HSF1 induces RNA polymerase II synthesis of ribosomal RNA in S. cerevisiae during nitrogen deprivation.

The resource intensive process of accurate ribosome synthesis is essential for cell viability in all organisms. Ribosome synthesis regulation centers on RNA polymerase I (pol I) transcription of a 35S rRNA precursor that is processed into the mature 18S, 5.8S and 25S rRNAs. During nutrient deprivation or stress, pol I synthesis of rRNA is dramatically reduced. Conversely, chronic stress such as mitochondrial dysfunction induces RNA polymerase II (pol II) to transcribe functional rRNA using an evolutionarily conserved cryptic pol II rDNA promoter suggesting a universal phenomenon. However, this polymerase switches and its role in regulation of rRNA synthesis remain unclear. In this paper, we demonstrate that extended nitrogen deprivation induces the polymerase switch via components of the environmental stress response. We further show that the switch is repressed by Sch9 and activated by the stress kinase Rim15. Like stress-induced genes, the switch requires not only pol II transcription machinery, including the mediator, but also requires the HDAC, Rpd3 and stress transcription factor Hsf1. The current work shows that the constitutive allele, Hsf1PO4* displays elevated levels of induction in non-stress conditions while binding to a conserved site in the pol II rDNA promoter upstream of the pol I promoter. Whether the polymerase switch serves to provide rRNA when pol I transcription is inhibited or fine-tunes pol I initiation via RNA interactions is yet to be determined. Identifying the underlying mechanism for this evolutionary conserved phenomenon will help understand the mechanism of pol II rRNA synthesis and its role in stress adaptation.

Structure-guided discovery of a novel, potent, and orally bioavailable 3,5-dimethylisoxazole aryl-benzimidazole BET bromodomain inhibitor.

The bromodomain and extra-terminal (BET) family of proteins, consisting of the bromodomains containing protein 2 (BRD2), BRD3, BRD4, and the testis-specific BRDT, are key epigenetic regulators of gene transcription and has emerged as an attractive target for anticancer therapy. Herein, we describe the discovery of a novel potent BET bromodomain inhibitor, using a systematic structure-based approach focused on improving potency, metabolic stability, and permeability. The optimized dimethylisoxazole aryl-benzimidazole inhibitor exhibited high potency towards BRD4 and related BET proteins in biochemical and cell-based assays and inhibited tumor growth in two proof-of-concept preclinical animal models.

Mitotic Activation of a Novel Histone Deacetylase 3-Linker Histone H1.3 Protein Complex by Protein Kinase CK2.

Histone deacetylase 3 (HDAC3) and linker histone H1 are involved in both chromatin compaction and the regulation of mitotic progression. However, the mechanisms by which HDAC3 and H1 regulate mitosis and the factors controlling HDAC3 and H1 activity during mitosis are unclear. Furthermore, as of now, no association between class I, II, or IV (non-sirtuin) HDACs and linker histones has been reported. Here we describe a novel HDAC3-H1.3 complex containing silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) and nuclear receptor corepressor 1 (N-CoR) that accumulated in synchronized HeLa cells in late G2 phase and mitosis. Nonetheless, the deacetylation activity by HDAC3 in the complex was evident only in mitotic complexes. HDAC3 associated with H1.3 was highly phosphorylated on Ser-424 only during mitosis. Isolation of inactive HDAC3-H1.3 complexes from late G2 phase cells, and phosphorylation of HDAC3 in the complexes at serine 424 by protein kinase CK2 (also known as casein kinase 2) activated the HDAC3 in vitro. In vivo, CK2α and CK2α' double knockdown cells demonstrated a significant decrease in HDAC3 Ser-424 phosphorylation during mitosis. HDAC3 and H1.3 co-localized in between the chromosomes, with polar microtubules and spindle poles during metaphase through telophase, and partially co-localized with chromatin during prophase and interphase. H1 has been reported previously to associate with microtubules and, therefore, could potentially function in targeting HDAC3 to the microtubules. We suggest that phosphorylation of HDAC3 in the complex by CK2 during mitosis activates the complex for a dual role: compaction of the mitotic chromatin and regulation of polar microtubules dynamic instability.

An intrinsically disordered region of methyl-CpG binding domain protein 2 (MBD2) recruits the histone deacetylase core of the NuRD complex.

