Induction of bacterial expression at the mRNA level by light.

Vital organismal processes, including development, differentiation and adaptation, involve altered gene expression. Although expression is frequently controlled at the transcriptional stage, various regulation mechanisms operate at downstream levels. Here, we leverage the photoreceptor NmPAL to optogenetically induce RNA refolding and the translation of bacterial mRNAs. Blue-light-triggered NmPAL binding disrupts a cis-repressed mRNA state, thereby relieves obstruction of translation initiation, and upregulates gene expression. Iterative probing and optimization of the circuit, dubbed riboptoregulator, enhanced induction to 30-fold. Given action at the mRNA level, the riboptoregulator can differentially regulate individual structural genes within polycistronic operons. Moreover, it is orthogonal to and can be wed with other gene-regulatory circuits for nuanced and more stringent gene-expression control. We thus advance the pAurora2 circuit that combines transcriptional and translational mechanisms to optogenetically increase bacterial gene expression by >1000-fold. The riboptoregulator strategy stands to upgrade numerous regulatory circuits and widely applies to expression control in microbial biotechnology, synthetic biology and materials science.

Emotional irritation before mental stress is associated with enhanced peripheral norepinephrine.

Research suggests equivocal findings on associations of catecholamines and mood. Our study investigated the associations of emotional state, blood pressure and catecholamines in 55 healthy males undergoing mental stress. We especially checked the reported link between norepinephrine (NE) and emotional irritation. Blood pressure (SBP, DBP) and heart rate (HR) were continuously monitored. NE and epinephrine (EPI) were measured before, after, and 20 minutes after stress. Participants were divided into irritated versus non-irritated and anxious versus non-anxious subjects by median split on their baseline questionnaires. The task elicited significant cardiovascular, hormonal, and psychological stress responses. NE levels were significantly correlated with irritation before stress. Irritated subjects showed significantly higher DBP and NE than non-irritated subjects. The higher NE and DBP levels in the irritated participants suggest detrimental psycho-physiological interrelations promoting the development of stress-mediated cardiovascular diseases. Heightened emotional irritation before stress may be regarded as a psychological risk factor.

Salt sensitivity, anxiety, and irritability predict blood pressure increase over five years in healthy males.

Salt sensitivity and psychological factors are thought to be associated with a higher risk for the development of hypertension but data on the relation between age-related blood pressure increase and salt sensitivity or psychological factors are scarce. A total of 31 healthy young males who were previously classified with respect to salt sensitivity, mental stress reactivity, trait-anxiety, trait-anger, and irritability were followed up 4.8 years later by 24 hr ambulatory blood pressure monitoring (ABP). Our results showed anxiety and irritability correlated significantly with 24-hr ABP 4.8 years later (p < 0.05). The increase of diastolic blood pressure over 4.8 years was higher in salt-sensitive than salt-resistant subjects (p < 0.07). Heart rate and diastolic blood pressure correlated significantly with systolic and diastolic 24-hr ABP and blood pressure reactivity under mental stress with diastolic 24-hr ABP. A regression analysis that included cardiovascular and psychological factors yielded 34% (systolic ABP, p < 0.009) and 58% (diastolic ABP, p < 0.0001) of variance. We concluded that anxiety and irritability are important predictors of blood pressure increase over time in healthy males.

Antiinflammatory effects of angiotensin II subtype 1 receptor blockade in hypertensive patients with microinflammation.

BACKGROUND: Experimental studies revealed proinflammatory properties of angiotensin II. We evaluated antiinflammatory effects of the angiotensin II subtype 1 receptor antagonist olmesartan medoxomil alone and in cotherapy with the HMG-CoA reductase inhibitor pravastatin in patients with essential hypertension and microinflammation. METHODS AND RESULTS: We measured a panel of vascular inflammation markers, including high-sensitivity C-reactive protein, and lipid levels during 12 weeks of therapy with olmesartan (n=100) or placebo (n=99) in a prospective double-blind multicenter study. Pravastatin was added to the double-blind therapy at week 6 in both treatment arms. Blood pressure control was achieved with addition of hydrochlorothiazide. Olmesartan treatment had already significantly reduced serum levels of high-sensitivity C-reactive protein (-15.1%; P<0.05), high-sensitivity tumor necrosis factor-alpha (-8.9%; P<0.02), interleukin-6 (-14.0%; P<0.05), and monocyte chemotactic protein-1 (-6.5%; P<0.01) after 6 weeks of therapy, whereas placebo treatment (ie, blood pressure reduction) had no major effect on inflammation markers. After 12 weeks of therapy, high-sensitivity C-reactive protein (-21.1%; P<0.02), high-sensitivity tumor necrosis factor-alpha (-13.6%; P<0.01), and interleukin-6 (-18.0%; P<0.01) decreased further with olmesartan and pravastatin cotherapy, but treatment with pravastatin alone (ie, cotherapy with placebo) did not significantly alter inflammation markers. In contrast, addition of pravastatin led to a significant (P<0.001) reduction in LDL cholesterol serum concentrations in the olmesartan and placebo treatment groups (-15.1% and -12.1%, respectively). CONCLUSIONS: Angiotensin II receptor blockade significantly reduces vascular microinflammation in patients with essential hypertension by as early as week 6 of therapy. This antiinflammatory action of angiotensin II receptor antagonists may contribute to their beneficial cardiovascular effects.

Reduced vagal activity in salt-sensitive subjects during mental challenge.

BACKGROUND: Salt-sensitive normotensive men exhibit an enhanced pressor and heart rate (HR) response to mental stress. Stress-induced HR acceleration may result from sympathetic activation or vagal withdrawal. We studied the importance of vagal withdrawal for the increased stress responsiveness of salt-sensitive subjects. METHODS: We studied cardiovascular reactivity to mental challenge in 17 salt-sensitive healthy white male students and 56 salt-resistant control subjects who were comparable with respect to age, body mass index, and physical fitness. Salt sensitivity was determined by a 2-week dietary protocol (20 mmol v 240 mmol sodium/day). Mental stress was induced by a computerized information-processing task (manometer test). Electrocardiogram and finger blood pressure (BP; Finapres, Ohmeda, Louisville, CO) were registered continuously to determine HR and interbeat-interval length. Time and frequency domain (spectral power) based measures of respiratory-related heart rate variability (HRV) were calculated to estimate vagal cardiac control; diastolic BP reactivity was assessed to estimate peripheral sympathetic effects. RESULTS: Stress-induced increase in HR was higher in salt-sensitive than in salt-resistant subjects. Salt-sensitive subjects, in comparison to salt-resistant subjects, showed significantly reduced respiratory-related HRV during baseline and mental stress conditions (P <.01). The increase in diastolic BP during mental challenge was significantly greater in salt-sensitive subjects (P <.05). CONCLUSIONS: Our findings suggest reduced vagal and increased sympathetic tone during mental challenge in salt-sensitive subjects. Altered autonomic nervous system function may contribute to later development of hypertension in salt-sensitive individuals.