Valine improves mitochondrial function and protects against oxidative stress.

Among the branched-chain amino acids, leucine and isoleucine have been well studied for their roles in improving mitochondrial function and reducing oxidative stress. However, role of valine in mitochondrial function regulation and oxidative stress management remains elusive. This study investigated valine effect on mitochondrial function and oxidative stress in vitro. Valine increased expression of genes involved in mitochondrial biogenesis and dynamics. It upregulates mitochondrial function at complexes I, II, and IV levels of electron transport chain. Flow cytometry studies revealed, valine reduced oxidative stress by significantly lowering mitochondrial reactive oxygen species and protein expression of 4-hydroxynonenal. Functional role of valine against oxidative stress was analyzed by XFe96 Analyzer. Valine sustained oxidative phosphorylation and improved ATP generation rates during oxidative stress. In conclusion, our findings shed more light on the critical function of valine in protecting mitochondrial function thereby preventing mitochondrial/cellular damage induced by oxidative stress.

P. gingivalis-LPS Induces Mitochondrial Dysfunction Mediated by Neuroinflammation through Oxidative Stress.

Porphyromonas gingivalis (P. gingivalis), a key pathogen in periodontitis, is associated with neuroinflammation. Periodontal disease increases with age; 70.1% of adults 65 years and older have periodontal problems. However, the P. gingivalis- lipopolysaccharide (LPS)induced mitochondrial dysfunction in neurodegenerative diseases remains elusive. In this study, we investigated the possible role of P. gingivalis-LPS in mitochondrial dysfunction during neurodegeneration. We found that P. gingivalis-LPS treatment activated toll-like receptor (TLR) 4 signaling and upregulated the expression of Alzheimer's disease-related dementia and neuroinflammatory markers. Furthermore, the LPS treatment significantly exacerbated the production of reactive oxygen species and reduced the mitochondrial membrane potential. Our study highlighted the pivotal role of P. gingivalis-LPS in the repression of serum response factor (SRF) and its co-factor p49/STRAP that regulate the actin cytoskeleton. The LPS treatment repressed the genes involved in mitochondrial function and biogenesis. P. gingivalis-LPS negatively altered oxidative phosphorylation and glycolysis and reduced total adenosine triphosphate (ATP) production. Additionally, it specifically altered the mitochondrial functions in complexes I, II, and IV of the mitochondrial electron transport chain. Thus, it is conceivable that P. gingivalis-LPS causes mitochondrial dysfunction through oxidative stress and inflammatory events in neurodegenerative diseases.

Rho/SRF Inhibitor Modulates Mitochondrial Functions.

CCG-1423 is a Rho A pathway inhibitor that has been reported to inhibit Rho/SRF-mediated transcriptional regulation. Serum response factor and its cofactors, which include ternary complex factors and myocardin-related transcription factors, regulate various cellular functions. In this study, we observed that CCG-1423 modulates the mitochondrial functions. The effect of this small molecule drug was determined by measuring mitochondrial function using an XFe96 Analyzer and an Oxygraph 2k (O2k) high-resolution respirometer. CCG-1423 treatment significantly reduced oxidative phosphorylation in a dose-dependent manner. However, CCG-1423 increased the glycolytic rate. We also observed that histone 4 at lysine-16 underwent hyperacetylation with the treatment of this drug. Immunolabeling with F-actin and MitoTracker revealed the alteration in the actin cytoskeleton and mitochondria. Taken together, our findings highlight a critical role of CCG-1423 in inhibiting the transcription of SRF/p49 and PGC-1α, ß, resulting in the downregulation of mitochondrial genes, leading to the repression of mitochondrial oxidative phosphorylation and overall ATP reduction. This study provides a better understanding of the effects of CCG-1423 on mitochondria, which may be useful for the assessment of the potential clinical application of CCG-1423 and its derivatives.

Alternative Splicing Increases Sirtuin Gene Family Diversity and Modulates Their Subcellular Localization and Function.

