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Editorial: Platelet Secretion, Brian Storrie, Sidney W. Whiteheart

Molecular and Cellular Biochemistry Faculty Publications

No abstract provided.

Genome Sequencing Of The Sweetpotato Whitefly Bemisia Tabaci Med/Q, Wen Xie, Chunhai Chen, Zezhong Yang, Litao Guo, Xin Yang, Dan Wang, Ming Chen, Jinqun Huang, Yanan Wen, Yang Zeng, Yating Liu, Jixing Xia, Lixia Tian, Hongying Cui, Qingjun Wu, Shaoli Wang, Baoyun Xu, Xianchun Li, Xinqiu Tan, Murad Ghanim, Baoli Qiu, Huipeng Pan, Dong Chu, Helene Delatte, M. N. Maruthi, Feng Ge, Xueping Zhou, Xiaowei Wang, Fanghao Wan, Yuzhou Du, Xuguo Joe Zhou

Entomology Faculty Publications

The sweetpotato whitefly Bemisia tabaci is a highly destructive agricultural and ornamental crop pest. It damages host plants through both phloem feeding and vectoring plant pathogens. Introductions of B. tabaci are difficult to quarantine and eradicate because of its high reproductive rates, broad host plant range, and insecticide resistance. A total of 791 Gb of raw DNA sequence from whole genome shotgun sequencing, and 13 BAC pooling libraries were generated by Illumina sequencing using different combinations of mate-pair and pair-end libraries. Assembly gave a final genome with a scaffold N50 of 437 kb, and a total length of 658 Mb. …

Capillaries, Old Age And Alzheimer’S Disease, Charles T. Ambrose

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Many of the minor complaints of old age may have a common etiology and are grouped together here under the term ‘the lesser ailments of aging’ (LAA). This essay proposes that they are due in large part to an age-linked reduced microcirculation. Capillary density (CD) in the tissues is determined by levels of angiogenic growth factors (AGFs). Over 47 studies have reported a reduced CD and/or waning AGFs throughout the bodies of aging animals and people. More convincing than such a generalization are the 80 sets of data comparing these two parameters in adult vs. the aged. These data have …

Polymer Micelle Formulation For The Proteasome Inhibitor Drug Carfilzomib: Anticancer Efficacy And Pharmacokinetic Studies In Mice, Ji Eun Park, Se-Eun Chun, Derek Alexander Reichel, Jee Sun Min, Su-Chan Lee, Songhee Han, Gongmi Ryoo, Yunseok Oh, Shin-Hyung Park, Heon-Min Ryu, Kyung Bo Kim, Ho-Young Lee, Soo Kyung Bae, Younsoo Bae, Wooin Lee

Pharmaceutical Sciences Faculty Publications

Carfilzomib (CFZ) is a peptide epoxyketone proteasome inhibitor approved for the treatment of multiple myeloma (MM). Despite the remarkable efficacy of CFZ against MM, the clinical trials in patients with solid cancers yielded rather disappointing results with minimal clinical benefits. Rapid degradation of CFZ in vivo and its poor penetration to tumor sites are considered to be major factors limiting its efficacy against solid cancers. We previously reported that polymer micelles (PMs) composed of biodegradable block copolymers poly(ethylene glycol) (PEG) and poly(caprolactone) (PCL) can improve the metabolic stability of CFZ in vitro. Here, we prepared the CFZ-loaded PM, PEG-PCL-deoxycholic …

Apolipoprotein E4 And Insulin Resistance Interact To Impair Cognition And Alter The Epigenome And Metabolome, Lance A. Johnson, Eileen Ruth S. Torres, Soren Impey, Jan F. Stevens, Jacob Raber

Physiology Faculty Publications

Apolipoprotein E4 (E4) and type 2 diabetes are major risk factors for cognitive decline and late onset Alzheimer’s disease (AD). E4-associated phenotypes and insulin resistance (IR) share several features and appear to interact in driving cognitive dysfunction. However, shared mechanisms that could explain their overlapping pathophysiology have yet to be found. We hypothesized that, compared to E3 mice, E4 mice would be more susceptible to the harmful cognitive effects of high fat diet (HFD)-induced IR due to apoE isoform-specific differences in brain metabolism. While both E3 and E4 mice fed HFD displayed impairments in peripheral metabolism and cognition, deficits in …

Recruitment Of Reviewers Is Becoming Harder At Some Journals: A Test Of The Influence Of Reviewer Fatigue At Six Journals In Ecology And Evolution, Charles W. Fox, Arianne Y. K. Albert, Timothy H. Vines

Entomology Faculty Publications

Background: It is commonly reported by editors that it has become harder to recruit reviewers for peer review and that this is because individuals are being asked to review too often and are experiencing reviewer fatigue. However, evidence supporting these arguments is largely anecdotal.

