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Background: Acetylcholine (ACh) and norepinephrine (NE) are representative neurotransmitters of parasympathetic and sympathetic nerves, respectively, that antagonize each other to coregulate internal body functions. This also includes the control of different kinds of hormone secretion from pancreatic islets. However, the molecular mechanisms have not been fully elucidated, and whether innervation in islets is abnormal in diabetes mellitus also remains unclear. Methods and results: Immunofluorescence colocalization and islet perfusion were performed and the results demonstrated that ACh/NE and their receptors were highly expressed in islet and rapidly regulated different hormones secretion. Phosphorylation is considered an important posttranslational modification in islet innervation and it was identified by quantitative proteomic and phosphoproteomic analyses in this study. The phosphorylated islet proteins were found involved in many biological and pathological processes, such as synaptic signalling transduction, calcium channel opening and insulin signalling pathway. Then, the kinases were predicted by motif analysis and further screened and verified by kinase‐specific siRNAs in different islet cell lines (αTC1‐6, Min6 and TGP52). After functional verification, Ksr2 and Pkacb were considered the key kinases of ACh and NE in insulin secretion, and Cadps, Mlxipl and Pdcd4 were the substrates of these kinases measured by immunofluorescence co‐staining. Then, the decreased expression of receptors, kinases and substrates of ACh and NE were found in diabetic mice and the aberrant rhythm in insulin secretion could be improved by combined interventions on key receptors (M3 (pilocarpine) or α2a (guanfacine)) and kinases (Ksr2 or Pkacb). Conclusions: Abnormal innervation was closely associated with the degree of islet dysfunction in diabetic mice and the aberrant rhythm in insulin secretion could be ameliorated significantly after intervention with key receptors and kinases in the early stage of diabetes mellitus, which may provide a promising therapeutic strategy for diabetes mellitus in the future. [ABSTRACT FROM AUTHOR]

Adverse maternal environment (AME) and high‐fat diet in early childhood increase the risk of cognitive impairment and depression later in life. Cognitive impairment associates with hippocampal dysfunction. A key regulator of hippocampal function is the glucocorticoid receptor. Increased hippocampal GR expression associates with cognitive impairment and depression. Transcriptional control of GR relies in part upon the DNA methylation status at multiple alternative initiation sites that are tissue specific, with exon 1.7 being hippocampal specific. Increased exon 1.7 expression associates with upregulated hippocampal GR expression in early life stress animal models. However, the effects of AME combined with postweaning western diet (WD) on offspring behaviors and the expression of GR exon 1 variants in the hippocampus are unknown. We hypothesized that AME and postweaning WD would impair cognitive function and cause depression‐like behavior in offspring in conjunction with dysregulated hippocampal expression of total GR and exon 1.7 variant in mice. We found that AME‐WD impaired learning and memory in male adult offspring concurrently with increased hippocampal expression of total GR and GR 1.7. We also found that increased GR 1.7 expression was associated with decreased DNA methylation at the GR 1.7 promoter. We speculate that decreased DNA methylation at the GR 1.7 promoter plays a role in AME‐WD induced increase of GR in the hippocampus. This increased GR expression may subsequently contribute to hippocampus dysfunction and lead to the cognitive impairment seen in this model. [ABSTRACT FROM AUTHOR]

The prevalence of obesity is rapidly increasing in the United States, particularly among women. Approximately 60−70% of hypertension in adults may be directly attributed to obesity. In addition, maternal obesity is a major risk factor for hypertensive disorders during pregnancy. The underlying mechanisms for the association between obesity and cardiovascular risk are multifactorial, but activation of the sympathetic nervous system is one significant contributing factor. This brief review summarizes the current knowledge on sex differences in sympathetic activity in obesity and its related hypertension, with a focus on studies in humans. Evidence suggests that abdominal visceral fat, rather than subcutaneous fat, is related to augmented sympathetic activity regardless of sex. Race/ethnicity may affect the relationship between obesity and sympathetic activity. Obesity‐related hypertension has an important neurogenic component, which is characterized by sympathetic overactivity. However, sex may influence the association between hypertension and sympathetic overactivity in obese people. Finally, both body weight and sympathetic overactivity seem to be involved in the development of gestational hypertensive disorders in women. Chronic hyperinsulinemia due to insulin resistance, high plasma levels of leptin, and/or obstructive sleep apnea may be responsible for sympathetic overactivity in obesity‐related hypertension. [ABSTRACT FROM AUTHOR]

Nano-sized molecularly imprinted polymers for tiliroside were successfully prepared by a precipitation polymerization method. Acrylamide, ethylene glycol dimethacrylate, azobisisobutyronitrile, and acetonitrile/dimethyl sulfoxide were used as functional monomer, cross-linker, initiator, and porogen, respectively. The structural features and morphological characterization of tiliroside-imprinted polymers were characterized by Fourier transform infrared spectroscopy and scanning electron microscopy, respectively. The adsorption experiments indicated that the tiliroside-imprinted polymers exhibited high selective recognition property to tiliroside. Scatchard analysis indicated that the homogeneous-binding sites were formed in the polymers. The selectivity test revealed that the adsorption capacity and selectivity of polymers to tiliroside was significantly higher than that of rutin, astragalin, and kaempferol. Finally, the tiliroside-imprinted polymers were employed as adsorbents in solid-phase extraction for the extraction of tiliroside from the ethyl acetate extract of the flowers of Edgeworthia gardneri (wall.) Meisn. The results demonstrated that the extraction recoveries of tiliroside ranged from 69.3 to 73.5% by using tiliroside-imprinted polymers coupled with solid-phase extraction method. These results indicated that the tiliroside-based molecularly imprinted solid-phase extraction method was proven to be an effective technique for the separation and enrichment of tiliroside from natural medicines. [ABSTRACT FROM AUTHOR]

In this article, the author focuses on the concept of syncope (fainting) prevention in blood donation. It mentions that adverse reaction occurs during close temporal proximity to whole blood donation among blood donors, and states the use of water or isotonic drink by donors to prevent syncopal reactions. It also mentions the use of blood donation with the help of glucose-sodium transporter.

Alcoholic liver disease is one of the diseases with the highest fatality rate worldwide. The cellular process of autophagy which recycles damaged organelles to maintain protein and organelle homeostasis is found to positively influence survival during hepatic insufficiency, although the mechanism is poorly understood. Palmatine (PLT) has a variety of biological functions, such as broad‐spectrum antibacterial action, neuroprotective, antioxidant stress, and antiviral and anti‐inflammatory activities. However, it is not known whether PLT has a protective effect against alcoholic liver injury. Here, we investigated the protective effect of PLT in a cellular model of alcohol‐induced acute liver injury and further explored its mechanism of action. In this study, we show for the first time that PLT attenuates alcohol‐induced hepatocyte injury by promoting autophagy to play an essential protective role. As PLT treatment induced a brief increase in LC3‐II conversion and p62 degradation, it also upregulated the expression of ATG5 and ATG7. The expression levels of the proapoptotic proteins Bax, Caspase 3, and Caspase 9 significantly decreased, while the antiapoptotic protein levels of Bcl‐2 upregulated after treatment with PLT. However, in presence of the autophagy inhibitor, 3‐methyladenine, the effect of PLT in inhibiting ethanol‐induced hepatocyte injury reversed significantly. Mechanistically, the protective effects of PLT may be mediated by promoting the activation of the AMP‐activated protein kinase/mammalian target of rapamycin signaling pathway. Therefore, we believe that the development of alcoholic liver injuries may be controlled by PLT by inhibiting hepatocyte apoptosis through the autophagy pathway. The study lays a solid theoretical and practical basis for future animal models and clinical studies of PLT. [ABSTRACT FROM AUTHOR]

The mechanisms governing brain vascularization during development remain poorly understood. A key regulator of developmental vascularization is delta like 4 (DLL4), a Notch ligand prominently expressed in endothelial cells (EC). Exposure to hyperoxia in premature infants can disrupt the development and functions of cerebral blood vessels and lead to long‐term cognitive impairment. However, its role in cerebral vascular development and the impact of postnatal hyperoxia on DLL4 expression in mouse brain EC have not been explored. We determined the DLL4 expression pattern and its downstream signalling gene expression in brain EC using Dll4+/+ and Dll4+/LacZ mice. We also performed in vitro studies using human brain microvascular endothelial cells. Finally, we determined Dll4 and Cldn5 expression in mouse brain EC exposed to postnatal hyperoxia. DLL4 is expressed in various cell types, with EC being the predominant one in immature brains. Moreover, DLL4 deficiency leads to persistent abnormalities in brain microvasculature and increased vascular permeability both in vivo and in vitro. We have identified that DLL4 insufficiency compromises endothelial integrity through the NOTCH‐NICD‐RBPJ‐CLDN5 pathway, resulting in the downregulation of the tight junction protein claudin 5 (CLDN5). Finally, exposure to neonatal hyperoxia reduces DLL4 and CLDN5 expression in developing mouse brain EC. We reveal that DLL4 is indispensable for brain vascular development and maintaining the blood–brain barrier's function and is repressed by neonatal hyperoxia. We speculate that reduced DLL4 signalling in brain EC may contribute to the impaired brain development observed in neonates exposed to hyperoxia. Key points: The role of delta like 4 (DLL4), a Notch ligand in vascular endothelial cells, in brain vascular development and functions remains unknown.We demonstrate that DLL4 is expressed at a high level during postnatal brain development in immature brains and DLL4 insufficiency leads to abnormal cerebral vasculature and increases vascular permeability both in vivo and in vitro.We identify that DLL4 regulates endothelial integrity through NOTCH‐NICD‐RBPJ‐CLDN5 signalling.Dll4 and Cldn5 expression are decreased in mouse brain endothelial cells exposed to postnatal hyperoxia. [ABSTRACT FROM AUTHOR]

