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Cell-surface receptor complexes mediated by pro-inflammatory Interleukin-12 and -23, both validated therapeutic targets, are incompletely understood due to the lack of structural insights into their complete extracellular assemblies. Furthermore, there is a paucity of structural details describing the IL-12:receptor interaction interfaces, in contrast to IL23:receptor complexes. Here we report cryo-EM structures of fully assembled IL-12/IL-23:receptor complexes comprising the complete extracellular segments of the cognate receptors. The structures reveal important commonalities but also surprisingly diverse features. Whereas IL-12 and IL-23 both utilize a conspicuously presented aromatic residue on their α-subunit as a hotspot to interact with the N-terminal Ig-domain of their high affinity receptors, only IL-12 juxtaposes receptor domains proximal to the cell-membrane. Collectively, our findings will enable a cytokine-specific interrogation of IL-12 and IL-23 signaling in physiology and disease.

Abnormalities in autonomic function have been observed in people with anorexia nervosa. However, the majority of investigations have utilised heart rate variability as the sole assessment of autonomic activity. The current study utilised a variety of methodologies to assess autonomic nervous system function in women with a current diagnosis of anorexia, a past diagnosis of anorexia who were weight-restored, and healthy controls. The sample included 37 participants: 10 participants with anorexia, 17 weight-restored participants (minimum body mass index > 18.5 for minimum of 12 months) and 10 controls. Assessments of autonomic function included muscle sympathetic nerve activity (MSNA) using microneurography, heart rate variability, baroreflex sensitivity, blood pressure variability, head-up tilt table test, sudomotor function and assessment of plasma catecholamines. MSNA (bursts/min) was significantly decreased in both anorexia (10.22 ± 6.24) and weight-restored (17.58 ± 1.68) groups, as compared to controls (23.62 ± 1.01, p

In Europe, the genusTolypella(Characeae) comprises four to eightTolypellaspecies in sectionsRothiaandTolypellathat have been distinguished by vegetative morphology and gametangial characters such as antheridial size and oospore cell wall ornamentation. However, morphological species differentiation is difficult in some cases due to overlapping and variable vegetative features, which in many cases are difficult to observe clearly.To clarify the taxonomic status of the five European species ofTolypellain sectionTolypella, sequence data of the plastid genesatpB,rbcL andpsbC forTolypella glomerata(Desv.) Leonh.,Tolypella hispanicaAllen,Tolypella nidifica(O.F. Müll.) A. Braun,Tolypella normaniana(Nordst.) Nordst. andTolypella salinaCor. were combined with data on oospore morphology, including oospore wall ornamentation.Gene sequence data identified five distinct clusters, but they differed from the morphologically identified five species. ‘T. glomerata’ consisted of some of the samples morphologically identified asT. glomerataand seven samples ofT. normaniana, while the remainingT. glomeratasamples clustered with specimens of unclear affiliation (“Tolypella. sp.”). ‘T. hispanicaI’ consisted of samples from various locations, whereas “T.hispanicaII” consisted of samples ofT. hispanicafrom the Mediterranean island, Sardinia. The remaining cluster consisted of all the specimens that had been determined asT. salinaorT. nidificain addition to two specimens ofT. normaniana. Oospore morphology was most clearly distinguishable forT. glomerata. Oospore characteristics for all other taxa were not as informative but showed some geographical and/or environmentally influenced differences, especially forT. nidificaandT. salina.Our results suggest a significantly different taxonomy ofTolypellasect.Tolypellain which specimens normally identified asT. glomeratamight be two different species,T. glomerataand an unidentified species;T. nidificaandT. salinaare not separate species;T. normanianais a diminutive variant ofT. nidificaorT. salina; andT. hispanicacomprises two different species, one from the Mediterranean island Sardnia.

