How do weather conditions and environmental characteristics influence aesthetic preferences of freshwater environments?

Freshwater (inland) blue space environments provide a range of public health benefits to visitors. However, health related exposure outcomes are dynamic and can vary depending on several factors, including the environmental characteristics of freshwater environments and their surroundings. Developing and managing inland blue spaces to promote health and wellbeing therefore requires an understanding of whether specific freshwater attributes, and prevailing weather conditions, enhance or devalue landscape aesthetics. The aim of this study was to utilise a mixed-methods research approach to investigate aesthetic preferences of inland blue spaces. A three-phase data collection method was adopted involving (i) analysis of a national-scale landscape image dataset; in combination with (ii) a national-scale online survey; and (iii) a series of in-person focus groups. We found environmental characteristics associated with the waterbody itself, as well as the characteristics of the nearby green space, to have a significant impact on the overall aesthetic appeal of inland blue spaces. Strong preference was demonstrated for inland blue spaces perceived to be of a high environmental quality and which have a natural, rather than human-modified, appearance. The findings highlight the need to conserve the quality of both the waterbody and waterside environment to encourage frequent recreational use and maintain the beneficial public health outcomes associated with inland blue spaces.

A Touchscreen Device for Behavioral Testing in Pigs.

Pigs are becoming more common research models due to their utility in studying neurological conditions such as traumatic brain injury, Alzheimer's disease, and Huntington's Disease. However, behavioral tasks often require a large apparatus and are not automated, which may disinterest researchers in using important functional measures. To address this, we developed a touchscreen that pigs could be trained on for behavioral testing. A rack-mounted touchscreen monitor was placed in an enclosed, weighted audio rack. A pellet dispenser was operated by a radio frequency transceiver to deliver fruit-flavored sugar pellets from across the testing room. Programs were custom written in Python and executed on a microcomputer. A behavioral shaping program was designed to train pigs to interact with the screen and setup responses for future tasks. Pigs rapidly learned to interact with the screen. To demonstrate efficacy in more complex behavior, two pigs were trained on a delay discounting tasks and two pigs on a color discrimination task. The device held up to repeated testing of large pigs and could be adjusted to the height of minipigs. The device can be easily recreated and constructed at a relatively low cost. Research topics ranging from brain injury to pharmacology to vision could benefit from behavioral tasks designed to specifically interrogate relevant function. More work will be needed to develop tests which are of specific relevance to these disciplines.

Different frequencies of active interruptions to sitting have distinct effects on 22 h glycemic control in type 2 diabetes.

BACKGROUND & AIMS: Whether the frequency of interruptions to sitting time involving simple resistance activities (SRAs), compared to uninterrupted sitting, differentially affected 22 h glycemic control in adults with medication-controlled type 2 diabetes (T2D). METHODS & RESULTS: Twenty-four participants (13 men; mean ± SD age 62 ± 8 years) completed three 8 h laboratory conditions: SIT: uninterrupted sitting; SRA3: sitting interrupted with 3 min of SRAs every 30 min; and, SRA6: sitting interrupted with 6 min of SRAs every 60 min. Flash glucose monitors assessed glycemic control over a 22 h period. No differences were observed between conditions for overall 22 h glycemic control as measured by AUCtotal, mean glucose and time in hyperglycemia. During the 3.5 h post-lunch period, mean glucose was significantly lower during SRA6 (10.1 mmol·L-1, 95%CI 9.2, 11.0) compared to SIT (11.1 mmol·L-1, 95%CI 10.2, 12.0; P = 0.006). Post-lunch iAUCnet was significantly lower during SRA6 (6.2 mmol·h·L-1, 95%CI 3.3, 9.1) compared to SIT (9.9 mmol·h·L-1, 95%CI 7.0, 12.9; P = 0.003). During the post-lunch period, compared to SIT (2.2 h, 95%CI 1.7, 2.6), time in hyperglycemia was significantly lower during SRA6 (1.5 h, 95%CI 1.0, 1.9, P = 0.001). Nocturnal mean glucose was significantly lower following the SRA3 condition (7.6 mmol·L-1, 95%CI 7.1, 8.1) compared to SIT (8.1 mmol·L-1, 95%CI 7.6, 8.7, P = 0.024). CONCLUSIONS: With standardized total activity time, less-frequent active interruptions to sitting may acutely improve glycemic control; while more-frequent interruptions may be beneficial for nocturnal glucose in those with medication-controlled T2D.