Main body: We examine responses of individuals to review invitations for six journals in ecology and evolution. The proportion of invitations that lead to a submitted review has been decreasing steadily over 13 years (2003–2015) for four of the six journals examined, with a cumulative effect that has been quite substantial (average decline from 56% of …

Intracellular Nanoparticle Dynamics Affected By Cytoskeletal Integrity, Martha E. Grady, Emmabeth Parrish, Matthew A. Caporizzo, Sarah C. Seeger, Russell J. Composto, David M. Eckmann

Mechanical Engineering Faculty Publications

The cell interior is a crowded chemical space, which limits the diffusion of molecules and organelles within the cytoplasm, affecting the rates of chemical reactions. We provide insight into the relationship between non-specific intracellular diffusion and cytoskeletal integrity. Quantum dots entered the cell through microinjection and their spatial coordinates were captured by tracking their fluorescence signature as they diffused within the cell cytoplasm. Particle tracking revealed significant enhancement in the mobility of biocompatible quantum dots within fibrosarcoma cells versus their healthy counterparts, fibroblasts, as well as in actin destabilized fibroblasts versus untreated fibroblasts. Analyzing the displacement distributions provided insight into …

Aberrant Coordination Geometries Discovered In The Most Abundant Metalloproteins, Sen Yao, Robert M. Flight, Eric C. Rouchka, Hunter N. B. Moseley

Molecular and Cellular Biochemistry Faculty Publications

Metalloproteins bind and utilize metal ions for a variety of biological purposes. Due to the ubiquity of metalloprotein involvement throughout these processes across all domains of life, how proteins coordinate metal ions for different biochemical functions is of great relevance to understanding the implementation of these biological processes. Toward these ends, we have improved our methodology for structurally and functionally characterizing metal binding sites in metalloproteins. Our new ligand detection method is statistically much more robust, producing estimated false positive and false negative rates of ∼0.11% and ∼1.2%, respectively. Additional improvements expand both the range of metal ions and their …

Selective Immunoproteasome Inhibitors With Non-Peptide Scaffolds, Chang-Guo Zhan, Kyung Bo Kim, Vinod Kasam, Na-Re Lee

Pharmaceutical Sciences Faculty Patents

Compounds useful for inhibiting the immunoproteasome have the formula of [image on patent].

Methods and compounds for inhibiting the immunoproteasome, particularly, immunoproteasome inhibitors with non-peptide scaffolds, are described.

Amidated Dopamine Neuron Stimulating Peptides For Cns Dopaminergic Upregulation, Luke H. Bradley, Don M. Gash, Greg A. Gerhardt

Neuroscience Faculty Patents

The present invention relates to novel proteins, referred to herein as amidated glial cell line-derived neurotrophic factor (GDNF) peptides (or "Amidated Dopamine Neuron Stimulating peptides (ADNS peptides)"), that are useful for treating brain diseases and injuries that result in dopaminergic deficiencies.

Zhx2 (Zinc Fingers And Homeoboxes 2) Regulates Major Urinary Protein Gene Expression In The Mouse Liver, Jieyun Jiang, Kate Townsend Creasy, Justin Purnell, Martha L. Peterson, Brett T. Spear

Microbiology, Immunology, and Molecular Genetics Faculty Publications

The mouse major urinary proteins (Mups) are encoded by a large family of highly related genes clustered on chromosome 4. Mups, synthesized primarily and abundantly in the liver and secreted through the kidneys, exhibit male-biased expression. Mups bind a variety of volatile ligands; these ligands, and Mup proteins themselves, influence numerous behavioral traits. Although urinary Mup protein levels vary between inbred mouse strains, this difference is most pronounced in BALB/cJ mice, which have dramatically low urinary Mup levels; this BALB/cJ trait had been mapped to a locus on chromosome 15. We previously identified Zhx2 (zinc fingers and homeoboxes 2) as …