The MBD2-NuRD (Nucleosome Remodeling and Deacetylase) complex is an epigenetic reader of DNA methylation that regulates genes involved in normal development and neoplastic diseases. To delineate the architecture and functional interactions of the MBD2-NuRD complex, we previously solved the structures of MBD2 bound to methylated DNA and a coiled-coil interaction between MBD2 and p66α that recruits the CHD4 nucleosome remodeling protein to the complex. The work presented here identifies novel structural and functional features of a previously uncharacterized domain of MBD2 (MBD2IDR). Biophysical analyses show that the MBD2IDR is an intrinsically disordered region (IDR). However, despite this inherent disorder, MBD2IDR increases the overall binding affinity of MBD2 for methylated DNA. MBD2IDR also recruits the histone deacetylase core components (RbAp48, HDAC2 and MTA2) of NuRD through a critical contact region requiring two contiguous amino acid residues, Arg(286) and Leu(287). Mutating these residues abrogates interaction of MBD2 with the histone deacetylase core and impairs the ability of MBD2 to repress the methylated tumor suppressor gene PRSS8 in MDA-MB-435 breast cancer cells. These findings expand our knowledge of the multi-dimensional interactions of the MBD2-NuRD complex that govern its function.

Aerobic fitness impacts sympathoadrenal axis responses to concurrent challenges.

The combination of mental and physical challenges can elicit exacerbated cardiorespiratory (CR) and catecholamine responses above that of a single challenge alone. PURPOSE: This study examined the effects of a combination of acute mental challenges and physical stress on cardiorespiratory and catecholamine responses. METHOD: Eight below-average fitness (LF VO2max = 36.58 ± 3.36 ml-1 kg-1 min-1) and eight above-average fitness (HF VO2max = 51.18 ± 2.09 ml-1 kg-1 min-1) participants completed an exercise-alone condition (EAC) session consisting of moderate-intensity cycling at 60% VO2max for 37 min, and a dual-challenge condition (DCC) that included concurrent participation in mental challenges while cycling. RESULT: The DCC resulted in increases in perceived workload, CR, epinephrine, and norepinephrine responses overall. HF participants had greater absolute CR and catecholamine responses compared to LF participants and quicker HR recovery after the dual challenge. CONCLUSION: These findings demonstrate that cardiorespiratory fitness does impact the effect of concurrent stressors on CR and catecholamine responses.

Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-δ, as therapy for previously treated indolent non-Hodgkin lymphoma.

Idelalisib (GS-1101, CAL-101), an oral inhibitor of phosphatidylinositol 3-kinase-δ, was evaluated in a phase I study in 64 patients with relapsed indolent non-Hodgkin lymphoma (iNHL). Patients had a median (range) age of 64 (32-91) years, 34 (53%) had bulky disease (≥1 lymph nodes ≥5 cm), and 37 (58%) had refractory disease. Patients had received a median (range) of 4 (1-10) prior therapies. Eight dose regimens of idelalisib were evaluated; idelalisib was taken once or twice daily continuously at doses ranging from 50 to 350 mg. After 48 weeks, patients still benefitting (n = 19; 30%) enrolled into an extension study. Adverse events (AEs) occurring in 20% or more patients (total%/grade ≥3%) included diarrhea (36/8), fatigue (36/3), nausea (25/3), rash (25/3), pyrexia (20/3), and chills (20/0). Laboratory abnormalities included neutropenia (44/23), anemia (31/5), thrombocytopenia (25/11), and serum transaminase elevations (48/25). Twelve (19%) patients discontinued therapy due to AEs. Idelalisib induced disease regression in 46/54 (85%) of evaluable patients achieving an overall response rate of 30/64 (47%), with 1 patient having a complete response (1.6%). Median duration of response was 18.4 months, median progression-free survival was 7.6 months. Idelalisib is well tolerated and active in heavily pretreated, relapsed/refractory patients with iNHL. These trials were registered at clinicaltrials.gov as NCT00710528 and NCT01090414.

Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia.

