozoan Trypanosoma cruzi, is a public health concern, mainly among countries in South and Central America. However, despite the large number of immigrants from endemic countries living in the USA, awareness of CD is poor in the medical community, and therefore it is significantly underdiagnosed. To avoid the catastrophic cardiac complications of CD and to prevent maternal–fetal transmission, widespread educational programs highlighting the need for diagnosis are urgently needed.

Dietary Saturated Fats And Health: Are The Us Guidelines Evidence-Based?, Arne Astrup, Nina Teicholz, Faidon Magkos, Dennis M Bier, J Thomas Brenna, Janet C King, Andrew Mente, José M Ordovas, Jeff S Volek, Salim Yusuf, Ronald M Krauss

Children’s Nutrition Research Center Staff Publications

The last decade has seen nearly 20 papers reviewing the totality of the data on saturated fats and cardiovascular outcomes, which, altogether, have demonstrated a lack of rigorous evidence to support continued recommendations either to limit the consumption of saturated fatty acids or to replace them with polyunsaturated fatty acids. These papers were unfortunately not considered by the process leading to the most recent U.S. Dietary Guidelines for Americans, the country's national nutrition policy, which recently reconfirmed its recommendation to limit saturated fats to 10% or less of total energy intake, based on insufficient and inconsistent evidence. Continuation of a …

Integrated Behavioral Health (Ibh) Program Updates And Evidence For Ibh In Sud, Rachelle Rene, Phd, Bcb, Hsmi

Department of Family & Community Medicine Presentations and Grand Rounds

Learning Objectives

At the end of this presentation, the participant will be able to:

1. Describe core components of the Primary Care Behavioral Health Model
2. Identify IBH Program implementation highlights and challenges
3. Discuss at least one intervention to address SUD in primary care

The Dynamic Proteome Of Lyme Disease Borrelia, Anahita Fouladzadeh, Mohsen Dorraki, Kay Khine Myo Min, Michaelia P Cockshell, Emma J Thompson, Johan W Verjans, Andrew Allison, Claudine S Bonder, Derek Abbott

Faculty, Staff and Student Publications

The growth of solid tumours relies on an ever-increasing supply of oxygen and nutrients that are delivered via vascular networks. Tumour vasculature includes endothelial cell lined angiogenesis and the less common cancer cell lined vasculogenic mimicry (VM). To study and compare the development of vascular networks formed during angiogenesis and VM (represented here by breast cancer and pancreatic cancer cell lines) a number of in vitro assays were utilised. From live cell imaging, we performed a large-scale automated extraction of network parameters and identified properties not previously reported. We show that for both angiogenesis and VM, the characteristic network path …

Water, Sanitation And Hygiene: A Leading Cause Of Viral Transmission In Pakistan?, Zouina Sarfraz, Azza Sarfraz, Aman Siddiqui, Ali Totonchian, Muzna Sarfraz, Ivan Cherrez-Ojeda

Department of Paediatrics and Child Health

No abstract provided.

Discovery Of Potent Bet Bromodomain 1 Stereoselective Inhibitors Using Dna-Encoded Chemical Library Selections, Rajesh Sharma, Kyoung-Jae Choi, My Diem Quan, Sonum Sharma, Banumathi Sankaran, Hyekyung Park, Anel Lagrone, Jean J Kim, Kevin R Mackenzie, Allan Chris M Ferreon, Choel Kim, Josephine C Ferreon

Faculty, Staff and Students Publications

Expression of a few master transcription factors can reprogram the epigenetic landscape and three-dimensional chromatin topology of differentiated cells and achieve pluripotency. During reprogramming, thousands of long-range chromatin contacts are altered, and changes in promoter association with enhancers dramatically influence transcription. Molecular participants at these sites have been identified, but how this re-organization might be orchestrated is not known. Biomolecular condensation is implicated in subcellular organization, including the recruitment of RNA polymerase in transcriptional activation. Here, we show that reprogramming factor KLF4 undergoes biomolecular condensation even in the absence of its intrinsically disordered region. Liquid-liquid condensation of the isolated KLF4 …

2021 September 21 - Medical Student Education Committee Minutes, Medical Student Education Committee, East Tennessee State University

Medical Student Education Committee Minutes

No abstract provided.

2021-09-21_Michiganoverview_Covidlongtermcare, Michigan Department Of Health & Human Services

Michigan COVID-19 Long Term Care Data

The COVID Long Term Care Facilities page was obtained from Michigan's COVID-19 data page: https://www.michigan.gov/coronavirus/0,9753,7-406-98163_98173-526911--,00.html.