An easily prepared tetraphosphine N, N, N′, N′-tetra(diphenylphosphinomethyl)-1,2-ethylenediamine (L1) associated with [Pd(η3-C3H5)Cl]2 affords an efficient catalyst for Suzuki-Miyaura coupling of 3-pyridineboronic acid with heteroaryl bromides. Reaction could be performed with as little as 0.02 mol% catalyst and a high turnover number of 2500 is obtained. A wide range of substrates is investigated with satisfactory yields, and good compatibility with aminogroup-substituted pyridines and unprotected indole is exhibited. This protocol can also be applied successfully to the reaction of heteroaryl bromides with 3-thiopheneboronic acid. This Pd-tetraphosphine catalyst efficiently restrains the poisoning effect from heteroaryls, and shows good stability and longevity. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Key points Recent studies have suggested the presence of cardiac atrophy as a key component of the pathogenesis of the postural orthostatic tachycardia syndrome (POTS), similar to physical deconditioning; exercise intolerance is associated with a reduced stroke volume (SV) in POTS which may be the cause of the high heart rate (HR) at rest and during exercise., We determined whether physical 'reconditioning' with exercise training improves exercise performance in POTS., A lower SV resulted in a higher HR in POTS at any given oxygen uptake () during exercise while the cardiac output ()- relationship remained normal. was lower in POTS than healthy sedentary controls., After 3 months of training in POTS, HR became lower at any given due to increased SV without changes in the - relationship. increased due to increased peak SV, and was proportional to total blood volume. HR recovery from exercise was faster after training than before training., Thus, exercise training improves physical fitness and cardiovascular responses during exercise in POTS., Abstract Recent studies have suggested the presence of cardiac atrophy as a key component of the pathogenesis of the postural orthostatic tachycardia syndrome (POTS), similar to physical deconditioning. It has also been shown that exercise intolerance is associated with a reduced stroke volume (SV) in POTS, and that the high heart rate (HR) observed at rest and during exercise in these patients is due to this low SV. We tested the hypotheses that (a) circulatory control during exercise is normal in POTS; and (b) that physical 'reconditioning' with exercise training improves exercise performance in patients with POTS. Nineteen (18 women) POTS patients completed a 3 month training programme. Cardiovascular responses during maximal exercise testing were assessed in the upright position before and after training. Resting left ventricular diastolic function was evaluated by Doppler echocardiography. Results were compared with those of 10 well-matched healthy sedentary controls. A lower SV resulted in a higher HR in POTS at any given oxygen uptake () during exercise while the cardiac output ()- relationship was normal. was lower in POTS than controls (26.1 ± 1.0 (SEM) vs. 36.3 ± 0.9 ml kg−1 min−1; P < 0.001) due to a lower peak SV (65 ± 3 vs. 80 ± 5 ml; P= 0.009). After training in POTS, HR became lower at any given due to increased SV without changes in the - relationship. increased by 11% ( P < 0.001) due to increased peak SV ( P= 0.021) and was proportional to total blood volume. Peak HR was similar, but HR recovery from exercise was faster after training than before training ( P= 0.036 for training and 0.009 for interaction). Resting diastolic function was mostly normal in POTS before training, though diastolic suction was impaired ( P= 0.023). There were no changes in any Doppler index after training. These results suggest that short-term exercise training improves physical fitness and cardiovascular responses during exercise in patients with POTS. [ABSTRACT FROM AUTHOR]

Key points Syncope is a common clinical condition occurring even in healthy people without manifest cardiovascular disease; we determined the role of cardiac output and sympathetic vasoconstriction in neurally mediated (pre)syncope. [ABSTRACT FROM AUTHOR]

Young women are more susceptible to orthostatic intolerance than men, though the sex-specific pathophysiology remains unknown. As blood pressure (BP) is regulated through the baroreflex mechanism, we tested the hypothesis that baroreflex control of muscle sympathetic nerve activity (MSNA) during orthostasis is impaired in women and can be affected by the menstrual cycle. MSNA and haemodynamics were measured supine and during a graded upright tilt (30 deg for 6 min, 60 deg for 45 min or till presyncope) in 11 young men and 11 women during the early follicular (EFP) and mid-luteal phase (MLP) of the menstrual cycle. Sympathetic baroreflex sensitivity was quantified using the slope of the linear correlation between total activity and diastolic BP during spontaneous breathing. Baroreflex function was further assessed during a Valsalva manoeuvre (VM). Although MSNA burst frequency responses during tilting were similar between sexes and menstrual phases, increases in total activity were lower in women during EFP than MLP ( P= 0.030), while total peripheral resistance and plasma noradrenaline were not similarly lower; upright total activity tended to be lower in women during EFP than men ( P= 0.102). Sympathetic baroreflex sensitivity did not differ between sexes ( P= 0.676) supine (−281 ± 46 (s.e.m.) units beat−1 mmHg−1 in men vs−252 ± 52 in EFP and −272 ± 40 in MLP in women), at 30 deg tilt (−648 ± 129 vs−611 ± 79 and −487 ± 94), and at 60 deg tilt (−792 ± 135 vs−831 ± 92 and −814 ± 142); this sensitivity was not affected by the menstrual cycle ( P= 0.747). Similar sympathetic baroreflex sensitivity between sexes and phases was also observed during the VM. Cardiovagal baroreflex sensitivity assessed during decreasing BP (i.e. early phase II of the VM) was comparable between sexes, but it was greater in men than women during increasing BP (i.e. phase IV); the menstrual cycle had no influences on cardiovagal baroreflex sensitivity. We conclude that the menstrual cycle affects sympathetic neural responses but not sympathetic baroreflex sensitivity during orthostasis, though upright vasomotor sympathetic activity is not clearly different between men and women. Not only sympathetic but also cardiovagal baroreflex sensitivity is similar between sexes and menstrual phases during a hypotensive stimulus. However, cardiovagal baroreflex-mediated bradycardia during a hypertensive stimulus is different between sexes but not affected by the menstrual cycle. Thus, other factors rather than sympathetic baroreflex control mechanisms contribute to sex differences in orthostatic tolerance in young humans. [ABSTRACT FROM AUTHOR]

Vasomotor sympathetic activity plays an important role in arterial pressure maintenance via the baroreflex during acute orthostasis in humans. If orthostasis is prolonged, blood pressure may be supported additionally by humoral factors with a possible reduction in sympathetic baroreflex sensitivity. We tested the hypothesis that baroreflex control of muscle sympathetic nerve activity (MSNA) decreases during prolonged upright posture. MSNA and haemodynamics were measured supine and during 45 min 60 deg upright tilt in 13 healthy individuals. Sympathetic baroreflex sensitivity was quantified using the slope of the linear correlation between MSNA and diastolic pressure during spontaneous breathing. It was further assessed as the relationship between MSNA and stroke volume, with stroke volume derived from cardiac output (C2H2 rebreathing) and heart rate. Total peripheral resistance was calculated from mean arterial pressure and cardiac output. We found that MSNA increased from supine to upright (17 ± 8 (s.d.) versus 38 ± 12 bursts min−1; P < 0.01), and continued to increase to a smaller degree during sustained tilt (39 ± 11, 41 ± 12, 43 ± 13 and 46 ± 15 bursts min−1 after 10, 20, 30 and 45 min of tilt; between treatments P < 0.01). Sympathetic baroreflex sensitivity increased from supine to upright (−292 ± 180 versus−718 ± 362 units beat−1 mmHg−1; P < 0.01), but remained unchanged as tilting continued (−611 ± 342 and −521 ± 221 units beat−1 mmHg−1 after 20 and 45 min of tilt; P= 0.49). For each subject, changes in MSNA were associated with changes in stroke volume ( r= 0.88 ± 0.13, P < 0.05), while total peripheral resistance was related to MSNA during 45 min upright tilt ( r= 0.82 ± 0.15, P < 0.05). These results suggest that the vasoconstriction initiated by sympathetic adrenergic nerves is maintained by ongoing sympathetic activation during sustained (i.e. 45 min) orthostasis without obvious changes in vasomotor sympathetic neural control. [ABSTRACT FROM AUTHOR]

Summary: Neuropathic pain is a common and debilitating modality of chronic pain induced by a lesion or disease of the somatosensory nervous system. Albeit the elucidation of numerous pathophysiological mechanisms and the development of potential treatment compounds, safe and reliable therapies of neuropathic pain remain poor. Multiple stress/cell death pathways have been shown to be implicated in neuroinflammation during neuropathic pain. Here, we summarize the current knowledge of stress/cell death pathways and present an overview of the roles and molecular mechanisms of stress/cell death pathways in neuroinflammation during neuropathic pain, covering intrinsic and extrinsic apoptosis, autophagy, mitophagy, ferroptosis, pyroptosis, necroptosis, and phagoptosis. Small molecule compounds that modulate stress/cell death pathways in alleviating neuropathic pain are discussed mainly based on preclinical neuropathic pain models. These findings will contribute to in‐depth understanding of the pathological processes during neuropathic pain as well as bridge the gap between basic and translational research to uncover new neuroprotective interventions. [ABSTRACT FROM AUTHOR]

Noble‐metal‐free perovskite oxides are promising and well‐known catalysts for high‐temperature gas‐phase oxidation reactions, but their application in selective oxidation reactions in the liquid phase has rarely been studied. We report the liquid‐phase oxidation of cinnamyl alcohol over spray‐flame synthesized LaCo1–xFexO3 perovskite nanoparticles with tert‐butyl hydroperoxide (TBHP) as the oxidizing agent under mild reaction conditions. The catalysts were characterized by XRD, BET, EDS and elemental analysis. LaCo0.8Fe0.2O3 showed the best catalytic properties indicating a synergistic effect between cobalt and iron. The catalysts were found to be stable against metal leaching as proven by hot filtration, and the observed slight deactivation is presumably due to segregation as determined by EDS. Kinetic studies revealed an apparent activation energy of 63.6 kJ mol−1. Combining kinetic findings with TBHP decomposition as well as control experiments revealed a complex reaction network. [ABSTRACT FROM AUTHOR]