In a phase 1 trial, idelalisib (GS-1101, CAL-101), a selective inhibitor of the lipid kinase PI3Kδ, was evaluated in 54 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) with adverse characteristics including bulky lymphadenopathy (80%), extensive prior therapy (median 5 [range 2-14] prior regimens), treatment-refractory disease (70%), unmutated IGHV (91%), and del17p and/or TP53 mutations (24%). Patients were treated at 6 dose levels of oral idelalisib (range 50-350 mg once or twice daily) and remained on continuous therapy while deriving clinical benefit. Idelalisib-mediated inhibition of PI3Kδ led to abrogation of Akt phosphorylation in patient CLL cells and significantly reduced serum levels of CLL-related chemokines. The most commonly observed grade ≥3 adverse events were pneumonia (20%), neutropenic fever (11%), and diarrhea (6%). Idelalisib treatment resulted in nodal responses in 81% of patients. The overall response rate was 72%, with 39% of patients meeting the criteria for partial response per IWCLL 2008 and 33% meeting the recently updated criteria of PR with treatment-induced lymphocytosis.(1,2) The median progression-free survival for all patients was 15.8 months. This study demonstrates the clinical utility of inhibiting the PI3Kδ pathway with idelalisib. Our findings support the further development of idelalisib in patients with CLL. These trials were registered at clinicaltrials.gov as #NCT00710528 and #NCT01090414.

Incidence and Duration of Continuously Measured Oxygen Desaturation During Emergency Department Intubation.

STUDY OBJECTIVE: Desaturation during intubation has been associated with serious complications, including dysrhythmias, hemodynamic decompensation, hypoxic brain injury, and cardiac arrest. We seek to determine the incidence and duration of oxygen desaturation during emergency department (ED) rapid sequence intubation. METHODS: This study included adult rapid sequence intubation cases conducted between September 2011 and July 2012 in an urban, academic, Level I trauma center ED. We obtained continuous vital signs with BedMasterEX data acquisition software. Start and completion times of rapid sequence intubation originated from nursing records. We defined oxygen desaturation as (1) cases exhibiting SpO2 reduction to less than 90% if the starting SpO2 was greater than or equal to 90%, or (2) a further reduction in SpO2 in cases in which starting SpO2 was less than 90%. We used multivariable logistic regression to predict oxygen desaturation during rapid sequence intubation. RESULTS: During the study period, there were 265 rapid sequence intubation cases. The study excluded 99 cases for failure of electronic data acquisition, inadequate documentation, or poor SpO2 waveform during rapid sequence intubation, and excluded cases managed by anesthesia providers, leaving 166 patients in the analysis. After preoxygenation, starting SpO2 was greater than 93% in 124 of 166 cases (75%) and SpO2 was less than 93% in the remaining 46 cases. Oxygen desaturation occurred in 59 patients (35.5%). The median duration of desaturation was 80 seconds (interquartile range 40, 155). Multivariable analysis demonstrated that oxygen desaturation was associated with preintubation SpO2 less than 93% (odds ratio [OR] 5.1; 95% confidence interval (CI) 2.3 to 11.0), multiple intubation attempts (>1 attempt) (OR 3.4; 95% CI 1.4 to 6.1), and rapid sequence intubation duration greater than 3 minutes (OR 2.7; 95% CI 1.2 to 6.1). CONCLUSION: In this series, 1 in 3 patients undergoing ED rapid sequence intubation experienced oxygen desaturation for a median duration of 80 seconds. Preintubation saturation less than 93%, multiple intubation attempts, and prolonged intubation time are independently associated with oxygen desaturation. Clinicians should use strategies to prevent oxygen desaturation during ED rapid sequence intubation.

Stress Markers During a Rally Car Competition.

The aim of the study was to assess the stress responses in drivers during an official rally car race and the influence of fitness and body composition on stress hormones. Fitness and body composition were assessed in 9 rally car drivers with an incremental exercise test for determination of maximum aerobic speed (MAS) and 6-site skinfold method, respectively. Before (pre) and after (post) the first stage of an official rally car race, data were collected for heart rate (HR), blood samples were collected for analysis of hormones (i.e., epinephrine [EPI], norepinephrine [NE], cortisol, and aldosterone) and metabolites (i.e., lactate [LA], glucose, and ammonia). There were significant (p ≤ 0.05) increases in all assessed variables except glucose at postrace. Heart rate increased 93% (p ≤ 0.05) at the end of the race stage, reaching 88.77 ± 4.96% of HRpeak. Also, EPI and NE significantly (p = 0.001) increased by 45 and 65%, respectively, and LA increased by 395% (p < 0.001). Significant correlations between percent body fat (%BF) and postrace EPI (r = 0.95; p < 0.001), and percentage change of EPI (r = 0.83; p = 0.012) were observed. The MAS was not associated to any metabolic or hormonal variable. These results suggest that psycho-physiological stress induced by the race elicited important changes in hormonal and metabolic variables and that %BF could be an important mediator of psycho-physiological stress in rally car drivers. Specific programs, including both strength and aerobic training, and nutritional plans should be implemented for appropriate conditioning of rally car drivers.