Alternative splicing generates multiple distinct isoforms that increase transcriptome and proteome diversity. There are seven sirtuin genes in humans, each consists of multiple exons that are likely to undergo alternative splicing. Our aim was to characterize the effect of alternative splicing on the sirtuin genes. Here, we report the identification of 23 human sirtuin isoforms, most of which were not previously reported. Five of the sirtuin genes had more than one isoform, whereas sirtuin-6 had nine isoforms. Exon skipping was the main event. Most of the sirtuin isoforms were deficient in parts of the protein domains, including the catalytic domain, the N- or C-terminus, nuclear localization signal or mitochondrial targeting signal. The domain loss caused potential structural changes. Three SIRT1 isoforms had a differential effect on the mitochondrial oxygen consumption rate. Age-related changes in the expression of SIRT1 isoforms were observed in the human heart in fetus, adults, and very old individuals. We also identified 15 sirtuin isoforms in mice. Our data indicate that alternative splicing increases sirtuin gene diversity and may modulate subcellular localization and function, thereby adding complexity to the gene regulation of mitochondrial respiration, metabolism, and cardiac function during maturation and aging.

Overexpression of p49/STRAP alters cellular cytoskeletal structure and gross anatomy in mice.

BACKGROUND: The protein p49/STRAP (SRFBP1) is a transcription cofactor of serum response factor (SRF) which regulates cytoskeletal and muscle-specific genes. RESULTS: Two conserved domains were found in the p49/STRAP protein. The SRF-binding domain was at its N-terminus and was highly conserved among mammalian species, xenopus and zebrafish. A BUD22 domain was found at its C-terminus in three sequence databases. The BUD22 domain was conserved among mammalian p49/STRAP proteins, and yeast cellular morphogenesis proteins, which is involved in ribosome biogenesis that affects growth rate and cell size. The endogenous p49/SRAP protein was localized mainly in the nucleus but also widely distributed in the cytoplasm, and was in close proximity to the actin. Transfected GFP-p49/STRAP protein co-localized with nucleolin within the nucleolus. Overexpression of p49/STRAP reduced actin content in cultured cells and resulted in smaller cell size versus control cells. Increased expression of p49/STRAP in transgenic mice resulted in newborns with malformations, which included asymmetric abdominal and thoracic cavities, and substantial changes in cardiac morphology. p49/STRAP altered the expression of certain muscle-specific genes, including that of the SRF gene, which is a key regulator of cardiac genes at the developmental, structural and maintenance level and has two SRE binding sites. CONCLUSIONS: Since p49/STRAP is a co-factor of SRF, our data suggest that p49/STRAP likely regulates cell size and morphology through SRF target genes. The function of its BUD22 domain warrants further investigation. The observed increase in p49/STRAP expression during cellular aging may contribute to observed morphological changes in senescence.

Predicting coronary heart disease events in women: a longitudinal cohort study.

BACKGROUND: More than 240 000 women in the United States die of coronary heart disease annually. Identifying women's symptoms that predict a coronary heart disease event such as myocardial infarction (MI) could decrease mortality. OBJECTIVE: For this longitudinal observational study, we recruited 1097 women, who were either clinician referred or self-referred to a cardiologist and undergoing initial evaluation by a cardiologist, to assess the utility of the prodromal symptoms (PS) section of the McSweeney Acute and Prodromal Myocardial Infarction Symptom Survey (MAPMISS) in predicting the occurrence of cardiac events in women. METHODS AND RESULTS: Seventy-seven women experienced events (angioplasty, stent placement, coronary artery bypass, MI, death) during the 2-year follow up. The most common events were stents alone (38.9%) or in combination with angioplasty (18.2%). Ten women had MIs; 4 experienced cardiac death. Cox proportional hazards was used to model time to event. The prodromal score was significantly associated with risk of an event (hazard ratio, 1.10; 95% confidence interval, 1.06-1.13), as was the number of PSs endorsed by each woman per visit. After covariate adjustment, 5 symptoms were significantly associated with increased risk: discomfort in jaws/teeth, unusual fatigue, arm discomfort, shortness of breath, and general chest discomfort (hazard ratio, 3.97; 95% confidence interval, 2.32-6.78). Women reporting 1 or more of these symptoms were 4 times as likely to experience a cardiac event as women with none. CONCLUSIONS: Both the MAPMISS PS scores and number of PS were significantly associated with cardiac events, independent of risk factors, suggesting that there are specific PSs that can be easily assessed using the MAPMISS. This instrument could be an important component of a predictive screen to assist clinicians in deciding the course of management for women.