Recent findings in experimental models have shown that the microRNA miR-132 (mir-132) is an important regulator of liver homeostasis and lipid metabolism. We aimed to assess miR-132 expression in liver and fat tissues of obese individuals and examine its association with blood pressure (BP) and hepatic steatosis. We examined obese individuals undergoing bariatric surgery for weight loss (n = 19). Clinical and demographic information was obtained. Quantitative PCR was performed to determine tissue expression of miR-132 in liver and subcutaneous and visceral fat biopsies obtained during bariatric surgery. Liver biopsies were read by a single liver pathologist and graded for steatosis, inflammation and fibrosis. Participants (aged 39 ± 8.1 years) had a body mass index (BMI) of 42 ± 4.5 kg/m2 and presented with 2.2 ± 1.2 metabolic abnormalities. Supine BP was 127 ± 16/74 ± 11 mmHg. Hepatic and visceral fat expression of miR-132 were correlated (r = 0.59, P = 0.033). There was no correlation between subcutaneous and visceral expression of miR-132 (r = -0.31, P = 0.20). Hepatic and visceral fat miR-132 expression were associated with BMI (r = 0.62 and r = 0.68, P = 0.049 respectively) and degree of liver steatosis (r = 0.60 and r = 0.55, P < 0.05, respectively). Subcutaneous fat miRNA-132 expression was correlated to office systolic BP (r = 0.46, P < 0.05), several aspects of 24 h BP (24 h systolic BP: r = 0.52; day systolic BP: r = 0.59, P < 0.05 for all), plasma triglycerides (r = 0.51, P < 0.01) and liver enzymes (ALT: r = -0.52; AST: r = -0.48, P < 0.05 for all). We found an association between miR-132 and markers of cardiovascular and metabolic disease. Reduction of miR-132 may be a target for the regulation of liver lipid homeostasis and control of obesity-related blood pressure.

Amongst other immune cells, neutrophils play a key role in systemic inflammation leading to cardiovascular disease and can release inflammatory factors, including lipocalin-2 (LCN2). LCN2 drives cardiac hypertrophy and plays a role in maladaptive remodelling of the heart and has been associated with renal injury. While lifestyle factors such as diet and exercise are known to attenuate low-grade inflammation, their ability to modulate plasma LCN2 levels is unknown. Forty-eight endurance athletes and 52 controls (18–55 years) underwent measurement for various cardiovascular health indicators, along with plasma LCN2 concentration. No significant difference in LCN2 concentration was seen between the two groups. LCN2 was a very weak predictor or absent from models describing blood pressures or predicting athlete status. In another cohort, 57 non-diabetic overweight or obese men and post-menopausal women who fulfilled Adult Treatment Panel III metabolic syndrome criteria were randomly allocated into either a control, modified Dietary Approaches to Stop Hypertension (DASH) diet, or DASH and exercise group. Pre- and post-intervention demographic, cardiovascular health indicators, and plasma LCN2 expression were measured in each individual. While BMI fell in intervention groups, LCN2 levels remained unchanged within and between all groups, as illustrated by strong correlations between LCN2 concentrations pre- and 12 weeks post-intervention (r = 0.743, P

Objective: The aim of the current study was to investigate cardiovascular responses to a brief social exclusion stressor, the Cyberball task, and to determine whether individual differences in depression, anxiety, and perceived social isolation moderate physiological stress responses. Methods: Sixty-four participants engaged in the Cyberball task while heart rate, blood pressure, and respiratory rate were continuously measured. Results: Systolic (M = 121.61, SD = 13.34) and diastolic (M = 77.34, SD = 7.56) blood pressure increased significantly during the exclusion condition compared with the rest condition (M = 117.81, SD = 12.71, M = 75.63, SD = 7.39, respectively). Significant correlations were also found between social anxiety (r = −0.25) and depression (r = −0.25) scores with systolic blood pressure from the exclusion condition. Further, participants who reported high depression scores had attenuated cardiovascular responses to social exclusion. Conclusions: Overall, cardiovascular activity were elevated after a brief social stressor, but those with clinically relevant cut off scores on the CES-D had attenuated cardiovascular responses These findings support the growing body of literature surrounding cardiovascular stress reactivity to stress induced from social exclusion.