p66Alpha-MBD2 coiled-coil interaction and recruitment of Mi-2 are critical for globin gene silencing by the MBD2-NuRD complex.

Nucleosome remodeling complexes comprise several large families of chromatin modifiers that integrate multiple epigenetic control signals to play key roles in cell type-specific transcription regulation. We previously isolated a methyl-binding domain protein 2 (MBD2)-containing nucleosome remodeling and deacetylation (NuRD) complex from primary erythroid cells and showed that MBD2 contributes to DNA methylation-dependent embryonic and fetal ß-type globin gene silencing during development in vivo. Here we present structural and biophysical details of the coiled-coil interaction between MBD2 and p66α, a critical component of the MBD2-NuRD complex. We show that enforced expression of the isolated p66α coiled-coil domain relieves MBD2-mediated globin gene silencing and that the expressed peptide interacts only with a subset of components of the MBD2-NuRD complex that does not include native p66α or Mi-2. These results demonstrate the central importance of the coiled-coil interaction and suggest that MBD2-dependent DNA methylation-driven gene silencing can be disrupted by selectively targeting this coiled-coil complex.

Epoxyeicosatrienoic acids prevent cisplatin-induced renal apoptosis through a p38 mitogen-activated protein kinase-regulated mitochondrial pathway.

Soluble epoxide hydrolase (sEH) catalyzes the conversion of epoxyeicosatrienoic acids into less active eicosanoids, and inhibitors of sEH have anti-inflammatory and antiapoptotic properties. Based on previous observations that sEH inhibition attenuates cisplatin-induced nephrotoxicity by modulating nuclear factor-κB signaling, we hypothesized that this strategy would also attenuate cisplatin-induced renal apoptosis. Inhibition of sEH with AR9273 [1-adamantan-1-yl-3-(1-methylsulfonyl-piperidin-4-yl-urea)] reduced cisplatin-induced apoptosis through mechanisms involving mitochondrial apoptotic pathways and by reducing reactive oxygen species. Renal mitochondrial Bax induction following cisplatin treatment was significantly decreased by treatment of mice with AR9273 and these antiapoptotic effects involved p38 mitogen-activated protein kinase signaling. Similar mechanisms contributed to reduced apoptosis in Ephx2(-/-) mice treated with cisplatin. Moreover, in pig kidney proximal tubule cells, cisplatin-induced mitochondrial trafficking of Bax and cytochrome c, caspase-3 activation, and oxidative stress are significantly attenuated in the presence of epoxyeicosatrienoic acids (EETs). Collectively, these in vivo and in vitro studies demonstrate a role for EETs in limiting cisplatin-induced renal apoptosis. Inhibition of sEH represents a novel therapeutic strategy for protection against cisplatin-induced renal damage.

Solution structure and dynamic analysis of chicken MBD2 methyl binding domain bound to a target-methylated DNA sequence.

The epigenetic code of DNA methylation is interpreted chiefly by methyl cytosine binding domain (MBD) proteins which in turn recruit multiprotein co-repressor complexes. We previously isolated one such complex, MBD2-NuRD, from primary erythroid cells and have shown it contributes to embryonic/fetal ß-type globin gene silencing during development. This complex has been implicated in silencing tumor suppressor genes in a variety of human tumor cell types. Here we present structural details of chicken MBD2 bound to a methylated DNA sequence from the ρ-globin promoter to which it binds in vivo and mediates developmental transcriptional silencing in normal erythroid cells. While previous studies have failed to show sequence specificity for MBD2 outside of the symmetric mCpG, we find that this domain binds in a single orientation on the ρ-globin target DNA sequence. Further, we show that the orientation and affinity depends on guanine immediately following the mCpG dinucleotide. Dynamic analyses show that DNA binding stabilizes the central ß-sheet, while the N- and C-terminal regions of the protein maintain mobility. Taken together, these data lead to a model in which DNA binding stabilizes the MBD2 structure and that binding orientation and affinity is influenced by the DNA sequence surrounding the central mCpG.