Diagnosing Alzheimer's disease: update for the primary care clinician.

Alzheimer's disease (AD) affects approximately 5.3 million Americans. Recently, new diagnostic criteria advanced by the National Institute of Aging have significantly improved our understanding of the AD continuum across several stages and is more scientifically based compared to the previously formulated criteria in 1984. Use by primary care physicians of these new clinical criteria coupled with the understanding of the role of biomarkers will help you to make accurate diagnoses earlier in the disease process when intervention can be most beneficial.

RNA sequencing of formalin fixed paraffin-embedded heart tissue provides transcriptomic information about chemotherapy-induced cardiotoxicity.

Gene expression of formalin-fixed paraffin-embedded (FFPE) tissue may serve for molecular studies on cardiovascular diseases. Chemotherapeutics, such as doxorubicin (DOX) may cause heart injury, but the mechanisms of these side effects of DOX are not well understood. This study aimed to investigate whether DOX-induced gene expression in archival FFPE heart tissue in experimental rats would correlate with the gene expression in fresh-frozen heart tissue by applying RNA sequencing technology. The results showed RNA from FFPE samples was degraded, resulting in a lower number of uniquely mapped reads. However, DOX-induced differentially expressed genes in FFPE were related to molecular mechanisms of DOX-induced cardiotoxicity, such as inflammation, calcium binding, endothelial dysfunction, senescence, and cardiac hypertrophy signaling. Our data suggest that, despite the limitations, RNA sequencing of archival FFPE heart tissue supports utilizing FFPE tissues from retrospective studies on cardiovascular disorders, including DOX-induced cardiotoxicity.

Inhibitors of Rho/MRTF/SRF Transcription Pathway Regulate Mitochondrial Function.

RhoA-regulated gene transcription by serum response factor (SRF) and its transcriptional cofactor myocardin-related transcription factors (MRTFs) signaling pathway has emerged as a promising therapeutic target for pharmacological intervention in multiple diseases. Altered mitochondrial metabolism is one of the major hallmarks of cancer, therefore, this upregulation is a vulnerability that can be targeted with Rho/MRTF/SRF inhibitors. Recent advances identified a novel series of oxadiazole-thioether compounds that disrupt the SRF transcription, however, the direct molecular target of these compounds is unclear. Herein, we demonstrate the Rho/MRTF/SRF inhibition mechanism of CCG-203971 and CCG-232601 in normal cell lines of human lung fibroblasts and mouse myoblasts. Further studies investigated the role of these molecules in targeting mitochondrial function. We have shown that these molecules hyperacetylate histone H4K12 and H4K16 and regulate the genes involved in mitochondrial function and dynamics. These small molecule inhibitors regulate mitochondrial function as a compensatory mechanism by repressing oxidative phosphorylation and increasing glycolysis. Our data suggest that these CCG molecules are effective in inhibiting all the complexes of mitochondrial electron transport chains and further inducing oxidative stress. Therefore, our present findings highlight the therapeutic potential of CCG-203971 and CCG-232601, which may prove to be a promising approach to target aberrant bioenergetics.

Deletion of Interleukin-1ß Converting Enzyme Alters Mouse Cardiac Structure and Function.