This report is created by the Michigan Department of Health & Human Services from data self-reported by long-term care facilities into EMResource. Data for all reporting facilities is posted weekly each Monday.

The information below represents COVID-19 data reported directly to MDHHS by licensed and operating Skilled Nursing, Home for the Aged and Adult Foster Care facilities (licensed to serve 13 or more individuals) in Michigan from January 1, 2020. All long-term care facilities additionally have an obligation to report COVID-positive residents and/or staff …

2021-09-21_Michiganoverview_Covidsymptoms, Michigan Department Of Health & Human Services

Michigan COVID-19 Syndromic Surveillance System Data

The Syndromic Surveillance System Data report was obtained from Michigan's COVID-19 dashboard, from under the link "​Coronavirus Symptoms": https://www.michigan.gov/coronavirus. Data was compiled by the Michigan Department of Health and Human Services (MDHHS). The information was updated three times a week on Mondays, Wednesdays and Fridays.

Syndromic Surveillance System data is obtained from approximately 216 facilities participating in syndromic surveillance (139 Emergency Departments (ED), 77 Urgent Care) across the State of Michigan. The reporting is based on individuals who present at EDs and may not be representative of the overall population. The coronavirus-like symptoms query searches visit free-text (chief complaint, …

Covid-19, Where Do I Even Begin, Anonymous

Community Reflections

Class assignment for Western Civilization. Life was an emotional and mental roller coaster for everyone and I am sure the world was affected by this one way or another. As I sit here and write this out, I can’t help but remember how much I hated COVID-19.

Paliperidone 3-Month Injection For Treatment Of Schizophrenia: A Narrative Review, Amber N. Edinoff, Prithvi K. Doppalapudi, Claudia V. Orellana, Caroline Ochoa, Shelby J. Patti, Yahya A. Ghaffar, Elyse M. Cornett, Aaron J. Kaye, Omar Viswanath, Ivan Urits, Adam M. Kaye, Alan David Kaye

School of Pharmacy Faculty Articles

Given the typical age onset of schizophrenia, there are tremendous economic and social impacts that extend beyond the person and their families. One critical determinant of the diseases' impact is the patient's adherence to antipsychotic drug treatment. Approved in 2015 for the treatment of schizophrenia, paliperidone palmitate (Invega Trinza, a 3-month injection, noted as PP3M) is a second-generation long-acting injectable antipsychotic medication. Among the different formulations offered for palmitate paliperidone, including the 1 and 3-month formulations, the longer duration 3-month formulation was better at preventing relapse in schizophrenic patients. To date, different formulations of palmitate paliperidone that have been studied …

Using Pet Imaging To Track Sting-Induced Interferon Signaling, Enitome E. Bafor, Howard A. Young

United States Public Health Resources

In the 19th century, Ilya Metchnikoff defined and broadened our initial understanding of phagocytosis and, in 1908, went on to show that a cellular component (i.e., DNA) stimulates immune responses (1). About a century later, Janeway conceptualized pattern recognition receptors (PRRs) and pathogen-associated molecular patterns (PAMPs) (2). Since then, we know that PAMP recognition by innate immune cells via PRRs activates the production of several cytokines, including interferons (IFNs), with the eventual recruitment of lymphocytes. Subsequent research discovered that innate immune recognition of double-stranded DNA (dsDNA) triggers autoimmune diseases (3). However, before the discovery of dsDNA sensors, an endoplasmic reticulum …

Spatial Regulation By Multiple Gremlin1 Enhancers Provides Digit Development With Cis-Regulatory Robustness And Evolutionary Plasticity., Jonas Malkmus, Laurène Ramos Martins, Shalu Jhanwar, Bonnie Kircher, Victorio Palacio, Rushikesh Sheth, Francisca Leal, Amandine Duchesne, Javier Lopez-Rios, Kevin A Peterson, Robert Reinhardt, Koh Onimaru, Martin J Cohn, Aimée Zuniga, Rolf Zeller

Faculty Research 2021

Precise cis-regulatory control of gene expression is essential for normal embryogenesis and tissue development. The BMP antagonist Gremlin1 (Grem1) is a key node in the signalling system that coordinately controls limb bud development. Here, we use mouse reverse genetics to identify the enhancers in the Grem1 genomic landscape and the underlying cis-regulatory logics that orchestrate the spatio-temporal Grem1 expression dynamics during limb bud development. We establish that transcript levels are controlled in an additive manner while spatial regulation requires synergistic interactions among multiple enhancers. Disrupting these interactions shows that altered spatial regulation rather than reduced Grem1 transcript levels prefigures digit …