Attenuation of cisplatin-induced renal injury by inhibition of soluble epoxide hydrolase involves nuclear factor κB signaling.

Acute kidney injury is associated with a significant inflammatory response that has been the target of renoprotection strategies. Epoxyeicosatrienoic acids (EETs) are anti-inflammatory cytochrome P450-derived eicosanoids that are abundantly produced in the kidney and metabolized by soluble epoxide hydrolase (sEH; Ephx2) to less active dihydroxyeicosatrienoic acids. Genetic disruption of Ephx2 and chemical inhibition of sEH were used to test whether the anti-inflammatory effects of EETs, and other lipid epoxide substrates of sEH, afford protection against cisplatin-induced nephrotoxicity. EET hydrolysis was significantly reduced in Ephx2(-/-) mice and was associated with an attenuation of cisplatin-induced increases in serum urea nitrogen and creatinine levels. Histological evidence of renal tubular damage and neutrophil infiltration was also reduced in the Ephx2(-/-) mice. Likewise, cisplatin had no effect on renal function, neutrophil infiltration, or tubular structure and integrity in mice treated with the potent sEH inhibitor 1-adamantan-1-yl-3-(1-methylsulfonyl-piperidin-4-yl-urea) (AR9273). Consistent with the ability of EETs to interfere with nuclear factor-κB (NF-κB) signaling, the observed renoprotection was associated with attenuation of renal NF-κB activity and corresponding decreases in the expression of tumor necrosis factor (TNF) α, TNF receptor (TNFR) 1, TNFR2, and intercellular adhesive molecule-1 before the detection of tubular injury. These data suggest that EETs or other fatty acid epoxides can attenuate cisplatin-induced kidney injury and sEH inhibition is a novel renoprotective strategy.

Effects of carbohydrate supplementation on force output and time to exhaustion during static leg contractions superimposed with electromyostimulation.

The purpose of this study was to investigate the effects of carbohydrate ingestion on force output and time to exhaustion using single leg static contractions superimposed with brief periods of electromyostimulation. Six trained male subjects participated in a randomized, counterbalanced, double-blind study. The subjects were randomly assigned to placebo (PL) or carbohydrate (CHO). The subjects in CHO consumed 1 g of carbohydrate per kilogram of body mass loading dose and 0.17 g of carbohydrate per kilogram of body mass every 6 minutes during the exercise protocol. The PL received an equal volume of a solution made of saccharin and aspartame. The exercise protocol consisted of repeated 20-second static contractions of quadriceps muscle at 50% maximal voluntary contraction followed by 40-second rest until failure occurred. Importantly, the force output during quadriceps maximal voluntary contraction strength with superimposed electromyostimulation was measured in the beginning and every 5 minutes during the last 3 seconds of static contractions throughout the exercise protocol. Venous blood samples were taken preexercise, immediately postexercise, and at 5 minutes postexercise and analyzed for blood lactate. Our results indicate that time to exhaustion (PL = 16.0 ± 8.1 minutes; CHO = 29.0 ± 13.1 minutes) and force output (PL = 3,638.7 ± 524.5 N; CHO = 5,540.1 ± 726.1 N) were significantly higher (p < 0.05) in CHO compared with that in PL. Data suggest that carbohydrate ingestion before and during static muscle contractions can increase force output and increase time to exhaustion. Therefore, our data suggest that carbohydrate supplementation before and during resistance exercise might help increase the training volume of athletes.

Beliefs and Attitudes of Health Care Professionals Toward Mental Health Services Users' Rights: A Cross-Sectional Study from the United Arab Emirates.