Interleukin-1ß converting enzyme (ICE, caspase-1) is a thiol protease that cleaves the pro-inflammatory cytokine precursors of IL-1ß and IL-18 into active forms. Given the association between caspase-1 and cardiovascular pathology, we analyzed the hearts of ICE knockout (ICE KO) mice to test the hypothesis that caspase-1 plays a significant role in cardiac morphology and function. We characterized the histological and functional changes in the hearts of ICE KO mice compared to the Wild type. The cardiomyocytes from the neonatal ICE KO mice showed an impaired response to oxidative stress. Subsequently, the hearts from the ICE KO mice were hypertrophied, with a significant increase in the left ventricular and septal wall thickness and a greater LV mass/body weight ratio. The ICE KO mice hearts exhibited irregular myofibril arrangements and disruption of the cristae in the mitochondrial structure. Proapoptotic proteins that were significantly increased in the hearts of ICE KO versus the Wild type included pErk, pJNK, p53, Fas, Bax, and caspase 3. Further, the antiapoptotic proteins Bag-1 and Bcl-2 are activated in ICE KO hearts. Functionally, there was an increase in the left ventricular epicardial diameter and volume in ICE KO. In conclusion, our findings support the important role of caspase-1 in maintaining cardiac health; specifically, a significant decrease in caspase-1 is detrimental to the cardiovascular system.

Proteomic analysis of P. gingivalis-Lipopolysaccharide induced neuroinflammation in SH-SY5Y and HMC3 cells.

Chronic periodontitis and its keystone pathogen, Porphyromonas gingivalis, have increasingly been linked with Alzheimer's disease (AD). However, P.gingivalis-lipopolysaccharide (LPS) mediated release of neuroinflammatory proteins contributes to AD remains underexplored. In this study, we utilized data-independent acquisition mass spectrometry to characterize P.gingivalis-LPS induced profile of differentially expressed proteins associated with the neuroinflammatory response in human neuroblastoma (SH-SY5Y) and human microglial (HMC3) cells. We reported a set of 124 proteins in SH-SY5Y cells and 96 proteins in HMC3 cells whose levels were significantly upregulated or downregulated by exposure to P. gingivalis-LPS. Our findings demonstrate that P. gingivalis-LPS contributed to the elevated expressions of dementia biomarkers and pro-inflammatory cytokines that include APP, Aß1-42, Aß1-40, T-Tau, p-Tau, VEGF, TGF-ß, IL-1ß, IL-6 and TNF-α through 2 distinct pathways of extracellular sensing by cell surface receptors and intracellular cytosolic receptors. Interestingly, intracellular signaling proteins activated with P. gingivalis-LPS transfection using Lipofectamine™ 2000 had significantly higher fold change protein expression compared to the extracellular signaling with P. gingivalis-LPS treatment. Additionally, we also explored P. gingivalis-LPS mediated activation of caspase-4 dependent non canonical inflammasome pathway in both SH-SY5Y and HMC3 cells. In summary, P. gingivalis-LPS induced neuroinflammatory protein expression in SH-SY5Y and HMC3 cells, provided insights into the specific inflammatory pathways underlying the potential link between P. gingivalis-LPS infection and the pathogenesis of Alzheimer's disease and related dementias.

Short-Term Ingestion of Essential Amino Acid Based Nutritional Supplements or Whey Protein Improves the Physical Function of Older Adults Independently of Gut Microbiome.

SCOPE: Dietary proteins and essential amino acids (EAAs) are the major nutritional supplements that support the growth and activity of gut microbes contributing to the wellbeing of their host. This study hypothesizes that daily supplementation of the diet with either EAAs or whey protein for 12 weeks would improve the gut microbiome of older adults. METHODS AND RESULTS: The stool samples are processed and subjected to Illumina-based 16S ribosomal ribonucleic acid (rRNA) gene amplicon sequencing. In both groups, the most abundant families are found in order of relative abundance included: Bacteroidaceae, Lachnospiraceae, Ruminococcaceae, Prevotellaceae, Rikenellaceae, Enterobacteriaceae, Oscillospiraceae, Tannerellaceae, and Akkermansiaceae, which indicate that these subjects are able to maintain a same healthy microbial diversity in their guts. A significant finding is a reduction of proinflammatory cytokine, interleukin-18 (IL-18) in the EAAs group. It also uses the standard 6-min walking test (6MWT) as a measure of cardiopulmonary fitness. At the end of the study, the subjects in the EAAs group perform significantly better in the 6MWT as compared to the whey group. CONCLUSION: It seems plausible that the improved physical performance and reduced proinflammatory cytokine, IL-18 seen in the EAAs group, are independent of changes in gut microbiota.