The impact of age on exercise pressor responses is equivocal, likely because of sex‐specific neuro‐cardiovascular changes with age. However, assessments of the interactive effects of age and sex on muscle sympathetic nerve activity (MSNA) responses to exercise are lacking. We tested the hypothesis that older females would exhibit exaggerated increases in blood pressure (BP) and MSNA discharge patterns during handgrip exercise compared with similarly aged males and young adults. Twenty‐five young (25 (2) years; mean (SD)) males (YM; n = 12) and females (YF; n = 13) and 23 older (71 (5) years) males (OM; n = 11) and females (OF; n = 12) underwent assessments of BP, total peripheral resistance (TPR; Modelflow) and MSNA action potential (AP) discharge patterns (microneurography) during incremental rhythmic handgrip exercise and post‐exercise circulatory occlusion (PECO). OM demonstrated larger ∆BP and ∆TPR from baseline than YM (both P < 0.001) despite smaller increases in ∆APs/burst (OM: 0.4 (3) vs. YM: 5 (3) spikes/burst, P < 0.001) and ∆AP clusters/burst (OM: 0.1 (1) vs. YM: 1.8 (1) clusters/burst, P < 0.001) during exercise. Testosterone was lower in OM than YM (P < 0.001) and was inversely related to ∆BP but positively related to ∆AP clusters/burst in males (both P = 0.03). Conversely, YF and OF demonstrated similar ∆BP and ∆AP discharge during exercise (range: P = 0.75–0.96). Age and sex did not impact haemodynamics or AP discharge during PECO (range: P = 0.08‐0.94). Altogether, age‐related changes in neuro‐cardiovascular reactivity exist in males but not females during fatiguing exercise and seem to be related to testosterone. This sex‐specific impact of age underscores the importance of considering biological sex when assessing age‐related changes in neuro‐cardiovascular control during exercise. Key points: Older males have the largest increase in blood pressure despite having the smallest increases in sympathetic vasomotor outflow during rhythmic handgrip exercise.Young males demonstrate greater increases in sympathetic action potential (AP) discharge compared with young females during rhythmic handgrip exercise.Older adults (regardless of sex) demonstrate smaller increases in muscle sympathetic nerve activity (MSNA) burst amplitude and total AP clusters compared with young adults during exercise, as well as smaller increases in integrated MSNA burst frequency, incidence and total MSNA activity during post‐exercise circulatory occlusion (i.e. independent effect of age).Males, but not females (regardless of age), reflexively modify AP conduction velocity during exercise.Our results indicate that age and sex independently and interactively impact the neural and cardiovascular homeostatic adjustments to fatiguing small muscle mass exercise. [ABSTRACT FROM AUTHOR]

Monolayer WS2(1-x)Se2x (x = 0.18, 0.3, 0.43) is are prepared by simultaneous sulfurization and selenation of WO3 deposited by CVD with 5% H2/Ar as the carrier gas on a Si/SiO2 (300 nm) substrate in a two-zone heater (830 °C at the WO3 deposition site, 300 °C at the S/Se site, 15 min). [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is a T cell‐mediated autoimmune disease. Increased incidence of T1D was reported in patients receiving IFN‐α treatment. However, the exact mechanisms of IFN‐α that facilitate the pathogenesis of T1D are not fully understood. To explore the mechanism of IFN‐α on the immune system and islets, non‐obese diabetic (NOD) mice were injected with IFN‐α and the progression of autoimmune insulitis was assessed by haematoxylin and eosin (HE) staining, immunohistochemical and flow cytometry analysis. Transcriptional profiling of islets treated with IFN‐α was explored by RNA‐seq. IFN‐α induced antigen presentation was evaluated by qRT‐PCR, western blot and immunofluorescence, and key transcription factors were inhibited by small interfering RNAs (siRNAs). Our data show that IFN‐α contributed to the progression of autoimmune insulitis in NOD mice by promoting the proliferation of CD8+ T cells. IFN‐α upregulated antigen presentation related genes MHC I, TAP1, B2M, PSMB8, NLRC5 and transcriptional regulator STAT1, STAT2, IRF7 at a time and dose‐dependent manner. The silence of STAT1 or STAT2 both weakened IFN‐α‐induced increase of antigen presenting related molecules. IRF7 was also merely influenced by STAT1 silence. The knockdown of IRF7 decreased the IFN‐α induced expressions of TAP1, PSMB8 and MHC I and prevented the expression of STAT2 but not STAT1. Our study demonstrated that STAT1‐IRF7‐MHC I complex axis were crucial for IFN‐α signalling in islets, and created positive feedback through IRF7‐STAT2 cascade amplifying signals which accelerated the process of T1D. [ABSTRACT FROM AUTHOR]

Land use mix (LUM) is a key part of urban form, but the definitions and measures of LUM are debated. This study aims to reveal the spatial characteristics of LUM patterns by using a sample of 216 streets in Shanghai, a megacity of China. Firstly, a systematic quantitative framework for sustainable LUM is proposed. Then, an LUM degree index (LMDI) that integrates diversity, proximity and compatibility is developed to address the possible bias of a single dimension. Results suggest that areas with high diversity are not necessarily mixed, due to inaccessibility or negative externalities of land uses. Subsequently, spatial characteristics of LUM patterns that combine LMDI with dominant mix‐typologies are analyzed. Results show that residential & service‐dominated streets tend to exhibit higher mix, and are mainly distributed in the city center or the administrative core area. However, 44.4% of the streets with residential & industrial‐dominated or equally distributed mix have lower mix degree and are generally located in the outskirts. More optimized policies for urban periphery areas should be considered. LUM patterns present a detailed perspective to measure and depict the spatial features of LUM, and have the potential to assist urban planners in making decisions. [ABSTRACT FROM AUTHOR]

Pseudomonas plecoglossicida is an important pathogen in aquaculture and causes serious economic losses. Our previous study indicated that znuA gene might play an important role in the pathogenicity of P. plecoglossicida. Five shRNAs were designed and synthesized to silence the znuA gene of P. plecoglossicida. Two of the five mutants of P. plecoglossicida exhibited significant reduction in the expression level of znuA mRNA with different efficiencies. The mutant with the highest silencing efficiency of 89.2% was chosen for further studies. Intrapleural injection of the znuA‐RNAi strain at a dose of 105 cfu/fish did not cause the death of Epinephelus coioides, and no significant signs were observed at the spleen surface of infected E. coioides, while the counterpart E. coioides infected by the same dose of wild‐type strain of P. plecoglossicida all died in 5 days post‐infection (dpi). The expression of znuA gene of znuA‐RNAi strain in E. coioides was always lower than that in wild‐type strain of P. plecoglossicida. The pathogen load in the early stage of infection was higher than that in the later stage of infection. Although the infection of the znuA‐RNAi strain of P. plecoglossicida could induce the production of antibodies in E. coioides, it failed to produce a good immune protection against the infection of wild‐type strain of P. plecoglossicida. Compared with the transcriptome data of E. coioides infected by the wild‐type strain of P. plecoglossicida, the transcriptome data of E. coioides infected by the znuA‐RNAi strain of P. plecoglossicida have altered significantly. Among them, KEGG enrichment analysis showed that the focal adhesion pathway was significantly enriched and exhibited the largest number of 302 DEMs (differentially expressed mRNAs). These results showed that the immune response of E. coioides to P. plecoglossicida infection was significantly affected by the RNAi of znuA gene. [ABSTRACT FROM AUTHOR]

Using the mixed‐metal approach, a direct synthesis route at ambient pressure was developed for a new type of bimetallic metal‐organic framework based on the CPO‐27 structure. The structural characterization of CPO‐27(Cu0.6−CS−Co0.4) using X‐ray diffraction, transmission electron microscopy, energy‐dispersive X‐ray mapping and X‐ray absorption spectroscopy revealed that the Cu2+ and Co2+ ions were exclusively incorporated at the metal positions of the CPO‐27 lattice, but with a core‐shell distribution within the crystallites. The parent framework material was then utilized as a precursor for the generation of novel bimetallic carbon‐supported materials using the controlled thermal decomposition in a reducing atmosphere. During this decomposition process, the distribution of the two metals remained the same, which resulted in unique needle‐shaped particles with a high dispersion of cobalt at the periphery of the amorphous carbon and agglomerated copper particles in the inside. [ABSTRACT FROM AUTHOR]

Biomass‐derived 5‐hydroxymethylfurfural (HMF) is regarded as one of the most promising platform chemicals to produce 2,5‐dimethylfuran (DMF) as a potential liquid transportation fuel. Pd nanoparticles supported on N‐containing and N‐free mesoporous carbon materials were prepared, characterized, and applied in the hydrogenolysis of HMF to DMF under mild reaction conditions. Quantitative conversion of HMF to DMF was achieved in the presence of formic acid (FA) and H2 over Pd/NMC within 2 h. The reaction mechanism, especially the multiple roles of FA, was explored through a detailed comparative study by varying hydrogen source, additive, and substrate as well as by applying in situ ATR‐IR spectroscopy. The major role of FA is to shift the dominant reaction pathway from the hydrogenation of the aldehyde group to the hydrogenolysis of the hydroxymethyl group via the protonation by FA at the C‐OH group, lowering the activation barrier of the C−O bond cleavage and thus significantly enhancing the reaction rate. XPS results and DFT calculations revealed that Pd2+ species interacting with pyridine‐like N atoms significantly enhance the selective hydrogenolysis of the C−OH bond in the presence of FA due to their high ability for the activation of FA and the stabilization of H−. [ABSTRACT FROM AUTHOR]