Sequential Social Experiences Interact To Modulate Aggression But Not Brain Gene Expression In The Honey Bee (Apis Mellifera), Clare C. Rittschof

Entomology Faculty Publications

Background: In highly structured societies, individuals behave flexibly and cooperatively in order to achieve a particular group-level outcome. However, even in social species, environmental inputs can have long lasting effects on individual behavior, and variable experiences can even result in consistent individual differences and constrained behavioral flexibility. Despite the fact that such constraints on behavior could have implications for behavioral optimization at the social group level, few studies have explored how social experiences accumulate over time, and the mechanistic basis of these effects. In the current study, I evaluate how sequential social experiences affect individual and group level aggressive phenotypes, …

Roadmap To A Comprehensive Clinical Data Warehouse For Precision Medicine Applications In Oncology, David J. Foran, Wenjin Chen, Huiqi Chu, Evita Sadimin, Doreen Loh, Gregory Riedlinger, Lauri A. Goodell, Shridar Ganesan, Kim Hirshfield, Lorna Rodriguez, Robert S. Dipaola

Internal Medicine Faculty Publications

Leading institutions throughout the country have established Precision Medicine programs to support personalized treatment of patients. A cornerstone for these programs is the establishment of enterprise-wide Clinical Data Warehouses. Working shoulder-to-shoulder, a team of physicians, systems biologists, engineers, and scientists at Rutgers Cancer Institute of New Jersey have designed, developed, and implemented the Warehouse with information originating from data sources, including Electronic Medical Records, Clinical Trial Management Systems, Tumor Registries, Biospecimen Repositories, Radiology and Pathology archives, and Next Generation Sequencing services. Innovative solutions were implemented to detect and extract unstructured clinical information that was embedded in paper/text documents, including synoptic …

Cpt1a Methylation Is Associated With Plasma Adiponectin, S. Aslibekyan, A. N. Do, H. Xu, S. Li, M. R. Irvin, D Zhi, H. K. Tiwari, D. M. Absher, A. R. Shuldiner, T. Zhang, W. Chen, K. Tanner, C. Hong, B. D. Mitchell, G. Berenson, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

Background and Aims—Adiponectin, an adipose-secreted protein that has been linked to insulin sensitivity, plasma lipids, and inflammatory patterns, is an established biomarker for metabolic health. Despite clinical relevance and high heritability, the determinants of plasma adiponectin levels remain poorly understood.

Methods and Results—We conducted the first epigenome-wide cross-sectional study of adiponectin levels using methylation data on 368,051 cytosine-phosphate-guanine (CpG) sites in CD4+ T-cells from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n= 991). We fit linear mixed models, adjusting for age, sex, study site, T-cell purity, and family. We have identified a positive association (regression …

Micrornas, Heart Failure, And Aging: Potential Interactions With Skeletal Muscle, Kevin A. Murach, John J. Mccarthy

Center for Muscle Biology Faculty Publications

MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by targeting mRNAs for degradation or translational repression. MiRNAs can be expressed tissue specifically and are altered in response to various physiological conditions. It has recently been shown that miRNAs are released into the circulation, potentially for the purpose of communicating with distant tissues. This manuscript discusses miRNA alterations in cardiac muscle and the circulation during heart failure, a prevalent and costly public health issue. A potential mechanism for how skeletal muscle maladaptations during heart failure could be mediated by myocardium-derived miRNAs released to the circulation is presented. An overview …

Emerging Roles Of Xenobiotic Detoxification Enzymes In Metabolic Diseases, Michael C. Petriello, Jessie B. Hoffman, Andrew J. Morris, Bernhard Hennig

Superfund Research Center Faculty Publications

Mammalian systems have developed extensive molecular mechanisms to protect against the toxicity of many exogenous xenobiotic compounds. Interestingly, many detoxification enzymes, including cytochrome P450s and flavin-containing monooxygenases, and their associated transcriptional activators [e.g. the aryl hydrocarbon receptor (AhR)], have now been shown to have endogenous roles in normal physiology and the pathology of metabolic diseases. This mini-review will focus on two such instances: the role of flavin-containing monooxygenase 3 (FMO3) in the formation of the cardiometabolic disease biomarker trimethylamine-N-oxide (TMAO) and the role of AhR as a sensor of endogenous ligands such as those generated by the gut microbiota. Understanding …