Serotonin-induced vascular permeability is mediated by transient receptor potential vanilloid 4 in the airways and upper gastrointestinal tract of mice.

Endothelial and epithelial cells form physical barriers that modulate the exchange of fluid and molecules. The integrity of these barriers can be influenced by signaling through G protein-coupled receptors (GPCRs) and ion channels. Serotonin (5-HT) is an important vasoactive mediator of tissue edema and inflammation. However, the mechanisms that drive 5-HT-induced plasma extravasation are poorly defined. The Transient Receptor Potential Vanilloid 4 (TRPV4) ion channel is an established enhancer of signaling by GPCRs that promote inflammation and endothelial barrier disruption. Here, we investigated the role of TRPV4 in 5-HT-induced plasma extravasation using pharmacological and genetic approaches. Activation of either TRPV4 or 5-HT receptors promoted significant plasma extravasation in the airway and upper gastrointestinal tract of mice. 5-HT-mediated extravasation was significantly reduced by pharmacological inhibition of the 5-HT2A receptor subtype, or with antagonism or deletion of TRPV4, consistent with functional interaction between 5-HT receptors and TRPV4. Inhibition of receptors for the neuropeptides substance P (SP) or calcitonin gene-related peptide (CGRP) diminished 5-HT-induced plasma extravasation. Supporting studies assessing treatment of HUVEC with 5-HT, CGRP, or SP was associated with ERK phosphorylation. Exposure to the TRPV4 activator GSK1016790A, but not 5-HT, increased intracellular Ca2+ in these cells. However, 5-HT pre-treatment enhanced GSK1016790A-mediated Ca2+ signaling, consistent with sensitization of TRPV4. The functional interaction was further characterized in HEK293 cells expressing 5-HT2A to reveal that TRPV4 enhances the duration of 5-HT-evoked Ca2+ signaling through a PLA2 and PKC-dependent mechanism. In summary, this study demonstrates that TRPV4 contributes to 5-HT2A-induced plasma extravasation in the airways and upper GI tract, with evidence supporting a mechanism of action involving SP and CGRP release.

Frequency of Interruptions to Sitting Time: Benefits for Postprandial Metabolism in Type 2 Diabetes.

OBJECTIVE: To determine whether interrupting sitting with brief bouts of simple resistance activities (SRAs) at different frequencies improves postprandial glucose, insulin, and triglycerides in adults with medication-controlled type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: Participants (n = 23, 10 of whom were female, with mean ± SD age 62 ± 8 years and BMI 32.7 ± 3.5 kg · m-2) completed a three-armed randomized crossover trial (6- to 14-day washout): sitting uninterrupted for 7 h (SIT), sitting with 3-min SRAs (half squats, calf raises, gluteal contractions, and knee raises) every 30 min (SRA3), and sitting with 6-min SRAs every 60 min (SRA6). Net incremental areas under the curve (iAUCnet) for glucose, insulin, and triglycerides were compared between conditions. RESULTS: Glucose and insulin 7-h iAUCnet were attenuated significantly during SRA6 (glucose 17.0 mmol · h · L-1, 95% CI 12.5, 21.4; insulin 1,229 pmol · h · L-1, 95% CI 982, 1,538) in comparison with SIT (glucose 21.4 mmol · h · L-1, 95% CI 16.9, 25.8; insulin 1,411 pmol · h · L-1, 95% CI 1,128, 1,767; P < 0.05) and in comparison with SRA3 (for glucose only) (22.1 mmol · h · L-1, 95% CI 17.7, 26.6; P = 0.01) No significant differences in glucose or insulin iAUCnet were observed in comparison of SRA3 and SIT. There was no statistically significant effect of condition on triglyceride iAUCnet. CONCLUSIONS: In adults with medication-controlled T2D, interrupting prolonged sitting with 6-min SRAs every 60 min reduced postprandial glucose and insulin responses. Other frequencies of interruptions and potential longer-term benefits require examination to clarify clinical relevance.