Aus Biomasse gewonnenes 5‐Hydroxymethylfurfural (HMF) gilt als vielversprechende Plattformchemikalien zur Herstellung von 2,5‐Dimethylfuran (DMF) als flüssigen Transportkraftstoff. Pd‐Nanopartikel auf N‐haltigen und N‐freien mesoporösen Kohlenstoffmaterialien wurden hergestellt, charakterisiert und bei der Hydrogenolyse von HMF zu DMF unter milden Reaktionsbedingungen eingesetzt. Die quantitative Umwandlung von HMF zu DMF wurde in Gegenwart von Ameisensäure (FA) und H2 über Pd/NMC innerhalb von 2 h erreicht. Der Reaktionsmechanismus wurde durch Variation der Wasserstoffquelle, des Additivs und des Substrats sowie durch In‐situ‐ATR‐IR‐Spektroskopie erforscht. Die Hauptrolle von FA besteht darin, den dominanten Reaktionsweg von der Hydrierung der Aldehydgruppe zur Hydrogenolyse der Hydroxymethylgruppe über die Protonierung durch FA an der C‐OH‐Gruppe zu verlagern, wodurch die Aktivierungsbarriere der C‐O‐Bindungsspaltung gesenkt und somit die Reaktionsgeschwindigkeit deutlich erhöht wird. XPS‐Ergebnisse und DFT‐Berechnungen zeigten, dass Pd2+‐Spezies, die mit pyridinartigen N‐Atomen interagieren, die selektive Hydrogenolyse der C‐OH‐Bindung in Anwesenheit von FA aufgrund ihrer hohen Fähigkeit zur Aktivierung von FA und zur Stabilisierung von H− deutlich verbessern. [ABSTRACT FROM AUTHOR]

Key points: Haemorrhage is the leading cause of battlefield and civilian trauma deaths. Given that a haemorrhagic injury on the battlefield is almost always associated with pain, it is paramount that the administered pain medication does not disrupt the physiological mechanisms that are beneficial in defending against the haemorrhagic insult.Current guidelines from the US Army's Committee on Tactical Combat Casualty Care (CoTCCC) for the selection of pain medications administered to a haemorrhaging soldier are based upon limited scientific evidence, with the clear majority of supporting studies being conducted on anaesthetized animals. Specifically, the influence of low‐dose ketamine, one of three analgesics employed in the pre‐hospital setting by the US Army, on haemorrhagic tolerance in humans is unknown.For the first time in conscious males and females, the findings of the present study demonstrate that the administration of an analgesic dose of ketamine does not compromise tolerance to a simulated haemorrhagic insult.Increases in muscle sympathetic nerve activity during progressive lower‐body negative pressure were not different between trials. Despite the lack of differences for muscle sympathetic nerve activity responses, mean blood pressure and heart rate were higher during moderate hypovolemia after ketamine vs. placebo administration. Haemorrhage is the leading cause of battlefield and civilian trauma deaths. For a haemorrhaging soldier, there are several pain medications (e.g. ketamine) recommended for use in the prehospital, field setting. However, the data to support these recommendations are primarily limited to studies in animals. Therefore, it is unknown whether ketamine adversely affects physiological mechanisms responsible for maintenance of arterial blood pressure (BP) during haemorrhage in humans. In humans, ketamine has been demonstrated to raise resting BP, although it has not been studied with the concomitant central hypovolemia that occurs during haemorrhage. Thus, the present study aimed to test the hypothesis that ketamine does not impair haemorrhagic tolerance in humans. Thirty volunteers (15 females) participated in this double‐blinded, randomized, placebo‐controlled trial. A pre‐syncopal limited progressive lower‐body negative pressure (LBNP; a validated model for simulating haemorrhage) test was conducted following the administration of ketamine (20 mg) or placebo (saline). Tolerance was quantified as a cumulative stress index and compared between trials using a paired, two‐tailed t test. We compared muscle sympathetic nerve activity (MSNA; microneurography), beat‐to‐beat BP (photoplethysmography) and heart rate (electrocardiogram) responses during the LBNP test using a mixed effects model (time [LBNP stage] × drug). Tolerance to the LBNP test was not different between trials (Ketamine: 635 ± 391 vs. Placebo: 652 ± 360 mmHg‧min, p = 0.77). Increases in MSNA burst frequency (time: P < 0.01, trial: p = 0.27, interaction: p = 0.39) during LBNP stages were no different between trials. Despite the lack of differences for MSNA responses, mean BP (time: P < 0.01, trial: P < 0.01, interaction: p = 0.01) and heart rate (time: P < 0.01, trial: P < 0.01, interaction: P < 0.01) were higher during moderate hypovolemia after ketamine vs. placebo administration (P < 0.05 for all, post hoc), but not at the end of LBNP. These data, which are the first to be obtained in conscious humans, demonstrate that the administration of low‐dose ketamine does not impair tolerance to simulated haemorrhage or mechanisms responsible for maintenance of BP. Key points: Haemorrhage is the leading cause of battlefield and civilian trauma deaths. Given that a haemorrhagic injury on the battlefield is almost always associated with pain, it is paramount that the administered pain medication does not disrupt the physiological mechanisms that are beneficial in defending against the haemorrhagic insult.Current guidelines from the US Army's Committee on Tactical Combat Casualty Care (CoTCCC) for the selection of pain medications administered to a haemorrhaging soldier are based upon limited scientific evidence, with the clear majority of supporting studies being conducted on anaesthetized animals. Specifically, the influence of low‐dose ketamine, one of three analgesics employed in the pre‐hospital setting by the US Army, on haemorrhagic tolerance in humans is unknown.For the first time in conscious males and females, the findings of the present study demonstrate that the administration of an analgesic dose of ketamine does not compromise tolerance to a simulated haemorrhagic insult.Increases in muscle sympathetic nerve activity during progressive lower‐body negative pressure were not different between trials. Despite the lack of differences for muscle sympathetic nerve activity responses, mean blood pressure and heart rate were higher during moderate hypovolemia after ketamine vs. placebo administration. [ABSTRACT FROM AUTHOR]

Key points: In this study, we focused on muscle sympathetic nerve activity (MSNA) burst size and occurrence separately as subcomponents of the sympathetic baroreflex in older adults, and we found that the distribution (variation) of burst size against burst occurrence was greater in women than men.Older women had greater carotid artery stiffness compared with older men, while blood pressure (BP) distribution (variation) was comparable between sexes.Sympathetic baroreflex sensitivity assessed with burst incidence was less sensitive as the carotid artery became stiffer in older men and women, while that assessed with burst area was more sensitive as the carotid artery became stiffer in older women but not in older men.These results help us understand the mechanisms underlying the compensation for the impaired response of MSNA burst occurrence in older women with greater carotid artery stiffness to regulate BP similar to that in older men. There are sex differences in arterial stiffness and neural control of blood pressure (BP) among older adults. We examined whether the sympathetic response to BP is greater in older women than men in burst size but not burst occurrence. Burst occurrence and size were assessed with burst interval and area of muscle sympathetic nerve activity, respectively, and the distributions of these indices were evaluated by range during supine rest in 61 healthy older subjects (30 men (69 ± 6 years) and 31 women (68 ± 6 years); means ± SD). Also, we analysed sympathetic baroreflex sensitivity (BRS) with burst occurrence and area simultaneously. Carotid β‐stiffness was measured with B‐mode ultrasonic image and carotid BP. The range of burst interval was smaller in older women than men (P = 0.002), while there was no difference in the range of burst area. Carotid β‐stiffness was greater in older women than men (6.7 ± 2.7 vs. 5.1 ± 2.7, P = 0.027). Sympathetic BRS assessed with burst incidence was lower in older women than men (‐2.3 ± 1.4 vs. ‐3.3 ± 1.4 bursts·100 beats‐1 mmHg‐1, P = 0.007), while this sex difference was observed when assessed with burst area after adjusting for carotid β‐stiffness (‐116.1 ± 135.0 vs. ‐185.9 ± 148.2 a.u. burst‐1 mmHg‐1, P = 0.040), but not before. Sympathetic BRS assessed with burst area was negatively (more sensitive) correlated with carotid β‐stiffness in older women (r = ‐0.53, P = 0.002) but not men. These data suggest that the response of burst size within each burst is augmented for the baroreflex BP control despite the impaired response of burst occurrence in older women with greater carotid stiffness. Key points: In this study, we focused on muscle sympathetic nerve activity (MSNA) burst size and occurrence separately as subcomponents of the sympathetic baroreflex in older adults, and we found that the distribution (variation) of burst size against burst occurrence was greater in women than men.Older women had greater carotid artery stiffness compared with older men, while blood pressure (BP) distribution (variation) was comparable between sexes.Sympathetic baroreflex sensitivity assessed with burst incidence was less sensitive as the carotid artery became stiffer in older men and women, while that assessed with burst area was more sensitive as the carotid artery became stiffer in older women but not in older men.These results help us understand the mechanisms underlying the compensation for the impaired response of MSNA burst occurrence in older women with greater carotid artery stiffness to regulate BP similar to that in older men. [ABSTRACT FROM AUTHOR]

The anode oxygen evolution reaction (OER) is known to largely limit the efficiency of electrolyzers owing to its sluggish kinetics. While crystalline metal oxides are promising as OER catalysts, their amorphous phases also show high activities. Efforts to produce amorphous metal oxides have progressed slowly, and how an amorphous structure benefits the catalytic performances remains elusive. Now the first scalable synthesis of amorphous NiFeMo oxide (up to 515 g in one batch) is presented with homogeneous elemental distribution via a facile supersaturated co‐precipitation method. In contrast to its crystalline counterpart, amorphous NiFeMo oxide undergoes a faster surface self‐reconstruction process during OER, forming a metal oxy(hydroxide) active layer with rich oxygen vacancies, leading to superior OER activity (280 mV overpotential at 10 mA cm−2 in 0.1 m KOH). This opens up the potential of fast, facile, and scale‐up production of amorphous metal oxides for high‐performance OER catalysts. [ABSTRACT FROM AUTHOR]

The anode oxygen evolution reaction (OER) is known to largely limit the efficiency of electrolyzers owing to its sluggish kinetics. While crystalline metal oxides are promising as OER catalysts, their amorphous phases also show high activities. Efforts to produce amorphous metal oxides have progressed slowly, and how an amorphous structure benefits the catalytic performances remains elusive. Now the first scalable synthesis of amorphous NiFeMo oxide (up to 515 g in one batch) is presented with homogeneous elemental distribution via a facile supersaturated co‐precipitation method. In contrast to its crystalline counterpart, amorphous NiFeMo oxide undergoes a faster surface self‐reconstruction process during OER, forming a metal oxy(hydroxide) active layer with rich oxygen vacancies, leading to superior OER activity (280 mV overpotential at 10 mA cm−2 in 0.1 m KOH). This opens up the potential of fast, facile, and scale‐up production of amorphous metal oxides for high‐performance OER catalysts. [ABSTRACT FROM AUTHOR]