Resetting Of Auditory And Visual Segregation Occurs After Transient Stimuli Of The Same Modality, Nathan C. Higgins, Ambar G. Monjaras, Breanne D. Yerkes, David F. Little, Jessica E. Nave-Blodgett, Mounya Elhilali, Joel S. Snyder

Psychology Faculty Research

In the presence of a continually changing sensory environment, maintaining stable but flexible awareness is paramount, and requires continual organization of information. Determining which stimulus features belong together, and which are separate is therefore one of the primary tasks of the sensory systems. Unknown is whether there is a global or sensory-specific mechanism that regulates the final perceptual outcome of this streaming process. To test the extent of modality independence in perceptual control, an auditory streaming experiment, and a visual moving-plaid experiment were performed. Both were designed to evoke alternating perception of an integrated or segregated percept. In both experiments, …

Transcatheter Aortic Valve Replacement With Self-Expandable Supra-Annular Valves For Degenerated Surgical Bioprostheses: Insights From Transcatheter Valve Therapy Registry., Luis Augusto P Dallan, John K Forrest, Michael J Reardon, Wilson Y Szeto, Isaac George, Susheel Kodali, Neal S Kleiman, Steven J Yakubov, Kendra J Grubb, Fang Liu, Cristian Baeza, Guilherme F Attizzani

Heart and Vascular Articles

Background Transcatheter aortic valve replacement with supra-annular transcatheter heart valves has been adopted in patients with degenerated surgical aortic valves. The next generation self-expanding Evolut PRO valve has not been evaluated in patients with surgical valve failure. Methods and Results Patients undergoing transcatheter aortic valve replacement in degenerated surgical aortic valve procedures using the Evolut R or Evolut PRO transcatheter heart valves in the Society of Thoracic Surgeons and American College of Cardiology Transcatheter Valve Therapy Registry between April 2015 and June 2019 were evaluated. Transcatheter valve performance was evaluated by clinical site echocardiography. In-hospital, 30-day, and 1-year clinical outcomes …

Iron(Iii) Chelated Paramagnetic Polymeric Nanoparticle Formulation As A Next-Generation: T 1-Weighted Mri Contrast Agent, Ramesh Marasini, Sagar Rayamajhi, Anthony Moreno-Sanchez, Santosh Aryal

Pharmacy Faculty Publications and Presentations

Magnetic resonance imaging (MRI) is a routinely used imaging technique in medical diagnostics. To enhance the quality of MR images, contrast agents (CAs) are used, which account for nearly 40% of MRI exams in the clinic globally. The most used CAs are gadolinium-based CAs (GBCAs) but the use of GBCAs has been linked with metal-deposition in vital organs. Gadolinium deposition has been shown to be correlated with nephrogenic systemic fibrosis, a fibrosis of the skin and internal organs. Therefore, there is an unmet need for a new CA alternative to GBCAs for T 1-weighted Ce-MRI. Herein, we designed paramagnetic ferric …

Genetic Analysis Of Endometriosis And Depression Identifies Shared Loci And Implicates Causal Links With Gastric Mucosa Abnormality, Emmanuel Adewuyi, Divya Mehta, Yadav Sapkota, Asa Auta, Kosuke Yoshihara, Mette Nyegaard, Lyn R. Griffiths, Grant W. Montgomery, Daniel I. Chasman, Dale R. Nyholt

Research outputs 2014 to 2021

Evidence from observational studies indicates that endometriosis and depression often co-occur. However, conflicting evidence exists, and the etiology as well as biological mechanisms underlying their comorbidity remain unknown. Utilizing genome-wide association study (GWAS) data, we comprehensively assessed the relationship between endometriosis and depression. Single nucleotide polymorphism effect concordance analysis (SECA) found a significant genetic overlap between endometriosis and depression (PFsig-permuted = 9.99 × 10−4). Linkage disequilibrium score regression (LDSC) analysis estimated a positive and highly significant genetic correlation between the two traits (rG = 0.27, P = 8.85 × 10−27). A meta-analysis of endometriosis and depression GWAS (sample size = …

Metformin Selectively Dampens The Acute Inflammatory Response Through An Ampk-Dependent Mechanism, Thomas S Postler, Vincent Peng, Dev M Bhatt, Sankar Ghosh