Purpose: The beliefs and attitudes of healthcare professionals (HCPs) towards service user's rights in mental healthcare are critical to understanding as it impacts the quality of care and treatment, leading to social discrimination and possible coercive professional practices. This study aimed to investigate the association between the HCPs' beliefs and attitudes towards service users' rights in seeking treatment in the UAE and to identify or may predict the stigmatized attitudes and behaviors among HCPs. Patients and Methods: Data was collected from HCPs participants working at three healthcare entities (n=307) allocated at selected primary and tertiary healthcare settings that specifically treat mental disorders. The Health Professionals Beliefs and Attitudes towards Mental Health Users' Rights Scale (BAMHS) questionnaire was used to assess the beliefs and attitudes. Unconditional associations using regression models included whether HCPs provide care to specific mental health patients, whether treating mental health patients is part of their jobs, whether HCPs receive professional training for mental healthcare, nationality of HCPs, and the number of years of professional experience. Results: Our findings demonstrate that HPCs understand mental disorders and feel that individuals' rights should be equal to those who do not have mental disorders while believing in autonomy and freedom, but there is a level of discrimination and a high level of social distance. HCPs are less tolerant when interacting with those with mental disorders outside their professional lives. Conclusion: Interventions with long-term follow-up activities must be implemented and assessed using assessment systems that measure acquired knowledge and actual behavioral change to ensure anti-stigma impact in practice and policy.

Stroke clot retrieval from Taranaki, New Zealand: a real-world regional experience.

AIM: Stroke clot retrieval (SCR) is now considered a standard of care for select stroke patients with proximal large vessel occlusion (LVO) of the anterior circulation. Here we present the experience of regional Taranaki patients transferred by air for SCR and compare this to metropolitan Auckland patients who were transferred by road. The aim is to present and compare process metrics and outcomes between the regional and metropolitan centres. METHODS: This is a retrospective analysis of consecutive patients with anterior LVO transferred to Auckland City Hospital (ACH) for SCR from Taranaki, Waitemata and Counties Manukau district health boards (DHBs) between November 2017 and December 2020. RESULTS: Thirty Taranaki patients were transferred for SCR, compared to 244 patients from Waitemata and Counties Manukau DHBs. Taranaki patients were seven years older and less ethnically diverse but similar in other characteristics. The proportion of patients with an independent Modified Rankin Scale (mRS) score between 0 and 2 at three months was the same as for the regional and metropolitan centres. CONCLUSIONS: In this real-world study, regional stroke patients can achieve similar SCR outcomes to metropolitan patients. Overcoming the post-code lottery for hyperacute stroke care can be achieved in a New Zealand setting.

Aerobic fitness and physical activity levels of children born prematurely following randomization to postnatal dexamethasone.

OBJECTIVE: To investigate the effects of postnatal dexamethasone treatment on aerobic fitness and physical activity levels in school-aged children born with very low birth weight (VLBW). STUDY DESIGN: This was a follow-up study of 65 VLBW infants who participated in a randomized controlled trial of dexamethasone (DEX) to reduce ventilator dependency. Aerobic fitness was determined from peak oxygen uptake (VO(2peak)) with a cycle ergometer. Habitual physical activity was assessed by questionnaire. RESULTS: A trend for a treatment with an interaction between treatment and of diagnosis of chronic lung disease (CLD) was found, with the children in the placebo group with CLD having the lowest VO(2peak) (P = .09). Reduced fitness was seen in 53% of the group treated with DEX and 48% of the group given placebo. No between-group differences in physical activity were seen. Parental reports suggested that nearly two-thirds of the children participated in < 1 hour per week of vigorous physical activity, which was explained in part by decreased large airway function (r = 0.30; P = .03). CONCLUSIONS: We found no adverse effect of postnatal DEX on aerobic fitness or habitual physical activity at school age. However, the reduced fitness and physical activity levels emphasize the need for closer follow-up and early interventions promoting physical activity to reduce the risk of chronic disease in this at-risk population.

1-(1-acetyl-piperidin-4-yl)-3-adamantan-1-yl-urea (AR9281) as a potent, selective, and orally available soluble epoxide hydrolase inhibitor with efficacy in rodent models of hypertension and dysglycemia.