Exploring Individual And Structural Factors Associated With Employment Among Young Transgender Women Of Color Using A No-Cost Transgender Legal Resource Center, Brandon J. Hill, Kris Rosentel, Trevor Bak, Michael Silverman, Richard A. Crosby, Laura Salazar, Michele Kipke

Health, Behavior & Society Faculty Publications

Purpose: The purpose of this study was to explore individual and structural factors associated with employment among young transgender women (TW) of color.

Methods: Sixty-five trans women of color were recruited from the Transgender Legal Defense and Education Fund to complete a 30-min interviewer-assisted survey assessing sociodemographics, housing, workplace discrimination, job-seeking self-efficacy, self-esteem, perceived public passability, and transactional sex work.

Results: Logistic regression models revealed that stable housing (structural factor) and job-seeking self-efficacy (individual factor) were significantly associated with currently being employed.

Conclusion: Our findings underscore the need for multilevel approaches to assist TW of color gain employment.

Impact Of Nutrition On Pollutant Toxicity: An Update With New Insights Into Epigenetic Regulation, Jessie B. Hoffman, Michael C. Petriello, Bernhard Hennig

Superfund Research Center Faculty Publications

Exposure to environmental pollutants is a global health problem and is associated with the development of many chronic diseases, including cardiovascular disease, diabetes and metabolic syndrome. There is a growing body of evidence that nutrition can both positively and negatively modulate the toxic effects of pollutant exposure. Diets high in proinflammatory fats, such as linoleic acid, can exacerbate pollutant toxicity, whereas diets rich in bioactive and anti-inflammatory food components, including omega-3 fatty acids and polyphenols, can attenuate toxicant-associated inflammation. Previously, researchers have elucidated direct mechanisms of nutritional modulation, including alteration of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, …

Cytomegalovirus Serostatus, Inflammation, And Antibody Response To Influenza Vaccination In Older Adults: The Moderating Effect Of Beta Blockade, Rebecca G. Reed, Richard N. Greenberg, Suzanne C. Segerstrom

Psychology Faculty Publications

Cytomegalovirus (CMV) has been implicated as a factor in immunosenescence, including poor antibody response to vaccination and higher immune activation and inflammation. Some people may be more or less vulnerable to the negative effects of CMV. The present investigation tested the effects of beta-blocker use and chronological age on the associations between CMV and immunity in adults aged 60–91 (N=98; 69% CMV seropositive) who were administered the trivalent influenza vaccine for up to 5 years. Peak antibody response, corrected for baseline, and spring (persistent) antibody response, corrected for peak, were assessed, as well as beta-2 microglobulin (β2μ) and interleukin-6 (IL-6). …

Integrated Biomarker Profiling Of Smokers With Periodontitis, Radhakrishnan Nagarajan, Mohanad Al-Sabbagh, Dolph Dawson Iii, Jeffrey L. Ebersole

Institute for Biomedical Informatics Faculty Publications

Background

In the context of precision medicine, understanding patient‐specific variation is an important step in developing targeted and patient‐tailored treatment regimens for periodontitis. While several studies have successfully demonstrated the usefulness of molecular expression profiling in conjunction with single classifier systems in discerning distinct disease groups, the majority of these studies do not provide sufficient insights into potential variations within the disease groups.

Aim

The goal of this study was to discern biological response profiles of periodontitis and non‐periodontitis smoking subjects using an informed panel of biomarkers across multiple scales (salivary, oral microbiome, pathogens and other markers).