Effects of sedentary behaviour interventions on biomarkers of cardiometabolic risk in adults: systematic review with meta-analyses.

CONTEXT/PURPOSE: Observational and acute laboratory intervention research has shown that excessive sedentary time is associated adversely with cardiometabolic biomarkers. This systematic review with meta-analyses synthesises results from free living interventions targeting reductions in sedentary behaviour alone or combined with increases in physical activity. METHODS: Six electronic databases were searched up to August 2019 for sedentary behaviour interventions in adults lasting for ≥7 days publishing cardiometabolic biomarker outcomes covering body anthropometry, blood pressure, glucose and lipid metabolism, and inflammation (54 studies). The pooled effectiveness of intervention net of control on 15 biomarker outcomes was evaluated using random effects meta-analyses in the studies with control groups not providing other relevant interventions (33 studies; 6-25 interventions analysed). RESULTS: Interventions between 2 weeks and <6 months in non-clinical populations from North America, Europe and Australia comprised much of the evidence base. Pooled effects revealed small, significant (p<0.05) beneficial effects on weight (≈ -0.6 kg), waist circumference (≈ -0.7 cm), percentage body fat (≈ -0.3 %), systolic blood pressure (≈ -1.1 mm Hg), insulin (≈ -1.4 pM) and high-density lipoprotein cholesterol (≈ 0.04 mM). Pooled effects on the other biomarkers (p>0.05) were also small, and beneficial in direction except for fat-free mass (≈ 0.0 kg). Heterogeneity ranged widely (I2=0.0-72.9). CONCLUSIONS: Our review of interventions targeting sedentary behaviour reductions alone, or combined with increases in physical activity, found evidence of effectiveness for improving some cardiometabolic risk biomarkers to a small degree. There was insufficient evidence to evaluate inflammation or vascular function. Key limitations to the underlying evidence base include a paucity of high-quality studies, interventions lasting for ≥12 months, sensitive biomarkers and clinical study populations (eg, type 2 diabetes). PROSPERO TRIAL REGISTRATION NUMBER: CRD42016041742.

Acute effects of interrupting prolonged sitting on vascular function in type 2 diabetes.

In healthy and overweight/obese adults, interrupting prolonged sitting with activity bouts mitigates impairment in vascular function. However, it is unknown whether these benefits extend to those with type 2 diabetes (T2D), nor whether an optimal frequency of activity interruptions exist. We examined the acute effects on vascular function in T2D of interrupting prolonged sitting with simple resistance activities (SRA) at different frequencies. In a randomized crossover trial, 24 adults with T2D (35-70 yr) completed three 7-h conditions: 1) uninterrupted sitting (SIT), 2) sitting with 3-min bouts of SRA every 30 min (SRA3), and 3) sitting with 6 min bouts of SRA every 60 min (SRA6). Femoral artery flow-mediated dilation (FMD), resting shear rate, blood flow, and endothelin-1 were measured at 0, 1, 3.5, 4.5, and 6.5-7 h. Mean femoral artery FMD over 7 h was significantly higher in SRA3 (4.1 ± 0.3%) compared with SIT (3.7 ± 0.3%, P = 0.04) but not in SRA6. Mean resting femoral shear rate over 7 h was increased significantly for SRA3 (45.3 ± 4.1/s, P < 0.001) and SRA6 (46.2 ± 4.1/s, P < 0.001) relative to SIT (33.1 ± 4.1/s). Endothelin-1 concentrations were not statistically different between conditions. Interrupting sitting with activity breaks every 30 min, but not 60 min, significantly increased mean femoral artery FMD over 7 h, relative to SIT. Our findings suggest that more frequent and shorter breaks may be more beneficial than longer, less frequent breaks for vascular health in those with T2D.NEW & NOTEWORTHY This is the first trial to examine both the effects of interrupting prolonged sitting on vascular function in type 2 diabetes and the effects of the frequency and duration of interruptions. Brief, simple resistance activity bouts every 30 min, but not every 60 min, increased mean femoral artery flow-mediated dilation over 7 h, relative to uninterrupted sitting. With further supporting evidence, these initial findings can have important implications for cardiovascular health in type 2 diabetes.