2020-Current year OA Pubs

Metformin is a first-line drug in the treatment of type-2 diabetes mellitus (T2DM). In addition to its antigluconeogenic and insulin-sensitizing properties, metformin has emerged as a potent inhibitor of the chronic inflammatory response of macrophages. In particular, metformin treatment has been shown to reduce expression of interleukin (IL-) 1β during long-term exposure to the pro-inflammatory stimulus lipopolysaccharide (LPS) through a reduction in reactive oxygen species (ROS), which decreases the levels of the hypoxia-inducible factor (HIF) 1-α, and through enhanced expression of IL-10. However, the effect of metformin on the acute inflammatory response, before significant levels of ROS accumulate in the …

Clinical Outcomes In Patients Co-Infected With Covid-19 And Staphylococcus Aureus: A Scoping Review, Jenna Adalbert, Karan Varshney, Rachel Tobin, Rafael Pajaro

College of Population Health Faculty Papers

BACKGROUND: Endemic to the hospital environment, Staphylococcus aureus (S. aureus) is a leading bacterial pathogen that causes deadly infections such as bacteremia and endocarditis. In past viral pandemics, it has been the principal cause of secondary bacterial infections, significantly increasing patient mortality rates. Our world now combats the rapid spread of COVID-19, leading to a pandemic with a death toll greatly surpassing those of many past pandemics. However, the impact of co-infection with S. aureus remains unclear. Therefore, we aimed to perform a high-quality scoping review of the literature to synthesize the existing evidence on the clinical outcomes of COVID-19 …

Exploration Of The Psychometric Properties Of The Person-Centred Primary Care Measure (Pcpcm) In A Chinese Primary Care Population In Hong Kong: A Cross-Sectional Validation Study, Stephen J. Zyzanski, Kurt C. Stange

Faculty Scholarship

Objectives To evaluate the validity and psychometric properties of the Chinese Person-Centred Primary Care Measure (PCPCM) in a Chinese-speaking population. Design A cross-sectional study. Setting A primary care clinic in Hong Kong. Participants 300 Chinese adult patients (150 males and 150 females) were recruited from a primary care clinic to complete a questionnaire containing the PCPCM, Consultation and Relational Empathy (CARE), Patient Enablement Index (PEI) and Adult (short version) Primary Care Assessment Tool (PCAT). The Chinese PCPCM was readministered to 118 participants after 14 days for test-retest reliability. Outcome measures The construct validity, reliability and sensitivity of the Chinese PCPCM. …

Allocation Plans For Crisis Triage: How Well Would They Actually Work?, David Oxman

Division of Pulmonary, Allergy, and Critical Care Medicine Faculty Papers

COVID-19 has forced US state governments to create plans for rationing critical care resources that ensure the greatest population benefit. But a study by Jezmir and colleagues in this issue of Cell Reports Medicine raises doubts about whether these plans can distinguish those who would most benefit.

Associations Between Air Pollution Exposure And Empirically Derived Profiles Of Cognitive Performance In Older Women, Andrew J. Petkus, Diana Younan, Xinhui Wang, Daniel P. Beavers, Mark A. Espeland, Margaret Gatz, Tara Gruenewald, Joel D. Kaufman, Helena C. Chui, Joshua Millstein, Stephen R. Rapp, Joann E. Manson, Susan M. Resnick, Gregory A. Wellenius, Eric A. Whitsel, Keith Widaman, Jiu-Chiuan Chen