Material & Methods …

A Programmatic Approach To Long-Term Bridge Preventive Maintenance, Danny Wells, Bobby W. Meade, Theodore Hopwood Ii, Sudhir Palle

Kentucky Transportation Center Research Report

State transportation agencies use cost-effective preventive maintenance (PM) programs to preserve existing roadway systems, slow down their deterioration, and improve their functional condition. Currently, KYTC’s bridge inventory includes approximately 10,000 structures, and by 2018, most of these structures will have been in use for at least 50 years. Because there is insufficient funding available to pursue a large-scale bridge replacement program, it is critical for the Cabinet to prolong the lives of its bridges by using economical strategies. This report provides guidance that the Kentucky Transportation Cabinet (KYTC) can use to develop and implement a statewide bridge PM program. Drawing …

Epigenomic Reprogramming In Inorganic Arsenic-Mediated Gene Expression Patterns During Carcinogenesis, Meredith Eckstein, Rebekah Eleazer, Matthew Rea, Yvonne N. Fondufe-Mittendorf

Molecular and Cellular Biochemistry Faculty Publications

Arsenic is a ubiquitous metalloid that is not mutagenic but is carcinogenic. The mechanism(s) by which arsenic causes cancer remain unknown. To date, several mechanisms have been proposed, including the arsenic-induced generation of reactive oxygen species (ROS). However, it is also becoming evident that inorganic arsenic (iAs) may exert its carcinogenic effects by changing the epigenome, and thereby modifying chromatin structure and dynamics. These epigenetic changes alter the accessibility of gene regulatory factors to DNA, resulting in specific changes in gene expression both at the levels of transcription initiation and gene splicing. In this review, we discuss recent literature reports …

Habituation Of Distress And Craving During Treatment As Predictors Of Change In Ptsd Symptoms And Substance Use Severity, Christal L. Badour, Julianne C. Flanagan, Daniel F. Gros, Therese Killeen, Irene Pericot-Valverde, Kristina J. Korte, Nicholas P. Allan, Sudie E. Back

Psychology Faculty Publications

Objective—Increasing evidence supports the efficacy of trauma-focused exposure therapy in the treatment of posttraumatic stress disorder (PTSD) and co-occurring substance use disorders. Little is known, however, about the mechanisms of change in treatment for patients with PTSD and co-occurring substance use disorders. The aim of the present study was to examine whether within- and between-session habituation of distress and substance craving during imaginal exposure relates to treatment outcomes among U.S. military veterans with PTSD and a co-occurring substance use disorder (N = 54).

Method—Veterans received Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure, a manualized …

Using The Vehicle Routing Problem To Reduce Field Completion Times With Multiple Machines, Hasan Seyyedhasani, Joseph S. Dvorak

Biosystems and Agricultural Engineering Faculty Publications

The Vehicle Routing Problem (VRP) is a powerful tool used to express many logistics problems, yet unlike other vehicle routing challenges, agricultural field work consists of machine paths that completely cover a field. In this work, the allocation and ordering of field paths among a number of available machines has been transformed into a VRP that enables optimization of completion time for the entire field. A basic heuristic algorithm (a modified form of the common Clarke-Wright algorithm) and a meta-heuristic algorithm, Tabu Search, were employed for optimization. Both techniques were evaluated through computer simulations in two fields: a hypothetical basic …

Relb Expression Determines The Differential Effects Of Ascorbic Acid In Normal And Cancer Cells, Xiaowei Wei, Yong Xu, Fang Fang Xu, Luksana Chaiswing, David M. Schnell, Teresa Noel, Chi Wang, Jinfei Chen, Daret K. St. Clair, William H. St. Clair

Toxicology and Cancer Biology Faculty Publications

Cancer cells typically experience higher oxidative stress than normal cells, such that elevating pro-oxidant levels can trigger cancer cell death. Although pre-exposure to mild oxidative agents will sensitize cancer cells to radiation, this pre-exposure may also activate the adaptive stress defense system in normal cells. Ascorbic acid is a prototype redox modulator that when infused intravenously appears to kill cancers without injury to normal tissues; however, the mechanisms involved remain elusive. In this study, we show how ascorbic acid kills cancer cells and sensitizes prostate cancer to radiation therapy while also conferring protection upon normal prostate epithelial cells against radiation-induced …

Faster Self-Paced Rate Of Drinking For Alcohol Mixed With Energy Drinks Versus Alcohol Alone, Cecile A. Marczinski, Mark T. Fillmore, Sarah F. Maloney, Amy L. Stamates