Overcoming epidermal growth factor receptor resistance is a critical problem that needs to be solved in clinical practice. Drugs that downregulate the fatty acid synthase‐epidermal growth factor receptor will become novel treatments for non‐small cell lung cancer. Solanum nigrum, extracted with water at 4°C, shows strong cytotoxic activity and inhibits tumor growth in Lewis tumor bearing‐mice in a dose‐dependent manner. A novel active compound in S. nigrum, solaoiacid, was successfully separated and purified from S. nigrum by preparative high‐performance liquid chromatography with mass spectrometry and ultra high performance liquid chromatography with time‐of‐flight tandem mass spectrometry. The IC50 of solaoiacid on lung cancer cells was 2.3 µmol/L, which was significantly lower than that of the known steroidal glycoalkaloid. Label‐free proteomics and STRING Network analysis were used to identify significantly deregulated proteins in lung cancer cells that were treated with the fresh ripe fruit extracts of S. nigrum. S. nigrum regulates multiple signal pathways, including the epidermal growth factor receptor pathway. S. nigrum downregulated 24 main proteins with direct roles in fatty acid biosynthesis. Both S. nigrum and solaoiacid showed strong downregulation of the fatty acid synthase‐epidermal growth factor receptor and anti‐non‐small cell lung cancer effects, and thus will become a novel drug for the treatment of non‐small cell lung cancer. [ABSTRACT FROM AUTHOR]

Key points: Heart rate variability, a common and easily measured index of cardiovascular dynamics, is the output variable of complicated cardiovascular and respiratory control systems. Both neural and non‐neural control mechanisms may contribute to changes in heart rate variability.We previously developed an innovative method using transfer function analysis to assess the effect of prolonged exercise training on integrated cardiovascular regulation. In the present study, we modified and applied this to investigate the effect of 2 years of high‐intensity training on circulatory components to tease out the primary effects of training. Our method incorporated the dynamic Starling mechanism, dynamic arterial elastance and arterial–cardiac baroreflex function.The dynamic Starling mechanism gain and arterial–cardiac baroreflex gain were significantly increased in the exercise group. These parameters remained unchanged in the controls. Conversely, neither group experienced a change in dynamic arterial elastance. The integrated cardiovascular regulation gain in the exercise group was 1.34‐fold larger than that in the control group after the intervention.In these previously sedentary, otherwise healthy, middle‐aged adults, 2 years of high‐intensity exercise training improved integrated cardiovascular regulation by enhancing the dynamic Starling mechanism and arterial–cardiac baroreflex sensitivity. Assessing the effects of exercise training on cardiovascular variability is challenging because of the complexity of multiple mechanisms. In a prospective, parallel‐group, randomized controlled study, we examined the effect of 2 years of high‐intensity exercise training on integrated cardiovascular function, which incorporates the dynamic Starling mechanism, dynamic arterial elastance and arterial–cardiac baroreflex function. Sixty‐one healthy participants (48% male, aged 53 years, range 52–54 years) were randomized to either 2 years of exercise training (exercise group: n = 34) or control/yoga group (controls: n = 27). Before and after 2 years, subjects underwent a 6 min recording of beat‐by‐beat pulmonary artery diastolic pressure (PAD), stroke volume index (SV index), systolic blood pressure (sBP) and RR interval measurements with controlled respiration at 0.2 Hz. The dynamic Starling mechanism, dynamic arterial elastance and arterial–cardiac baroreflex function were calculated by transfer function gain between PAD and SV index; SV index and sBP; and sBP and RR interval, respectively. Fifty‐three participants (controls: n = 25; exercise group: n = 28) completed the intervention. After 2 years, the dynamic Starling mechanism gain (Group × Time interaction: P = 0.008) and the arterial–cardiac baroreflex gain (P = 0.005) were significantly increased in the exercise group but remained unchanged in the controls. There was no change in dynamic arterial elastance in either of the two groups. The integrated cardiovascular function gain in the exercise group increased 1.34‐fold, whereas there was no change in the controls (P = 0.02). In these previously sedentary, otherwise healthy middle‐aged adults, a 2 year programme of high‐intensity exercise training improved integrated cardiovascular regulation by enhancing the dynamic Starling mechanism and arterial–cardiac baroreflex sensitivity, without changing dynamic arterial elastance. Key points: Heart rate variability, a common and easily measured index of cardiovascular dynamics, is the output variable of complicated cardiovascular and respiratory control systems. Both neural and non‐neural control mechanisms may contribute to changes in heart rate variability.We previously developed an innovative method using transfer function analysis to assess the effect of prolonged exercise training on integrated cardiovascular regulation. In the present study, we modified and applied this to investigate the effect of 2 years of high‐intensity training on circulatory components to tease out the primary effects of training. Our method incorporated the dynamic Starling mechanism, dynamic arterial elastance and arterial–cardiac baroreflex function.The dynamic Starling mechanism gain and arterial–cardiac baroreflex gain were significantly increased in the exercise group. These parameters remained unchanged in the controls. Conversely, neither group experienced a change in dynamic arterial elastance. The integrated cardiovascular regulation gain in the exercise group was 1.34‐fold larger than that in the control group after the intervention.In these previously sedentary, otherwise healthy, middle‐aged adults, 2 years of high‐intensity exercise training improved integrated cardiovascular regulation by enhancing the dynamic Starling mechanism and arterial–cardiac baroreflex sensitivity. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?The venoarteriolar response (VAR) contributes substantially to the maintenance of orthostatic tolerance in humans. Despite its importance in haemodynamic homeostasis, the impact of ageing on the VAR remains understudied.What is the main finding and its importance?Older adults exhibit an augmented VAR in response to leg dependency. The age‐related augmentation of the VAR might be linked with progressive increases of peripheral vascular resistance with ageing. We found a modest but significant correlation between the leg VAR and the morning blood pressure surge in older adults. Augmented leg VAR might contribute to the blood pressure elevation in the early morning. The venoarteriolar response (VAR) is a non‐adrenergic, non‐baroreflex‐mediated mechanism of vasoconstriction, which has been proposed to contribute ∼45% of the increase in total peripheral resistance during orthostasis. Despite its importance in human cardiovascular control during orthostatic stress, there is no information available regarding the impact of age and sex on the VAR or its role in diurnal blood pressure (BP) variation. We studied 33 (15 women) young (mean ± SD; 28 ± 4 years old) and 26 (12 women) older (71 ± 3 years old) healthy individuals. Brachial and femoral blood flow were measured using Doppler ultrasound. The percentage reduction in vascular conductance (blood flow/mean BP) during 4 min of limb dependency (35–40 cm below the heart level) was used to assess the VAR. The morning surge in BP was assessed using 24 h ambulatory BP monitoring. Peak VAR in the lower limb, but not in the upper limb, was significantly higher in the older than the younger adults (33 ± 4 versus 26 ± 6%, older versus young; P < 0.05). There was no sex difference in the VAR in either the young or the older group. A greater leg VAR was related to a greater morning surge in BP in older adults (r = −0.4, P = 0.02) but not in the young adults (r = −0.26, P = 0.1). Thus, advancing age enhances the VAR in the lower limb and is associated with the morning blood pressure surge in older adults. Sex does not affect this local axonal reflex in healthy humans. [ABSTRACT FROM AUTHOR]

Here, we report a highly water‐soluble colorimetric and fluorescent pH probe that works in the pH range 0.2–3.0. The probe showed a rapid response, high stability, and excellent reversibility to acidity. Moreover, the fluorescence of probe was not influenced by the existence of high concentration of cations. The pKa of probe was calculated to be 2.25 ± 0.06. Furthermore, the pH test papers coated with the probe exhibited a distinct color change in acidic conditions. [ABSTRACT FROM AUTHOR]

Visible light driven photocatalysts based on crystalline microporous metal halogenides received much less attention compared with dense or composite oxide semiconductors. Using the well-known photosensitive transition metal-complexes [TM(2,2-bipy)3]2+ (TM=Fe, Co, Ni, Ru) as templates, a special three-dimensional (3D) metal halogenide framework of [TM(2,2-bipy)3]Cu4Br6 was designed with [Cu4Br4] cluster as 4-connected node. These microporous materials feature narrow band gaps and stable visible light driven photocatalytic properties including water reduction to provide H2 and photodegradation of organic pollutants. The study of electronic band structure shows that the TM complexes effectively prevent the recombination of photo-induced electron/hole pairs leading to excellent photocatalytic activity and photochemical stability. This work represents the first 3D microporous metal halogenides used as visible light driven photocatalyst to provide hydrogen energy. [ABSTRACT FROM AUTHOR]

Background Adverse maternal lifestyle resulting in adverse early life environment (AELE) increases risks for neuropsychiatric disorders in offspring. Neuropsychiatric disorders are associated with impaired neurogenesis and neuro-inflammation in the hippocampus (HP). Microglia are neuro-inflammatory cells in the brain that regulate neurogenesis via toll-like receptors (TLR). TLR-9 is implicated in neurogenesis inhibition and is responsible for stress-related inflammatory responses. We hypothesized that AELE would increase microglia cell count and increase TLR-9 expression in juvenile mouse HP. These increases in microglia cell count and TLR-9 expression would be associated with decrease neural stem cell count and neuronal cell count. Methods We developed a mouse model of AELE combining Western diet and a stress environment. Stress environment consisted of random change from embryonic day 13 (E13) to E17 as well as static change in maternal environment from E13 to postnatal day 21(P21). At P21, we measured hippocampal cell numbers of microglia, neural stem cell and neuron, as well as hippocampal TLR-9 expression. Results AELE significantly increased total microglia number and TLR-9 expression in the hippocampus. Concurrently, AELE significantly decreased neural stem cell and neuronal numbers. Conclusions AELE increased the neuro-inflammatory cellular response in the juvenile HP. We speculate that increased neuro-inflammatory responses may contribute to impaired neurogenesis seen in this model. [ABSTRACT FROM AUTHOR]

The Microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper family factor that is essential for terminal osteoclast differentiation. Previous work demonstrates that phosphorylation of MITF by p38 MAPK downstream of Receptor Activator of NF kB Ligand (RANKL) signaling is necessary for MITF activation in osteoclasts. The spontaneous Mitf cloudy eyed ( ce) allele results in production of a truncated MITF protein that lacks the leucine zipper and C-terminal end. Here we show that the Mitfce allele leads to a dense bone phenotype in neonatal mice due to defective osteoclast differentiation. In response to RANKL stimulation, in vitro osteoclast differentiation was impaired in myeloid precursors derived from neonatal or adult Mitfce/ce mice. The loss of the leucine zipper domain in Mitfce/ce mice does not interfere with the recruitment of MITF/PU.1 complexes to target promoters. Further, we have mapped the p38 MAPK docking site within the region deleted in Mitfce. This interaction is necessary for the phosphorylation of MITF by p38 MAPK. Site-directed mutations in the docking site interfered with the interaction between MITF and its co-factors FUS and BRG1. MITF-ce fails to recruit FUS and BRG1 to target genes, resulting in decreased expression of target genes and impaired osteoclast function. These results highlight the crucial role of signaling dependent MITF/p38 MAPK interactions in osteoclast differentiation. J. Cell. Physiol. 231: 630-640, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Individuals with hypertension and sympathetic overactivity are at risk for cardiovascular events. Renin inhibitors are new while thiazide diuretics are first-class drugs used for treatment of hypertension. The purpose of this study was to determine whether 6 months of treatment with aliskiren ( ALSK) or hydrochlorothiazide ( HCTZ) would alter blood pressure ( BP) and muscle sympathetic nerve activity ( MSNA) indices in older mild hypertensives during a cold pressor test ( CPT). We hypothesized that the ALSK group would demonstrate a blunted response compared to HCTZ. Nineteen (9 men, 10 women) subjects performed a CPT pre- and post treatment where heart rate ( HR), systolic BP ( SBP) and diastolic BP ( DBP), and MSNA were measured. Blood samples were withdrawn for assessment of renal-adrenal hormones. Both medications lowered ambulatory SBP and DBP ( P < 0.05). Direct renin tended to be higher in the ALSK group after treatment ( P = 0.081). Aldosterone was higher in the HCTZ group after treatment ( P < 0.001). As expected, both groups showed increases in HR, SBP, DBP, and MSNA during the CPT (all P < 0.05). All cardiovascular and MSNA responses were similar pre- and post treatment in both groups (peak CPT SBP: 26 ± 10 vs. 17 ± 21 and 21 ± 20 vs. 29 ± 15 mmHg for pre vs. post for HCTZ and ALSK, respectively; peak CPT MSNA burst frequency: 13 ± 8 vs. 11 ± 11 and 11 ± 17 vs. 6 ± 13 bursts/min; all P > 0.05). Treatment with these antihypertensive medications lowered BP but was not successful in lowering the responsiveness to the CPT. [ABSTRACT FROM AUTHOR]

R4051 --> 752.5 --> Background: Posttraumatic stress disorder (PTSD) is more prevalent in women than men and is associated with an increased risk for dementia. Indeed, we previously showed that cognitive function is impaired in women with PTSD, but the underlying mechanisms remain unknown. In patients with mild cognitive impairment, the cardiovascular response during cognitive tasks have been shown to be blunted. Thus, we hypothesized that cardiovascular and sympathetic neural responses to a cognitive task would be smaller in women with PTSD than healthy women. Methods: We measured heart rate (HR), mean arterial pressure (MAP), cardiac output (CO, Modelflow), total peripheral resistance (TPR = MAP/CO), and muscle sympathetic nerve activity (MSNA, microneurography) in 16 women with PTSD (42 ± 11 [SD] yrs) and 9 age‐matched healthy women (controls; 41 ± 9 yrs) during 3 min of the Stroop Color and Word Test (SCWT) in the supine position. Results: In response to SCWT, HR, MAP, and CO increased (all P < 0.001) but TPR remained unchanged (P = 0.753) in both groups. Increases (Δ) in HR (6 ± 4 vs. 11 ± 6 bpm) and CO (0.6 ± 0.6 vs. 0.9 ± 0.4 L/min) during SCWT were smaller in PTSD than controls (both P < 0.05), while ΔMAP was similar between groups (P = 0.169). MSNA burst frequency and incidence were significantly higher in women with PTSD than controls at baseline and throughout SCWT (P = 0.003), but ΔMSNA during SCWT was similar between groups. Conclusions: Cardiovascular, but not sympathetic neural responses to SCWT were blunted in women with PTSD. Our findings suggest that cognitive impairment in women with PTSD may be related to the insufficient cardiac response rather than sympathetic vasoconstriction during cognitive tasks. [ABSTRACT FROM AUTHOR]

R2284 --> 752.6 --> Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder that is more prevalent in women than men and has been linked to an elevated risk of developing cardiovascular disease. Although the physiological mechanisms are unclear, it is thought that exaggerated neuro‐cardiovascular reactivity is partially responsible. Indeed, women with PTSD demonstrate exaggerated muscle sympathetic nerve activity (MSNA) responses at the onset of exercise. However, it is unknown whether PTSD modifies the underlying sympathetic action potentials (AP) coding patterns that comprise the integrated MSNA signal during fatiguing exercise in women. We therefore hypothesized that women with PTSD will exhibit exaggerated MSNA and AP recruitment compared to women without PTSD during fatiguing handgrip exercise. MSNA and AP discharge patterns (via microneurography and a continuous wavelet transform) were assessed in eleven women with PTSD (43±11 [SD] years) and thirteen women without PTSD (Controls; 40±8 years) during isometric handgrip exercise (IHG) to fatigue at 40% of maximal voluntary contraction (MVC) force, followed by 2 minutes of post‐exercise circulatory occlusion (PECO), and three minutes of recovery. The IHG time was divided equally into five stages. IHG duration (P=0.867) and MVC (P=0.226) were similar between both groups. PTSD did not modify the increase in MSNA and AP frequency or incidence during IHG and PECO (all group‐by‐stage interactions: P=0.294‐0.380). Conversely, throughout IHG and PECO, AP content per burst was greater in the Controls compared to women with PTSD (main effect of group: P=0.026). Furthermore, relative to Controls, women with PTSD were unable to increase the number of AP clusters per burst during the first (Controls: ∆1.3±1.2 vs. PTSD: ∆‐0.2±0.8 clusters/burst; P=0.016) and last minute (Controls: ∆1.2±1.1 vs. PTSD: ∆‐0.1±0.8 clusters/burst; P=0.022) of PECO, and recruited fewer subpopulations of previously silent axons during the first (Controls: ∆5±4 vs. PTSD: ∆1±2 clusters; P=0.020) and last minute (Controls: ∆4±2 vs. PTSD: ∆1±2 clusters; P=0.021) of PECO. Lastly, although an interaction effect was observed for the AP cluster size‐latency relationship during IHG and PECO (P=0.042), post‐hoc analyses revealed that PTSD did not modify this relationship (all P=0.658‐0.999). These data indicate that the central features of sympathetic outflow are impaired in women with PTSD during skeletal muscle metaboreflex activation. [ABSTRACT FROM AUTHOR]

R4109 --> 857.2 --> Maternal obesity increases the risk of adverse pregnancy outcomes. The mechanisms that contribute to this elevated risk are unclear but may be related to overactivation of the sympathetic nervous system. Indeed, sympathetic activation during pregnancy is now regarded as a normal adaptation to maintain homeostasis. However, sympathetic overactivation is associated with gestational hypertensive disorders. It is unknown whether the health related problems linked to maternal obesity (i.e., inflammation, insulin resistance, dyslipidemia) results in sympathetic overactivation during pregnancy. We hypothesized that maternal obesity would induce greater increases in resting muscle sympathetic nerve activity (MSNA) during pregnancy when compared with normal‐weight women. Blood pressure (BP), heart rate and MSNA (microneurography) were recorded during 5 min of supine rest in 14 normal‐weight (Age 30±1.6 [SE] yrs; BMI 22.1±0.6 kg/m2) and 14 obese (Age 28±0.8 yrs; BMI 33.9±1.0 kg/m2) women during early pregnancy (5‐12 weeks), late pregnancy (32 to 34 weeks) and 6‐10 weeks postpartum. Gestational weight gain from early to late pregnancy was not significantly different between groups (11.8±0.9 kg vs. 9.2±2.1 kg, P=0.23). Resting MSNA burst frequency was not different between normal‐weight and obese groups during early pregnancy (17±3 bursts/min vs. 22±4 bursts/min, P=0.35) or postpartum (10±2 bursts/min vs. 8±2 bursts/min P=0.74) but was significantly greater in the obese group during late pregnancy (23±4 bursts/min vs. 35±4 bursts/min, Figure A, P=0.031). There were no significant changes in resting MSNA from early to late pregnancy in the normal‐weight group (P=0.67) whereas the obese group had significant increases in MSNA from early to late pregnancy (P=0.002). These findings were also apparent when MSNA was characterized as burst incidence and total activity (Figure B and C). Although still within the normotensive range, women with obesity had greater levels of systolic BP when compared with normal‐weight women across all time points (Figure D, group main effect P=0.002). Diastolic BP was lower during pregnancy when compared with postpartum and this was similar between groups (Figure E, gestation main effect P<0.001). Heart rate was greater during early pregnancy when compared with postpartum and increased similarly in both groups during late pregnancy (Figure F, gestation main effect P<0.001). These findings suggest that maternal obesity is associated with greater increases in sympathetic activation even during normotensive pregnancy and may play a role in the increased risk of adverse maternal and fetal outcomes in women with obesity. [ABSTRACT FROM AUTHOR]