1-(1-Acetyl-piperidin-4-yl)-3-adamantan-1-yl-urea 14a (AR9281), a potent and selective soluble epoxide hydrolase inhibitor, was recently tested in a phase 2a clinical setting for its effectiveness in reducing blood pressure and improving insulin resistance in pre-diabetic patients. In a mouse model of diet induced obesity, AR9281 attenuated the enhanced glucose excursion following an intraperitoneal glucose tolerance test. AR9281 also attenuated the increase in blood pressure in angiotensin-II-induced hypertension in rats. These effects were dose-dependent and well correlated with inhibition of the sEH activity in whole blood, consistent with a role of sEH in the observed pharmacology in rodents.

Stress reactivity to repeated low-level challenges: a pilot study.

The purpose of this study was to examine the effects of a mental challenge on cardiovascular and endocrine [epinephrine (EPI), norepinephrine (NE), and cortisol (CORT)] responses to subsequent low-intensity physical exertion. Twelve males (23.25±0.45 years) completed three sessions, including a graded exercise test on a cycle ergometer and two counter-balanced mental stress trials. In the mental challenge-control condition (MC), participants sat quietly for 20 min following a 20 min mental challenge whereas in the mental challenge-exercise condition (MEC) subjects cycled at 35% of maximal oxygen consumption (VO2max) following the mental challenge. Repeated-measures ANOVAs were used to assess state anxiety (SAI), cardiovascular variables, EPI, NE, and CORT levels across time between conditions. Participants reported significantly greater increases in SAI scores immediately after the mental challenge, which then decreased post-challenge in both conditions. Neither EPI or NE demonstrated an alteration in levels in either condition, but CORT significantly increased after the mental challenge in both conditions and then maintained a significantly greater level during the MEC compared to the MC condition from midexercise through 15 min of recovery. Area-under-the-curve calculations for CORT was significantly greater in the MEC compared to the MC. Results suggest that the initial mental challenge may have acted to enhance the overall adrenal response to the subsequent anticipation of and actual participation in the low-level physical challenge.

The role of age in the physiological adaptations and psychological responses in bikini-physique competitor contest preparation: a case series.

The increased popularity of the bikini-physique competitions has not translated to greater research identifying the influence of age on adaptations during contest preparation. The purpose of this case series was to observe how age may influence the adaptations normally seen during preparation and the exploration of newer protocols to address adaptations more relative to the judging standards. Over a 16-week pre-contest preparation, a 32-y bikini competitor (BC) and 44-y master's bikini competitor (MBC) visited the laboratory bi-weekly to observe changes in body fat mass (BF), lean body mass (LBM), bone mineral density (BMD), total body water (TBW); exploratory measures of deltoid cross-sectional area (DeltCSA), gluteus maximus muscle thickness (GMMT), and subcutaneous adipose tissue thickness (SAT); reproductive hormones estradiol (E2), luteinizing hormone (LH), and energy balance hormones triiodothyronine (T3), leptin and ghrelin; hydration status during contest preparation and the week of competition; resting metabolic rate (RMR); psychometric data related to perceived anxiety, stress, and body image were assessed. No differences between BC and MBC were observed in BF, LBM, BMD, and TBW. Both competitors showed a small loss in LBM. Both BC and MBC showed a contrasting increase in DeltCSA and a loss in GMMT. MBC showed to be slightly more dehydrated (1.025 vs 1.021 g·mL- 1) than BC. Both competitors maintained a euhydration status the day of the competition. No time differences were found between BC and MBC during RMR. BC showed a higher mean difference RMR compared to MBC (2.66 ± 0.75 kcal·kgLBM- 1·d- 1). MBC showed a higher mean difference in LH concentration (84.6 ± 6.01 IU·L- 1), which may be explained by perimenopausal status. MBC had a higher mean difference concentration of leptin (2.51 ± 0.24 ng·mL- 1·kgFM- 1), which was unperturbed by fat loss may be interrelated LH. BC self-reported a higher mean energy intake (15.07 ± 3.43 kcal·kgLBM- 1·d- 1) and higher aerobic training volume (93.26 ± 40.68 min·d). BC and MBC showed similar composition changes, slightly differing metabolic rates, and differing hormonal LH and leptin responses. This finding is in contrast to previous work showing both LH inhibition and leptin diurnal disturbance in younger, female athletes with low energy availability. The exploratory measures may have some benefit for bikini-physique competitors related to the judging criteria. Age did not seem to play a role in contest preparation adaptations.