The transient receptor potential vanilloid 4 (TRPV4) ion channel mediates protease activated receptor 1 (PAR1)-induced vascular hyperpermeability.

Endothelial barrier disruption is a hallmark of tissue injury, edema, and inflammation. Vascular endothelial cells express the G protein-coupled receptor (GPCR) protease acctivated receptor 1 (PAR1) and the ion channel transient receptor potential vanilloid 4 (TRPV4), and these signaling proteins are known to respond to inflammatory conditions and promote edema through remodeling of cell-cell junctions and modulation of endothelial barriers. It has previously been established that signaling initiated by the related protease activated receptor 2 (PAR2) is enhanced by TRPV4 in sensory neurons and that this functional interaction plays a critical role in the development of neurogenic inflammation and nociception. Here, we investigated the PAR1-TRPV4 axis, to determine if TRPV4 plays a similar role in the control of edema mediated by thrombin-induced signaling. Using Evans Blue permeation and retention as an indication of increased vascular permeability in vivo, we showed that TRPV4 contributes to PAR1-induced vascular hyperpermeability in the airways and upper gastrointestinal tract of mice. TRPV4 contributes to sustained PAR1-induced Ca2+ signaling in recombinant cell systems and to PAR1-dependent endothelial junction remodeling in vitro. This study supports the role of GPCR-TRP channel functional interactions in inflammatory-associated changes to vascular function and indicates that TRPV4 is a signaling effector for multiple PAR family members.

Interrupting Sitting Time with Simple Resistance Activities Lowers Postprandial Insulinemia in Adults with Overweight or Obesity.

OBJECTIVE: This study aimed to examine the effects on postprandial glucose and insulin responses of interrupting sitting time with brief bouts of simple resistance activities (SRAs) in adults with overweight or obesity. METHODS: Participants (n = 19) were recruited for a randomized crossover trial involving the following two 6-hour conditions: (1) uninterrupted sitting or (2) sitting with 3-minute bouts of SRAs (half-squats, calf raises, gluteal contractions, and knee raises) every 30 minutes (total duration = 27 minutes). Incremental areas under the curve (iAUC) for glucose, insulin, and insulin:glucose ratio were analyzed as prespecified secondary outcomes using mixed-effects log-linear regression adjusted for sex, BMI, treatment order, and preprandial values. Results are reported as multiplicative change (exponentiated coefficient [EC] with 95% CI) relative to the control condition. RESULTS: Glucose iAUC during the SRA condition was not significantly different from the prolonged sitting condition (EC = 0.92; 95% CI: 0.73-1.16; P = 0.43). However, SRAs lowered the postprandial insulin response by 26% (EC = 0.74; 95% CI: 0.64-0.85; P < 0.001), and there was a 23% lowering of the iAUC for insulin:glucose (EC = 0.77; 95% CI: 0.67-0.89; P < 0.001). CONCLUSIONS: In adults with overweight or obesity, frequent interruptions to sitting time with SRAs lowered postprandial insulin responses and insulin:glucose. These findings may have implications for mitigating cardiometabolic risk in adults with overweight or obesity who engage in prolonged periods of sitting.

Acute effects of active breaks during prolonged sitting on subcutaneous adipose tissue gene expression: an ancillary analysis of a randomised controlled trial.

Active breaks in prolonged sitting has beneficial impacts on cardiometabolic risk biomarkers. The molecular mechanisms include regulation of skeletal muscle gene and protein expression controlling metabolic, inflammatory and cell development pathways. An active communication network exists between adipose and muscle tissue, but the effect of active breaks in prolonged sitting on adipose tissue have not been investigated. This study characterized the acute transcriptional events induced in adipose tissue by regular active breaks during prolonged sitting. We studied 8 overweight/obese adults participating in an acute randomized three-intervention crossover trial. Interventions were performed in the postprandial state and included: (i) prolonged uninterrupted sitting; or prolonged sitting interrupted with 2-minute bouts of (ii) light- or (iii) moderate-intensity treadmill walking every 20 minutes. Subcutaneous adipose tissue biopsies were obtained after each condition. Microarrays identified 36 differentially expressed genes between the three conditions (fold change ≥0.5 in either direction; p < 0.05). Pathway analysis indicated that breaking up of prolonged sitting led to differential regulation of adipose tissue metabolic networks and inflammatory pathways, increased insulin signaling, modulation of adipocyte cell cycle, and facilitated cross-talk between adipose tissue and other organs. This study provides preliminary insight into the adipose tissue regulatory systems that may contribute to the physiological effects of interrupting prolonged sitting.