R2816 --> 857.6 --> Post‐menopausal women are at greater risk for cardiovascular disease compared with age‐matched men. An exaggerated morning blood pressure surge (MBPS) in post‐menopausal women is well established as an independent risk factor for cardiovascular events. Dietary nitrate supplements such as nitrate‐rich beetroot juice (BRJ) may reduce blood pressure (BP), but no study has investigated the chronic effects of BRJ on MBPS and sympathetic neural control during orthostasis in post‐menopausal women. We hypothesized that dietary nitrate supplements would decrease MBPS and muscle sympathetic nerve activity (MSNA, microneurography) in post‐menopausal women. We performed a double‐blind, placebo‐controlled, cross‐over trial and randomly assigned healthy women [n=14, 64±3 (SD) yr] to either dietary nitrate supplements (140 ml of BRJ; 800 mg nitrate/day) or placebo (140 ml of nitrate‐depleted BRJ daily) for 2 weeks each with ≥2 weeks of washout. Twenty‐four‐hour ambulatory BP monitoring was performed and MBPS was calculated as the morning systolic BP (SBP; averaged for 2 h after wake‐up) minus the lowest nocturnal SBP before and after 2‐week BRJ or placebo intervention. BP, heart rate, and MSNA were measured during 3‐min supine rest and 5‐min 60° head‐up tilt (HUT). Cardiac output (Qc; C2H2 rebreathing) and total peripheral resistance (TPR=mean BP/Qc × 80) were also measured. MBPS decreased after BRJ intervention (Figure A; p=0.043). BRJ did not change hemodynamics or MSNA during supine rest (Figure B‐E; all, p>0.05). However, upright TPR was reduced (Figure C; p=0.007), while Qc trended greater (Figure B; p=0.072) after BRJ intervention. During HUT, MSNA burst frequency (53±15 pre vs. 48±10 bursts/min post, p=0.508 for posture × intervention interaction) and burst incidence (70±17 vs. 63±15 bursts/100 heart beats, p=0.199 for interaction) were similar, but mean burst area (Figure D; p=0.010) and total activity (Figure E; p=0.015) were lower after BRJ intervention. Placebo had no significant impact on hemodynamics and MSNA in the supine position or during HUT in post‐menopausal women (all, p<0.05). Collectively, dietary nitrate supplements decrease morning surge in BP and upright MSNA and vasoconstriction in post‐menopausal women. Whether reductions in sympathetic activation and peripheral vasoconstriction during orthostasis contribute to the reduced MBPS in these women remains to be determined. [ABSTRACT FROM AUTHOR]

R2618 --> 857.5 --> Women who reached early menopause (EM, 40‐44 yrs) have a greater risk for cardiovascular disease than women with normal menopause (NM, 50‐54 yrs), which may be attributed to a longer duration of estrogen loss and a greater reduction in nitric oxide bioavailability in both the peripherals and center. Previous studies have shown that dietary nitrate supplementation improves cardiovascular function in older women, but how autonomic neural control changes in daily living, such as during exercise, has been involved is unclear. We examined the hypothesis that 2wks continuous use of dietary nitrate supplements would attenuate the exercise pressor reflex in older women with EM. Six EM (65±4 [SD] yrs) and 8 NM (64±2 yrs) women participated in this randomized, placebo‐controlled, double‐blind, cross‐over pilot study. All subjects underwent 2 wks of beetroot juice (BRJ; 140 ml containing ~800 mg nitrate per day) or placebo (140 ml nitrate‐depleted BRJ, daily) intervention with ≥14 days of wash‐out. Before and after each intervention period, subjects performed SHG using the dominant hand at 40% of maximum voluntary contraction (MVC) until fatigue, followed by 2 min of PECA with an upper arm cuff inflated to 250 mmHg. Heart rate (HR; ECG), blood pressure (BP; finger photoplethysmography), muscle sympathetic nerve activity (MSNA; microneurography), and respiration (capnography) were continuously measured. In addition, 24‐h ambulatory BP standard deviation (SD) was monitored before and after each intervention (an indication of BP variability). There were no differences in baseline HR, BP and MSNA, MVC, and the time to fatigue between the EM and NM groups before and after intervention (all p>0.05). At the first 30 s of SHG, the EM group showed significant decreases in MSNA burst frequency (DBF; ‐4.5±6.5 in EM vs. 2.5±6.2 bursts/min in NM, p=0.065) and burst incidence (DBI; ‐10.6±12.6 vs. 2.6±8.4 bursts/100 heartbeats, p=0.037) after BRJ intervention compared with the NM group (Figure1A and B). However, there were no differences between groups at fatiguing exercise and during PECA after the intervention. The interventional changes in 24‐h diastolic BP SD had a positive correlation with ΔMSNA BF (r=0.55, p=0.053) and BI (r=0.58, p=0.036) at the first 30 s of SHG in all subjects and EM individuals were in the left‐lower area (Figure2 A and B). These results suggest that dietary nitrate supplementation may attenuate and mechanoreflex, but not the metaboreflex, in older women with EM during static hand grip, which has a relation with BP variability during ambulation. Certainly, these preliminary observations need to be verified in more older women in future studies. [ABSTRACT FROM AUTHOR]

Key points Women with the postural orthostatic tachycardia syndrome (POTS) report fluctuations in orthostatic tolerance throughout the menstrual cycle., The mechanism(s) underlying blood pressure control across the menstrual cycle in women with POTS are unknown., The findings of the present study indicate that the menstrual cycle does not affect muscle sympathetic nerve activity but modulates blood pressure and vasoconstriction in POTS women during orthostatic stress., Factors other than sympathetic neural activity are likely responsible for the symptoms of orthostatic intolerance across the menstrual cycle in women with POTS., Abstract Patients with the postural orthostatic tachycardia syndrome (POTS) are primarily premenopausal women, which may be attributed to female sex hormones. We tested the hypothesis that hormonal fluctuations of the menstrual cycle alter sympathetic neural activity and orthostatic tolerance in POTS women. Ten POTS women were studied during the early follicular (EF) and mid-luteal (ML) phases of the menstrual cycle. Haemodynamics and muscle sympathetic nerve activity (MSNA) were measured when supine, during 60 deg upright tilt for 45 min or until presyncope, and during the cold pressor test (CPT) and Valsalva manoeuvres. Blood pressure and total peripheral resistance were higher during rest and tilting in the ML than EF phase; however, heart rate, stroke volume and cardiac output were similar between phases. There were no mean ± SD differences in MSNA burst frequency (8 ± 8 EF phase vs. 10 ± 10 bursts min-1 ML phase at rest; 34 ± 15 EF phase vs. 36 ± 16 bursts min-1 ML phase at 5 min tilt), burst incidence or total activity, nor any differences in the cardiovagal and sympathetic baroreflex sensitivities between phases under any condition. The incidence of presyncope was also the same between phases. There were no differences in haemodynamic or sympathetic responses to CPT or Valsalva. These results suggest that the menstrual cycle does not affect sympathetic neural activity but modulates blood pressure and vasoconstriction in POTS women during tilting. Thus, factors other than sympathetic neural activity are probably responsible for the symptoms of orthostatic intolerance across the menstrual cycle in women with POTS. [ABSTRACT FROM AUTHOR]

Key points Asian women have a lower prevalence of hypertensive disorders of pregnancy than Caucasian women., This is the first longitudinal study to investigate neural and humoral responses during pregnancy in Asians and Caucasians., The key finding was that Asians had attenuated sympathetic activation but enhanced renal-adrenal responsiveness during pregnancy compared to Caucasians., These results may provide insights into the pathophysiological mechanisms for racial differences in the prevalence of hypertensive disorders during pregnancy., Abstract Asians have a lower prevalence of hypertensive disorders of pregnancy than Caucasians. Since sympathetic overactivity and dysregulation of the renal-adrenal system (e.g. low aldosterone levels) have been found in preeclamptic women, we hypothesized that Asians have lower muscle sympathetic nerve activity (MSNA) and greater aldosterone concentrations during normal pregnancy than Caucasians. In a prospective study, blood pressure (BP), heart rate (HR), and MSNA were measured during supine and upright tilt (30 deg and 60 deg for 5 min each) in 9 Asians (32 ± 1 years (mean ± SEM)) and 12 Caucasians (29 ± 1 years) during pre-, early (≤8 weeks of gestation) and late (32-36 weeks) pregnancy, and post-partum (6-10 weeks after delivery). Supine MSNA increased with pregnancy in both groups ( P < 0.001); it was significantly lower in Asians than Caucasians (14 ± 3 vs. 23 ± 3 bursts min−1 and 16 ± 5 vs. 30 ± 3 bursts min−1 in early and late pregnancy, respectively; P = 0.023). BP decreased during early pregnancy ( P < 0.001), but was restored during late pregnancy. HR increased during pregnancy ( P < 0.001) with no racial difference ( P = 0.758). MSNA increased during tilting and it was markedly lower in Asians than Caucasians in late pregnancy (31 ± 6 vs. 49 ± 3 bursts min−1 at 60 deg tilt; P = 0.003). Upright BP was lower in Asians, even in pre-pregnancy ( P = 0.006), and this racial difference persisted during pregnancy. Direct renin and aldosterone increased during pregnancy (both P < 0.001); these hormones were greater in Asians ( P = 0.086 and P = 0.014). Thus, Asians have less sympathetic activation but more upregulated renal-adrenal responses than Caucasians during pregnancy. These results may explain, at least in part, why Asian women are at low risk of hypertensive disorders in pregnancy. [ABSTRACT FROM AUTHOR]