The Importance of Dopamine Deficiency Evaluation in Non-Alzheimer Disease Dementias.

BACKGROUND Dementia with Lewy bodies (DLB) is a common cause of dementia. Given the similarities between the symptoms of DLB and non-DLB Alzheimer disease (AD) and related dementias, patients can sometimes be misdiagnosed with AD. To increase the sensitivity of current DLB guidelines, the DLB Consortium published its fourth revised report in 2017 with increased diagnostic weight given to dopamine transporter (DAT) uptake in the basal ganglia, demonstrated by single-photon emission computed tomography or positron emission tomography imaging. We aimed to describe the role of DAT scans in evaluating dopamine deficiency in patients with overlapping symptoms of AD and DLB. CASE REPORT We present case studies of 3 patients with memory impairment who had a diagnosis of probable AD and were being treated with cholinesterase inhibitors. During treatment, dopamine deficiency was suspected and DAT scans were performed. All 3 patients revealed severe DAT deficits in the bilateral corpus striatum. These results were consistent with probable DLB as per the current revised DLB Consortium report. All patients received treatment with carbidopa/levodopa and demonstrated improved overall function. CONCLUSIONS All 3 of our cases demonstrated the role of DAT scans in evaluating dopamine deficiency syndromes in patients with overlapping symptoms of neurocognitive disorders. Thus, a DAT scan is critical for establishing an earlier and more definitive diagnosis of DLB, which provides treatment options for dopamine replacement. It also assists providers with prognostication of dopamine deficiency syndromes and is therefore beneficial in counseling patients and caregivers.

Differential plasma protein expression after ingestion of essential amino acid-based dietary supplement verses whey protein in low physical functioning older adults.

In a recent randomized, double-blind, placebo-controlled trial, we were able to demonstrate the superiority of a dietary supplement composed of essential amino acids (EAAs) over whey protein, in older adults with low physical function. In this paper, we describe the comparative plasma protein expression in the same subject groups of EAAs vs whey. The plasma proteomics data was generated using SOMA scan assay. A total of twenty proteins were found to be differentially expressed in both groups with a 1.5-fold change. Notably, five proteins showed a significantly higher fold change expression in the EAA group which included adenylate kinase isoenzyme 1, casein kinase II 2-alpha, Nascent polypeptide-associated complex subunit alpha, peroxiredoxin-1, and peroxiredoxin-6. These five proteins might have played a significant role in providing energy for the improved cardiac and muscle strength of older adults with LPF. On the other hand, fifteen proteins showed slightly lower fold change expression in the EAA group. Some of these 15 proteins regulate metabolism and were found to be associated with inflammation or other comorbidities. Gene Ontology (GO) enrichment analysis showed the association of these proteins with several biological processes. Furthermore, protein-protein interaction network analysis also showed distinct networks between upregulated and downregulated proteins. In conclusion, the important biological roles of the upregulated proteins plus better physical function of participants in the EAAs vs whey group demonstrated that EAAs have the potential to improve muscle strength and physical function in older adults. This study was registered with ClinicalTrials.gov: NCT03424265 "Nutritional interventions in heart failure."

Disparity and Multimorbidity in Heart Failure Patients Over the Age of 80.

Background: Healthcare is currently struggling to provide access and coverage for an increasingly diverse aging population who frequently have multiple co-morbid conditions complicating their care and medical management. Methods: This retrospective study analyzed the prevalence and distribution of common co-morbid conditions (hypertension, dyslipidemia, dementia, and diabetes mellitus) in 316 elderly heart failure patients (age range 80-103; mean 87 ±4.9). Results: Chart review analysis showed a racial distribution of 65 African American versus 251 Caucasian patients (21 vs. 79%). Hypertension was comparable in both groups (98.5% African American vs. 92.4% Caucasian). Dyslipidemia, diabetes and dementia diagnoses were all approximately 20% higher in African American versus Caucasian patients. The concurrent presence of all four conditions was approximately three times more prevalent in African Americans (18.5%) versus Caucasians (7.2%). Conclusion: Our study is unique for studying disparity in octogenarian and nonagenarians residing in a rural setting. Our results also highlight the importance of making a special effort to engage older African American patients in seeking healthcare. In addition, strategies must be designed to reduce barriers that impede access and availability of resources and clinical care, especially in economically underserved regions of the country.