Between-meal sucrose-sweetened beverage consumption impairs glycaemia and lipid metabolism during prolonged sitting: A randomized controlled trial.

BACKGROUND & AIMS: Chronic overconsumption of sugar-sweetened beverages (SSBs) is associated with unfavourable health effects, including promotion of obesity. However, the acute effects of consuming SSBs on glucose and lipid metabolism remain to be characterized in a real-world, post-prandial context of prolonged sitting. We quantified the acute effects of between-meal SSB consumption compared with water, on glucose and lipid metabolism in habitual soft drink consumers during prolonged sitting. METHODS: Twenty-eight overweight or obese young adults [15 males; 23 ± 3 (mean ± SD) years, body mass index (BMI) 31.0 ± 3.6 kg/m2) participated. During uninterrupted sitting and following standardized breakfast and lunch meals, each participant completed two 7-h conditions on separate days in a randomized, crossover design study. For each condition, participants consumed either a sucrose SSB or water mid-morning and mid-afternoon. Peak responses and total area under the curve (tAUC) over 7 h for blood glucose, insulin, C-peptide, triglyceride and non-esterified fatty acid (NEFA) concentrations were quantified and compared. RESULTS: Compared to water, SSB consumption significantly increased the peak responses for blood glucose (20 ± 4% (mean ± SEM)), insulin (43 ± 15%) and C-peptide (21 ± 6%) concentrations. The tAUC for all these parameters was also increased by SSB consumption. The tAUC for triglycerides was 15 ± 5% lower after SSBs and this was driven by males (P < 0.05), as females showed no difference between conditions. The tAUC for NEFAs was 13 ± 5% lower after the SSB condition (P < 0.05). CONCLUSIONS: Between-meal SSB consumption significantly elevated plasma glucose responses, associated with a sustained elevation in plasma insulin throughout a day of prolonged sitting. The SSB-induced reduction in circulating triglycerides and NEFAs indicates significant modulation of lipid metabolism, particularly in males. These metabolic effects may contribute to the development of metabolic disease when SSB consumption is habitual and co-occurring with prolonged sitting. Clinical Trial Registry number: ACTRN12616000840482, https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12616000840482.

Multibond Forming Tandem Reactions of Anilines via Stable Aryl Diazonium Salts: One-Pot Synthesis of 3,4-Dihydroquinolin-2-ones.

A fast and effective one-pot tandem process that generates Heck coupled products from readily available anilines via stable aryl diazonium tosylate salts was developed. The mild and simple procedure involves rapid formation of aryl diazonium salts using a polymer-supported nitrite reagent and p-tosic acid, followed by a base-free Heck-Matsuda coupling with acrylates and styrenes. Using 2-nitroanilines as substrates, the one-pot tandem process was extended for the direct synthesis of 3,4-dihydroquinolin-2-ones. In this case, following diazotization and Heck-Matsuda coupling to give methyl cinnamates, addition of hydrogen and reutilization of the palladium catalyst for reduction of the nitro group and hydrogenation of the alkene resulted in efficient formation of 3,4-dihydroquinolin-2-ones. The synthetic utility of this one-pot, four-stage process was demonstrated with the five-pot synthesis of a quinolinone-based sodium ion channel modulator.

Simple intermittent resistance activity mitigates the detrimental effect of prolonged unbroken sitting on arterial function in overweight and obese adults.