Psychology Faculty Publications

The consumption of alcohol mixed with energy drinks (AmED) has been associated with higher rates of binge drinking and impaired driving when compared with alcohol alone. However, it remains unclear why the risks of use of AmED are heightened compared with alcohol alone even when the doses of alcohol consumed are similar. Therefore, the purpose of this laboratory study was to investigate if the rate of self-paced beverage consumption was faster for a dose of AmED versus alcohol alone using a double-blind, within-subjects, placebo-controlled study design. Participants (n = 16) of equal gender who were social drinkers attended 4 separate …

Effect Of Cigarette Smoke Exposure And Mutant Kras Overexpression On Pancreatic Cell Proliferation, Howard P. Glauert, R. Scott Elliott, Sung Gu Han, Mark Athey, Eun Young Lee, C. Gary Gairola

Pharmacology and Nutritional Sciences Faculty Publications

Pancreatic cancer is the fourth leading cause of cancer‑associated mortality. The major risk factor for pancreatic cancer is cigarette smoking. Kras mutations are commonly observed in human pancreatic cancers. The present study examined the hypothesis that exposure to cigarette smoke and overexpression of a mutant Kras gene in the pancreas affects pancreatic cell proliferation in mice. Mice overexpressing the mutant Kras gene (KRas^G12D) in the pancreas as well as wild‑type mice were exposed to environmental tobacco smoke for 2 weeks. Overexpression of mutant Kras increased cell proliferation in pancreatic ductal, acinar and islet cells. Notably, cigarette smoke exposure …

Developmental Origins Of Cardiovascular Disease: Impact Of Early Life Stress In Humans And Rodents, Margaret O. Murphy, Dianne M. Cohn, Analia S. Loria

Pharmacology and Nutritional Sciences Faculty Publications

The Developmental Origins of Health and Disease (DOHaD) hypothesizes that environmental insults during childhood programs the individual to develop chronic disease in adulthood. Emerging epidemiological data strongly supports that early life stress (ELS) given by the exposure to adverse childhood experiences is regarded as an independent risk factor capable of predicting future risk of cardiovascular disease. Experimental animal models utilizing chronic behavioral stress during postnatal life, specifically maternal separation (MatSep) provides a suitable tool to elucidate molecular mechanisms by which ELS increases the risk to develop cardiovascular disease, including hypertension. The purpose of this review is to highlight current epidemiological …

Toxicity Evaluation Of Magnetic Hyperthermia Induced By Remote Actuation Of Magnetic Nanoparticles In 3d Micrometastasic Tumor Tissue Analogs For Triple Negative Breast Cancer, Nathanael A. Stocke, Pallavi Sethi, Amar Jyoti, Ryan Chan, Susanne M. Arnold, J. Zach Hilt, Meenakshi Upreti

Chemical and Materials Engineering Faculty Publications

Magnetic hyperthermia as a treatment modality is acquiring increased recognition for loco-regional therapy of primary and metastatic lung malignancies by pulmonary delivery of magnetic nanoparticles (MNP). The unique characteristic of magnetic nanoparticles to induce localized hyperthermia in the presence of an alternating magnetic field (AMF) allows for preferential killing of cells at the tumor site. In this study we demonstrate the effect of hyperthermia induced by low and high dose of MNP under the influence of an AMF using 3D tumor tissue analogs (TTA) representing the micrometastatic, perfusion independent stage of triple negative breast cancer (TNBC) that infiltrates the lungs. …

Effectiveness Of A Home-Based Eccentric-Exercise Program On The Torque-Angle Relationship Of The Shoulder External Rotators: A Pilot Study, Timothy L. Uhl, Thomas Rice, Brianna M. Papotto, Timothy A. Butterfield

Physical Therapy Faculty Publications

Context: The role of the rotator cuff is to provide dynamic stability to the glenohumeral joint. Human and animal studies have identified sarcomerogenesis as an outcome of eccentric training indicated by more torque generation with the muscle in a lengthened position. Objective: The authors hypothesized that a home-based eccentric-exercise program could increase the shoulder external rotators’ eccentric strength at terminal internal rotation (IR). Design: Prospective case series. Setting: Clinical laboratory and home exercising. Participants: 10 healthy subjects (age 30 ± 10 y). Intervention: All participants performed 2 eccentric exercises targeting the posterior shoulder for 6 wk using a home-based intervention …