A qualitative study of older adults' facilitators, barriers, and cues to action to engage in falls prevention using health belief model constructs.

BACKGROUND AND OBJECTIVES: Falls are the leading cause of fatal and nonfatal injuries among older adults. Decreasing falls is highly dependent on engagement in fall prevention activities. The Health Belief Model (HBM) theoretical framework was used to explore older adults' perceptions about falls prevention. RESEARCH DESIGN AND METHODS: An informed grounded theory approach was applied. Four focus groups were conducted using semi-structured interview guides based on the HBM with 27 community-dwelling older adults (average age = 78 years). Deductive content analysis was used to apply constructs of the HBM to the data and explain the findings. RESULTS: Potential reasons for not engaging in falls prevention included lack of self-perceived severity, susceptibility, and self-efficacy with a subtheme of lack of information about falls prevention from medical providers. Potential facilitators included older adults' knowledge and current engagement in falls prevention and socializing while engaging in falls prevention. Participants recommended cues to action to improve engagement in falls prevention from family, friends, physicians, pharmacists, and insurance companies; and using various modes to deliver cues to action, including print, audiovisual, online, and reminders. DISCUSSION AND IMPLICATIONS: In this study, the HBM was used to understand older adults' potential barriers, facilitators, and cues to action to support engagement in falls prevention. Engagement in fall prevention behaviors could be improved by addressing barriers such as lack of knowledge, and lack of self-perceived severity and susceptibility to falls. Reinforcing the benefits of fall prevention, and promoting cues to action to engage in falls prevention may also support engagement.

Older Adults' Perceptions and Recommendations Regarding a Falls Prevention Self-Management Plan Template Based on the Health Belief Model: A Mixed-Methods Study.

Falls are the leading cause of fatal and non-fatal injuries among older adults. Self-management plans have been used in different contexts to promote healthy behaviors, but older adults' perceptions of a falls prevention self-management plan template have not been investigated. Using mixed methods, we investigated older adults' perceptions and recommendations of a falls prevention self-management plan template aligned with the Health Belief Model. Four focus groups (n = 27, average age 78 years) were conducted using semi-structured interview guides. Participants also ranked the written plan on paper with respect to each item by the level of importance, where item 1 was the most important, and 10 was the least important. Focus groups were transcribed and analyzed. Descriptive statistics were calculated for item rankings. Older adults felt that the plan would raise awareness and help them to engage in falls prevention behaviors. Participants recommended adding graphics and using red to highlight the risk of falling. Participants opined that ranking the items by level of importance was challenging because they felt all items were important. 'What might happen to me if I fall' was ranked as the most important item (average 2.6), while 'How will I monitor progress' was the least important (average = 6.6). Considering that older adults need support to engage in falls prevention, future research should investigate the impact of implementing an individually tailored falls prevention self-management plan on older adults' engagement in falls prevention behaviors and outcomes of falls and injuries.

Quality Improvement in Delirium Health Literacy in Older Adult Patients and Their Caregivers Attending a Geriatric Clinic.

Background: Delirium is a common medical condition that is highly prevalent in older adults who are at increased risk for its development with any illness, post-surgery or during hospitalization. The purpose of our study was to evaluate the health literacy of older adult patients and their caregivers about delirium, offer a brief educational intervention, and reevaluate their knowledge post intervention. Materials and Methods: We conducted a quality improvement project, focused on delirium health literacy in older adult patients ≥60 years and their caregivers. Delirium knowledge of participants was evaluated in a pre-education survey after which they were given a delirium education booklet to read. A post-education delirium survey was conducted within 2-3 weeks of the educational intervention. Chi-square test was used to analyze the knowledge base of older adults. Results: The study population consisted of a total of 70 older adults who participated in pre-education (n=35) and post-education (n=35) surveys. Older adult patients and their caregivers had significant knowledge gaps about the potential causes or etiologies, risk factors, symptomatology, and prevention of delirium in the pre-education survey. After the educational intervention, in the post-education survey, there were overall improvements in knowledge base of older adults in differentiating delirium with dementia (43% vs 94%, p<0.01) recognizing signs and symptoms (77% vs 94%, p<0.05), complications (76% vs 100%, p<0.01) and identifying the etiological factors associated with delirium. Conclusion: The quality improvement project demonstrated that older adults and caregivers have significant knowledge deficits about the common condition of delirium. This study also demonstrated that older adults were able to improve their health literacy regarding delirium after the intervention. Appropriate education on delirium for patients and caregivers might help in earlier identification, prevention, and better overall management of delirium.