Psychology Faculty Articles and Research

Background:Elucidating associations between exposures to ambient air pollutants and profiles of cognitive performance may provide insight into neurotoxic effects on the aging brain. Objective:We examined associations between empirically derived profiles of cognitive performance and residential concentrations of particulate matter of aerodynamic diameter < 2.5 (PM2.5) and nitrogen dioxide (NO2) in older women. Method:Women (N = 2,142) from the Women’s Health Initiative Study of Cognitive Aging completed a neuropsychological assessment measuring attention, visuospatial, language, and episodic memory abilities. Average yearly concentrations of PM2.5 and NO2 were estimated at the participant’s addresses for the 3 years prior to the assessment. Latent profile structural equation models identified subgroups of women exhibiting similar profiles across tests. Multinomial regressions examined associations between exposures and latent profile classification, controlling for covariates. Result:Five latent profiles were identified: low performance across multiple domains (poor multi-domain; n = 282;13%), relatively poor verbal episodic memory (poor memory; n = 216; 10%), average performance across all domains (average multi-domain; n = 974; 45%), superior memory (n = 381; 18%), and superior attention (n = 332; 15%). Using women with average cognitive ability as the referent, higher PM2.5 (per interquartile range [IQR] = 3.64μg/m3) was associated with greater odds of being classified in the poor memory (OR = 1.29; 95% Confidence Interval [CI] = 1.10–1.52) or superior attention (OR = 1.30; 95% CI = 1.10–1.53) profiles. NO2 (per IQR = 9.86 ppb) was associated with higher odds of being classified in the poor memory (OR = 1.38; 95% CI = 1.17–1.63) and lower odds of being classified with superior memory (OR = 0.81; 95% CI = 0.67–0.97). Conclusion:Exposure to PM2.5 and NO2 are associated with patterns of cognitive performance characterized by worse verbal episodic memory relative to performance in other domains.

You Learn How To Hate': Adapting A Healthy Relationship Curriculum Using A Trauma-Informed Race Equity Lens, Shannon Guillot-Wright, Elizabeth D Torres, Bianca Obinyan, Jeff R Temple

Faculty, Staff and Student Publications

Teen dating violence is a public health concern that can lead to short- and long-term mental and physical health consequences, including depression, anxiety, risky behaviors, and unhealthy future relationships. Research shows that social and structural determinants of health, such as racism, low socio-economic status, and neighborhood conditions, may predispose certain communities to violence. to better understand methods to reduce TDV among ethnically and economically diverse populations, we used a trauma-informed race equity lens to adapt an efficacious prevention program known as

The Family Planning "Know-Do" Gap Among Married Women Of Reproductive Age In Urban Pakistan, S Yameen, Sidrah Nausheen, I Hussain, K Hackett, Arjumand Rizvi, Uzair Ansari, Zohra S. Lassi, D Canning, I Shah, Sajid Bashir Soofi

Centre of Excellence in Women and Child Health

Objective: To examine the prevalence and predictors of family planning (FP) know-do gaps among married women of reproductive age (MWRA) in low socio-economic urban areas of Karachi, Pakistan.
Design: This was a cross-sectional survey of randomly selected 7288 MWRA (16-49 years) to identify predictors of the know-do gap in FP using a logistic regression model.
Results: More than one third (35.5%) of MWRA had FP know-do gap, i.e., despite having a knowledge of contraceptives and desire to limit or delay childbearing, they were not using contraceptives. Women were less likely to use FP if they were getting older (25-35 years: …

Covid-19 And Family Planning In The Eastern Mediterranean Region, Azza Sarfraz, Zouina Sarfraz, Sameer Saleem Tebha, Namrata Hange, Kuchalambal Agadi, Alanna Barrios, Manish Kc, Gaurav Patel

Department of Paediatrics and Child Health

No abstract provided.

Mid-Upper Arm Circumference Assessment And Comparison With Weight For Length Z-Score In Infants ≤6 Months As An Indicator Of Severe Acute Malnutrition, Mahjabeen Zehra, Ali Faisal Saleem, Zaubina Kazi, Sadia Parkar

Department of Paediatrics and Child Health

Objective: To assess the frequency of severe acute malnutrition (SAM) and to determine the validity of mid-upper arm circumference (MUAC) as compared to weight for length z-score (WLZ-score) as an indicator of the nutritional status in this age group.
Methods: A cross-sectional study, with a purposive sampling was conducted from March 2018 to November 2018 to enroll 540 infants ≤6 months of age from three different sites in Karachi, Pakistan. The anthropometric measurements (MUAC, length and weight) were taken by experienced community health workers. The data were analyzed using SPSS. MUAC was compared with WLZ-score for sensitivity and specificity to …

Ucp3 (Uncoupling Protein 3) Insufficiency Exacerbates Left Ventricular Diastolic Dysfunction During Angiotensin Ii-Induced Hypertension, Xu Chen, Sadia Ashraf, Nadia Ashraf, Romain Harmancey

Faculty, Staff and Student Publications

Background Left ventricular diastolic dysfunction, an early stage in the pathogenesis of heart failure with preserved ejection fraction, is exacerbated by joint exposure to hypertension and obesity; however, the molecular mechanisms involved remain uncertain. The mitochondrial UCP3 (uncoupling protein 3) is downregulated in the heart with obesity. Here, we used a rat model of UCP3 haploinsufficiency (ucp3