New Findings What is the central question of this study? The study was designed to investigate the age- and sex-related differences in muscle sympathetic nerve activity (MSNA) in relation to age- and sex-related differences in haemodynamics, blood volume and left ventricular size and function., What is the main finding and its importance? Age-related increases in MSNA were associated with decreases in blood volume in men only, and only in men was there a significant relation between MSNA and forearm vascular resistance. These results show that age and sex independently alter the neural control of blood pressure and may provide insights into the pathogenesis of hypertension., We compared the effect of age- and sex-related differences in haemodynamics, blood volume (BV) and left ventricular (LV) size and mass on resting muscle sympathetic nerve activity (MSNA) in healthy, normotensive adults. Twenty young men (19-47 years old) and 20 young women (21-46 years old) as well as 15 older men (62-80 years old) and 15 older women (60-82 years old) were studied. Cardiac output (acetylene rebreathing), total peripheral resistance, forearm vascular resistance (FVR; venous occlusion plethysmography) and MSNA were measured during supine rest. Blood volume was calculated (CO rebreathing), and LV mass, end-diastolic (LVEDV) and end-systolic volumes (LVESV) were measured using magnetic resonance imaging. Cardiac index ( P < 0.001 and P = 0.016), BV (both P < 0.001), LV mass ( P < 0.001 and P = 0.002), LVEDV ( P < 0.001 and P = 0.002) and LVESV (both P < 0.001) were lower in the older and female groups, respectively. Total peripheral resistance was significantly higher in the older ( P < 0.001) and female groups ( P = 0.014), but FVR was increased in the female groups ( P = 0.048) only (age, P = 0.089). The MSNA was greater in the older groups ( P < 0.001) only (sex, P = 0.228). Increased MSNA was shown to correlate with a decrease in BV ( P = 0.004) in men only when adjusted for age (women, P = 0.133). There was a positive relation between MSNA and FVR ( P = 0.020) in men but not women ( P = 0.422). There were no significant relations between MSNA and LV mass, LVEDV or LVESV. The findings suggest that the increase in resting MSNA with age may be related to the decline in BV in men only, but it is unknown whether sex differences in sympathetic adrenergic vasoconstriction occur independently of these changes. [ABSTRACT FROM AUTHOR]

Key points Cardiovascular risk remains high in elderly patients with hypertension even with adequate blood pressure control; one possible mechanism may be sympathetic activation via the baroreflex in response to blood pressure reduction., We found that chronic diuresis increased vasomotor sympathetic activity in both the supine and the upright positions, while chronic renin inhibition did not affect sympathetic activity in the supine position but attenuated its response to head-up tilt in elderly hypertensive patients., The change of sympathetic activity by anti-hypertensive drug treatment was correlated with the change of aldosterone level in all patients., Upright sympathetic baroreflex sensitivity remained unchanged after diuresis or renin inhibition., These results suggest that chronic renin inhibition lowers blood pressure in elderly hypertensive patients without sympathetic activation, in contrast to diuresis which increases sympathetic activity through the augmented renin-angiotensin-aldosterone system., Abstract Cardiovascular risk remains high in patients with hypertension even with adequate blood pressure (BP) control. One possible mechanism may be sympathetic activation via the baroreflex. We tested the hypothesis that chronic inhibition of renin reduces BP without sympathetic activation, but diuresis augments sympathetic activity in elderly hypertensives. Fourteen patients with stage-I hypertension (66 ± 5 (SD) years) were treated with a direct renin inhibitor, aliskiren ( n= 7), or a diuretic, hydrochlorothiazide ( n= 7), for 6 months. Muscle sympathetic nerve activity (MSNA), BP, direct renin and aldosterone were measured during supine and a graded head-up tilt (HUT; 5 min 30° and 20 min 60°), before and after treatment. Sympathetic baroreflex sensitivity (BRS) was assessed. Both groups had similar BP reductions after treatment (all P < 0.01), while MSNA responses were different between hydrochlorothiazide and aliskiren ( P= 0.006 pre/post × drug). Both supine and upright MSNA became greater after hydrochlorothiazide treatment (supine, 72 ± 18 post vs. 64 ± 15 bursts (100 beats)−1 pre; 60° HUT, 83 ± 10 vs. 78 ± 13 bursts (100 beats)−1; P= 0.002). After aliskiren treatment, supine MSNA remained unchanged (69 ± 13 vs. 64 ± 8 bursts (100 beats)−1), but upright MSNA was lower (74 ± 15 vs. 85 ± 10 bursts (100 beats)−1; P= 0.012 for pre/post × posture). Direct renin was greater after both treatments (both P < 0.05), while upright aldosterone was greater after hydrochlorothiazide only ( P= 0.002). The change in upright MSNA by the treatment was correlated with the change of aldosterone ( r= 0.74, P= 0.002). Upright sympathetic BRS remained unchanged after either treatment. Thus, chronic renin inhibition may reduce upright MSNA through suppressed renin activity, while diuresis may evoke sympathetic activation via the upregulated renin-angiotensin-aldosterone system, without changing intrinsic sympathetic baroreflex function in elderly hypertensive patients. [ABSTRACT FROM AUTHOR]

Key points Sympathetic activity has been reported to increase in normotensive pregnant women, and to be even greater in women with gestational hypertension and preeclampsia at term., Whether sympathetic overactivity develops early during pregnancy, remaining high throughout gestation, or whether it only occurs at term providing the substrate for hypertensive disorders is unknown., We found that vasomotor sympathetic activity was markedly greater, diastolic pressure trended lower, total peripheral resistance decreased, sympathetic vascular transduction was blunted, and renin and aldosterone both were higher during early pregnancy (i.e. ≤8 weeks of gestation) than pre-pregnancy., It is suggested that sympathetic activation is a common characteristic of early pregnancy in normotensive women., These results help us better understand blood pressure control mechanisms during normal pregnancy in humans., Abstract Sympathetic activity has been reported to increase in normotensive pregnant women, and to be even greater in women with gestational hypertension and preeclampsia at term. Whether sympathetic overactivity develops early during pregnancy, remaining high throughout gestation, or whether it only occurs at term providing the substrate for hypertensive disorders is unknown. We tested the hypothesis that sympathetic activation occurs early during pregnancy in humans. Eleven healthy women (29 ± 3 (SD) years) without prior hypertensive pregnancies were tested during the mid-luteal phase (PRE) and early pregnancy (EARLY; 6.2 ± 1.2 weeks of gestation). Muscle sympathetic nerve activity (MSNA) and haemodynamics were measured supine, at 30 deg and 60 deg upright tilt for 5 min each. Blood samples were drawn for catecholamines, direct renin, and aldosterone. MSNA was significantly greater during EARLY than PRE (supine: 25 ± 8 vs. 14 ± 8 bursts min−1, 60 deg tilt: 49 ± 14 vs. 40 ± 10 bursts min−1; main effect, P < 0.05). Resting diastolic pressure trended lower ( P= 0.09), heart rate was similar, total peripheral resistance decreased (2172 ± 364 vs. 2543 ± 352 dyne s cm−5; P < 0.05), sympathetic vascular transduction was blunted (0.10 ± 0.05 vs. 0.36 ± 0.47 units a.u.−1 min−1; P < 0.01), and both renin (supine: 27.9 ± 6.2 vs. 14.2 ± 8.7 pg ml−1, P < 0.01) and aldosterone (supine: 16.7 ± 14.1 vs. 7.7 ± 6.8 ng ml−1, P= 0.05) were higher during EARLY than PRE. These results suggest that sympathetic activation is a common characteristic of early pregnancy in humans despite reduced diastolic pressure and total peripheral resistance. These observations challenge conventional thinking about blood pressure regulation during pregnancy, showing marked sympathetic activation occurring within the first few weeks of conception, and may provide the substrate for pregnancy induced cardiovascular complications. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases increase with advancing age, associated with left ventricular and arterial stiffening in humans. In contrast, daily exercise training prevents and/or improves both ventricular and arterial stiffening with ageing. We propose a new approach to quantify the dynamics of the Starling mechanism, namely the beat-to-beat modulation of stroke volume (SV) caused by beat-to-beat alterations in left ventricular filling, which we propose reflects the complex interaction between ventricular and arterial stiffness. We hypothesized that the dynamic Starling mechanism would be impaired with ageing, and that this impairment would be prevented and restored by daily exercise training. Two different approaches were employed: (1) a cross-sectional study to assess the effects of ageing and life-long exercise training; and (2) a longitudinal study to assess the effects of one-year endurance training in the elderly. Spectral transfer function gain between beat-to-beat changes in left ventricular end-diastolic pressure and SV was used as an index of the dynamic Starling mechanism. Gain was significantly lower in the sedentary elderly (70 ± 3 years) than in both young individuals (27 ± 6 years) and Masters athletes (68 ± 3 years), and it was significantly lower in Masters athletes than in young controls (elderly: 0.37 ± 0.11; Masters athletes: 0.96 ± 0.55; young: 1.52 ± 0.42 ml m−2 mmHg−1, mean ±s.d.). Gain increased by 65% after one-year exercise training in the elderly, although the response was quite variable ( P= 0.108). These findings suggest that the dynamic Starling mechanism is impaired with human ageing possibly due to ventricular–arterial stiffening. Life-long daily exercise training may minimize this impairment, although the effect may be limited particularly when started later in life. [ABSTRACT FROM AUTHOR]

We tested the hypothesis that whole‐body passive heat stress reduces arterial stiffness in older adults. At preheat stress (baseline) and when core temperature was elevated by 0.6 ± 0.2°C (mild) and 1.2 ± 0.3°C (moderate), arterial stiffness was measured in eight healthy younger (26 ± 5 years) and eight healthy older (70 ± 4 years) adults in the supine position. Arterial stiffness was estimated from carotid‐to‐femoral pulse wave velocity (cfPWV, applanation tonometry). cfPWV was higher at baseline in older adults (8.8 ± 2.3 m/sec vs. 5.6 ± 0.9 m/sec, P < 0.01) and this difference was maintained throughout passive heat stress (P < 0.01). cfPWV did not change (P ≥ 0.49) with passive heat stress in either younger (at moderate heat stress: 6.0 ± 1.0 m/sec) or older (at moderate heat stress: 8.5 ± 1.6 m/sec) adults. However, the influence of baseline cfPWV on the change in cfPWV during mild (r = −0.66, P = 0.04) and moderate (r = −0.87, P < 0.01) heat stress were inversely related in older adults, and the strength of these relations was not statistically different (P = 0.08). In younger adults, the influence of baseline cfPWV on the change in cfPWV during mild heat stress was also inversely related (r = −0.79, P = 0.01), while the strength of this relation was attenuated at moderate heat stress (r = −0.24, P = 0.30). Changes in arterial stiffness during passive heat stress in adults aged ≥65 year are likely dependent on the magnitude of baseline arterial stiffness and not necessarily age. [ABSTRACT FROM AUTHOR]