Prolonged sitting contributes to cardiovascular disease (CVD) risk. The underlying mechanisms are unknown but may include changes in arterial function and vasoactive mediators. We examined the effects of prolonged unbroken sitting, relative to regular active interruptions to sitting time, on arterial function in adults at increased CVD risk. In a randomized crossover trial, 19 sedentary overweight/obese adults (mean ± SD age 57 ± 12 yr) completed 2 laboratory-based conditions: 5 h uninterrupted sitting (SIT) and 5 h sitting interrupted every 30 min by 3 min of simple resistance activities (SRA). Femoral artery function [flow-mediated dilation (FMD)], blood flow, and shear rate were measured at 0 h, 30 min, 1 h, 2 h, and 5 h. Brachial FMD was assessed at 0 and 5 h. Plasma was collected hourly for measurement of endothelin-1 (ET-1), nitrates/nitrites, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1). There was a significant decline in femoral artery FMD, averaged over 5 h in the SIT condition, relative to SRA (P < 0.001). Plasma ET-1 total area under the curve over 5 h increased in the SIT condition compared with SRA (P = 0.006). There was no significant difference between conditions in femoral or brachial shear rate, brachial FMD, nitrates/nitrites, VCAM-1, or ICAM-1 (P > 0.05 for all). Five hours of prolonged sitting, relative to regular interruptions to sitting time, impaired femoral artery vasodilator function and increased circulating ET-1 in overweight/obese adults. There is the need to build on this evidence beyond acute observations to better understand the potential longer-term vascular-related consequences of prolonged sitting.NEW & NOTEWORTHY This is the first study to examine the effect of prolonged sitting on arterial function in adults at increased cardiovascular disease risk. We have shown that 5 h of prolonged sitting, relative to regular interruptions to sitting time, impaired femoral artery vasodilator function and increased circulating endothelin-1 in overweight/obese adults. There is now the need to build on this evidence beyond acute observations to better understand the potential longer-term vascular-related consequences of prolonged sitting.

Genome-Wide Screens Reveal New Gene Products That Influence Genetic Competence in Streptococcus mutans.

A network of genes and at least two peptide signaling molecules tightly control when Streptococcus mutans becomes competent to take up DNA from its environment. Widespread changes in the expression of genes occur when S. mutans is presented with competence signal peptides in vitro, including the increased production of the alternative sigma factor, ComX, which activates late competence genes. Still, the way that gene products that are regulated by competence peptides influence DNA uptake and cellular physiology are not well understood. Here, we developed and employed comprehensive transposon mutagenesis of the S. mutans genome, with a screen to identify mutants that aberrantly expressed comX, coupled with transposon sequencing (Tn-seq) to gain a more thorough understanding of the factors modulating comX expression and progression to the competent state. The screens effectively identified genes known to affect competence, e.g., comR, comS, comD, comE, cipB, clpX, rcrR, and ciaH, but disclosed an additional 20 genes that were not previously competence associated. The competence phenotypes of mutants were characterized, including by fluorescence microscopy to determine at which stage the mutants were impaired for comX activation. Among the novel genes studied were those implicated in cell division, the sensing of cell envelope stress, cell envelope biogenesis, and RNA stability. Our results provide a platform for determining the specific chemical and physical cues that are required for genetic competence in S. mutans, while highlighting the effectiveness of using Tn-seq in S. mutans to discover and study novel biological processes.IMPORTANCEStreptococcus mutans acquires DNA from its environment by becoming genetically competent, a physiologic state triggered by cell-cell communication using secreted peptides. Competence is important for acquiring novel genetic traits and has a strong influence on the expression of virulence-associated traits of S. mutans Here, we used transposon mutagenesis and genomic technologies to identify novel genes involved in competence development. In addition to identifying genes previously known to be required for comX expression, 20 additional genes were identified and characterized. The findings create opportunities to diminish the pathogenic potential of S. mutans, while validating technologies that can rapidly advance our understanding of the physiology, biology, and genetics of S. mutans and related pathogens.

A Functional Kinase Short Interfering Ribonucleic Acid Screen Using Protease-Activated Receptor 2-Dependent Opening of Transient Receptor Potential Vanilloid-4.