Older Adults' Perceptions Regarding the Role of Physical Therapists in Fall Prevention: A Qualitative Investigation.

BACKGROUND AND PURPOSE: Falls are a leading cause of injury, morbidity, and mortality among older adults. Physical therapists are underutilized for fall prevention despite strong evidence and recommendations regarding their effectiveness. The purpose of this study was to explore older adults' awareness of and perceptions regarding the role of physical therapists for fall prevention. A secondary purpose of the study was to identify barriers to utilization of preventive rehabilitation services. METHODS: A qualitative, descriptive, phenomenological approach was used. Participant demographics and fall history were obtained with a standard questionnaire. Four focus groups were conducted with 27 community-dwelling older adults (average age = 78 years). Focus groups were recorded, transcribed, and coded using thematic analysis. RESULTS: Surveys indicated 37% of participants experienced a fall in the last year and 26% reported sustaining an injury. Four main themes and 5 subthemes about older adults' perceptions of physical therapy providers emerged: (1) awareness of fall prevention (subthemes: I can or have taken action to prevent falls, I don't think about it, and I am more careful); (2) learning how to fall and being able to get up from the floor; (3) limited knowledge regarding the role of physical therapists for fall prevention; and (4) a physical therapist should be seen for a specific problem, or after a fall (subthemes: perceived need and costs, and access requires a doctor's prescription). CONCLUSION: Older adults lack awareness about the role of physical therapists for fall prevention, believing they should only seek treatment from a physical therapist to address a specific problem, or after a fall. The profession should consider addressing misconceptions and underutilization by educating the public that physical therapists can and do play an important role in the prevention of falls. Being explicit about the prevention of falls throughout an older adults' episode of care may further help reinforce the role of physical therapists for fall prevention and improve dissemination of this knowledge.

Regulation of cardiac microRNAs by serum response factor.

Serum response factor (SRF) regulates certain microRNAs that play a role in cardiac and skeletal muscle development. However, the role of SRF in the regulation of microRNA expression and microRNA biogenesis in cardiac hypertrophy has not been well established. In this report, we employed two distinct transgenic mouse models to study the impact of SRF on cardiac microRNA expression and microRNA biogenesis. Cardiac-specific overexpression of SRF (SRF-Tg) led to altered expression of a number of microRNAs. Interestingly, downregulation of miR-1, miR-133a and upregulation of miR-21 occurred by 7 days of age in these mice, long before the onset of cardiac hypertrophy, suggesting that SRF overexpression impacted the expression of microRNAs which contribute to cardiac hypertrophy. Reducing cardiac SRF level using the antisense-SRF transgenic approach (Anti-SRF-Tg) resulted in the expression of miR-1, miR-133a and miR-21 in the opposite direction. Furthermore, we observed that SRF regulates microRNA biogenesis, specifically the transcription of pri-microRNA, thereby affecting the mature microRNA level. The mir-21 promoter sequence is conserved among mouse, rat and human; one SRF binding site was found to be in the mir-21 proximal promoter region of all three species. The mir-21 gene is regulated by SRF and its cofactors, including myocardin and p49/Strap. Our study demonstrates that the downregulation of miR-1, miR-133a, and upregulation of miR-21 can be reversed by one single upstream regulator, SRF. These results may help to develop novel therapeutic interventions targeting microRNA biogenesis.