Protease-activated receptor 2 (PAR2) is a proinflammatory G-protein coupled receptor (GPCR) that is activated by inflammatory proteases, and its activation initiates signaling pathways that modulate the nonselective cation channel transient receptor potential vanilloid-4 (TRPV4). PAR2-dependent opening of TRPV4 has been attributed to kinase activation, but the identity of the responsible enzymes is unknown. Deciphering the signaling pathways involved in the PAR2-dependent opening of TRPV4 may yield new targets for pain treatment. This study has identified specific kinases that are involved in opening TRPV4, using a selective screen of short interfering ribonucleic acid (siRNA) SMARTpools, which individually targeted all human kinases, in human embryonic kidney 293 (HEK293) cells that stably express inducible TRPV4. This screen is unique because it uses a real-time assay measuring intracellular calcium with Fura-2AM dye. From the primary screen, subsequent confirmation screen, and on-target messenger ribonucleic acid expression analysis, we identified two kinases as crucial to the PAR2-dependent opening of TRPV4 in HEK293 cells, mitogen-activated protein kinase 13 and with no lysine kinase 4. In conclusion, this study describes a powerful new application of siRNA knockdown to identity signaling molecules that are responsible for the PAR2-dependent opening of TRPV4, which will help elucidate this signaling process.

Acute glucoregulatory and vascular outcomes of three strategies for interrupting prolonged sitting time in postmenopausal women: A pilot, laboratory-based, randomized, controlled, 4-condition, 4-period crossover trial.

BACKGROUND: Prolonged sitting is associated with cardiometabolic and vascular disease. Despite emerging evidence regarding the acute health benefits of interrupting prolonged sitting time, the effectiveness of different modalities in older adults (who sit the most) is unclear. METHODS: In preparation for a future randomized controlled trial, we enrolled 10 sedentary, overweight or obese, postmenopausal women (mean age 66 years ±9; mean body mass index 30.6 kg/m2 ±4.2) in a 4-condition, 4-period crossover feasibility pilot study in San Diego to test 3 different sitting interruption modalities designed to improve glucoregulatory and vascular outcomes compared to a prolonged sitting control condition. The interruption modalities included: a) 2 minutes standing every 20 minutes; b) 2 minutes walking every hour; and c) 10 minutes standing every hour. During each 5-hr condition, participants consumed two identical, standardized meals. Blood samples, blood pressure, and heart rate were collected every 30 minutes. Endothelial function of the superficial femoral artery was measured at baseline and end of each 5-hr condition using flow-mediated dilation (FMD). Participants completed each condition on separate days, in randomized order. This feasibility pilot study was not powered to detect statistically significant differences in the various outcomes, however, analytic methods (mixed models) were used to test statistical significance within the small sample size. RESULTS: Nine participants completed all 4 study visits, one participant completed 3 study visits and then was lost to follow up. Net incremental area under the curve (iAUC) values for postprandial plasma glucose and insulin during the 5-hr sitting interruption conditions were not significantly different compared to the control condition. Exploratory analyses revealed that the 2-minute standing every 20 minutes and the 2-minute walking every hour conditions were associated with a significantly lower glycemic response to the second meal compared to the first meal (i.e., condition-matched 2-hour post-lunch glucose iAUC was lower than 2-hour post-breakfast glucose iAUC) that withstood Bonferroni correction (p = 0.0024 and p = 0.0084, respectively). Using allometrically scaled data, the 10-minute standing every hour condition resulted in an improved FMD response, which was significantly greater than the control condition after Bonferroni correction (p = 0.0033). CONCLUSION: This study suggests that brief interruptions in prolonged sitting time have modality-specific glucoregulatory and vascular benefits and are feasible in an older adult population. Larger laboratory and real-world intervention studies of pragmatic and effective methods to change sitting habits are needed. TRIAL REGISTRATION: ClinicalTrials.gov NCT02743286.

Sedentary behavior as a risk factor for cognitive decline? A focus on the influence of glycemic control in brain health.

Cognitive decline leading to dementia represents a global health burden. In the absence of targeted pharmacotherapy, lifestyle approaches remain the best option for slowing the onset of dementia. However, older adults spend very little time doing moderate to vigorous exercise and spend a majority of time in sedentary behavior. Sedentary behavior has been linked to poor glycemic control and increased risk of all-cause mortality. Here, we explore a potential link between sedentary behavior and brain health. We highlight the role of glycemic control in maintaining brain function and suggest that reducing and replacing sedentary behavior with intermittent light-intensity physical activity may protect against cognitive decline by reducing glycemic variability. Given that older adults find it difficult to achieve current exercise recommendations, this may be an additional practical strategy. However, more research is needed to understand the impact of poor glycemic control on brain function and whether practical interventions aimed at reducing and replacing sedentary behavior with intermittent light intensity physical activity can help slow cognitive decline.

Television Viewing Time and Inflammatory-Related Mortality.

PURPOSE: Television (TV) viewing time is associated with increased risk of all-cause, cardiovascular and cancer mortality. Although TV time is detrimentally associated with key inflammatory markers, the associations of TV time with other inflammatory-related mortality (with a predominant inflammatory, oxidative or infectious component, but not attributable to cancer or cardiovascular causes), are unknown. METHODS: Among 8933 Australian adults (4593 never-smokers) from the baseline (1999-2000) Australian Diabetes, Obesity and Lifestyle Study (median follow-up, 13.6 yr), we examined TV time in relation to noninflammatory and inflammatory-related mortality (not attributable to cancer or cardiovascular causes, hereafter "inflammatory-related" mortality). Because smoking has a significant inflammatory component, we also examined this relationship in never-smokers. RESULTS: Of 896 deaths, 248 were attributable to cardiovascular disease, 346 to cancer, 130 to other inflammatory-related causes (71 for never-smokers), and 172 to noninflammatory-related causes (87 for never-smokers). After multivariate adjustment for age, sex, education, household income, smoking status, alcohol intake, energy intake, diet, and cardiometabolic risk biomarkers (model 3), every additional hours per day of TV time was associated with increased risk of inflammatory-related mortality in the overall population (hazard ratio, 1.12; 95% confidence interval, 1.00-1.25) and in never-smokers (1.18; 1.00, 1.40). These results were attenuated after additional adjustment for leisure-time physical activity. After multivariate adjustment (model 3), no association was observed for noninflammatory mortality in the overall population (0.95; 0.85, 1.07), but risk tended to decrease for never-smokers (0.85; 0.75, 1.02). CONCLUSIONS: In summary, before adjustment for leisure-time physical activity, TV time was associated with increased risk of inflammatory-related mortality. This is consistent with the hypothesis that high TV viewing may be associated with a chronic inflammatory state.

Breaking Up Prolonged Sitting Alters the Postprandial Plasma Lipidomic Profile of Adults With Type 2 Diabetes.

Context: Postprandial dysmetabolism in type 2 diabetes (T2D) is exacerbated by prolonged sitting and may trigger inflammation and oxidative stress. It is unknown what impact countermeasures to prolonged sitting have on the postprandial lipidome. Objective: In this study, we investigated the effects of regular interruptions to sitting, compared with prolonged sitting, on the postprandial plasma lipidome. Design: Randomized crossover experimental trial. Setting: Participants underwent three 7-hour conditions: uninterrupted sitting (SIT); light-intensity walking interruptions (LW); and simple resistance activity interruptions (SRA). Participants and Samples: Baseline (fasting) and 7-hour (postprandial) plasma samples from 21 inactive overweight/obese adults with T2D were analyzed for 338 lipid species using mass spectrometry. Main Outcome Measures: Using mixed model analysis (controlling for baseline outcome variable, gender, body mass index, and condition order), the percentage change in lipid species (baseline to 7 hours) was compared between conditions with Benjamini-Hochberg correction. Results: Thirty-seven lipids were different between conditions (P < 0.05). Compared with SIT, postprandial elevations in diacylglycerols, triacylglycerols, and phosphatidylethanolamines were attenuated in LW and SRA. Plasmalogens and lysoalkylphosphatidylcholines were reduced in SIT, compared with attenuated reductions or elevations in LW and SRA. Phosphatidylserines were elevated with LW, compared with reductions in SIT and SRA. Conclusion: Compared with SIT, LW and SRA were associated with reductions in lipids associated with inflammation; increased concentrations of lipids associated with antioxidant capacity; and differential changes in species associated with platelet activation. Acutely interrupting prolonged sitting time may impart beneficial effects on the postprandial plasma lipidome of adults with T2D. Evidence on longer-term intervention is needed.