Unlike noradrenaline, the sympathetic neurotransmitter which overflows to the circulation, adrenaline (ADR) is a secreted hormone, with a low plasma concentration, and plasma concentration for biological action a log order lower than that of noradrenaline. The venous drainage of the left adrenal medulla into the left renal vein does expose this vein to uniquely high plasma ADR concentrations and possible risk of thrombosis at high rates of ADR secretion. There is typically a different timeframe for adrenal medullary and sympathetic nervous system responses: ADR release is short term in contrast with sympathetic activation persisting for years in heart failure and hypertension. The historic view of Walter Cannon, subject to recent review, that the sympathoadrenal system is a unified biological system, was deconstructed further with demonstration of frequent mismatching of adrenal medullary and sympathetic nervous responses. Under gravity stimulation with standing, there is prompt sympathetic activation without ADR release. In many diseases, notably obesity, hypertension, heart failure and depressive illness, an activated sympathetic nervous system and silent adrenal medulla coexist. The therapeutic corollary of this is that ADR blockade is much less commonly needed clinically than pharmacological antagonism of the sympathetic nervous system.

COVID-19 pandemic and its associated social and physical distancing restrictions may have had a severe impact on health. In the present study, we investigate the changes in physical, social and mental health, as well as the health literacy of Australians subsequent to the onset of COVID-19 pandemic, and examine the influence of loneliness on these health-related factors. Using a retrospective cross-sectional study design, 607 Australian adults completed a self-report online survey which assessed their health-related factors before and after onset of the COVID-19 pandemic (data collected between June 2020 to November 2020). Australians reported statistically significant increase in a number of (poorer) health-related factors (e.g., weight gain, sleeping difficulties, poor somatic health, higher loneliness, more issues navigating the healthcare system) post onset of COVID-19 pandemic. Further, after adjusting for covariates, higher loneliness during pandemic predicted poorer health-related outcomes (e.g., more somatic health complaints, poorer quality of diet, poorer social support for health). The COVID-19 pandemic and its associated social and physical distancing restrictions may have contributed towards poorer health-related factors among Australian adults. Further, increased loneliness during the pandemic may have further worsened physical health and health literacy outcomes among Australians.

LtaA catalyzes glycolipid translocation by a 'trap-and-flip' mechanism, pointing to a shared mechanistic model among MFS lipid transporters. Asymmetric lateral openings allow access of the entire lipid substrate to the amphipathic central cavity. Transport of lipids across membranes is fundamental for diverse biological pathways in cells. Multiple ion-coupled transporters take part in lipid translocation, but their mechanisms remain largely unknown. Major facilitator superfamily (MFS) lipid transporters play central roles in cell wall synthesis, brain development and function, lipids recycling, and cell signaling. Recent structures of MFS lipid transporters revealed overlapping architectural features pointing towards a common mechanism. Here we used cysteine disulfide trapping, molecular dynamics simulations, mutagenesis analysis, and transport assays in vitro and in vivo, to investigate the mechanism of LtaA, a proton-dependent MFS lipid transporter essential for lipoteichoic acid synthesis in the pathogen Staphylococcus aureus. We reveal that LtaA displays asymmetric lateral openings with distinct functional relevance and that cycling through outward- and inward-facing conformations is essential for transport activity. We demonstrate that while the entire amphipathic central cavity of LtaA contributes to lipid binding, its hydrophilic pocket dictates substrate specificity. We propose that LtaA catalyzes lipid translocation by a 'trap-and-flip' mechanism that might be shared among MFS lipid transporters.

Acute head-down-tilt (HDT) simulates short duration hemodynamic impact of microgravity. We sought to determine whether an increase in ICP caused by acute HDT affects sympathetic nervous system activity and cerebral blood flow velocities (CBFV) in healthy male volunteers.HDT protocol was established as follows: basal condition immediately followed by gradual negative angles (-10°, -20° and -30°) lasting 10mn and then a return to basal condition. Velocities in the MCA (CBFV) were monitored using TCD. Sympathetic activity was assessed using MSNA. Baroreflex sensitivity (BRS) was measured using the sequence method. ICP changes were assessed using ultrasonography of the optic nerve sheath diameter (ONSD). Cerebral autoregulation (CA) was evaluated by transfer function and the autoregulatory index (Mxa).Twelve male volunteers (age: 35 ± 2 years) were included. Neither blood pressure nor heart rate was significantly modified during HDT. ONSD increased significantly at each step of HDT and remained elevated during Recovery. MSNA burst incidence increased at -30°. A positive correlation between variations in ONSD and variations in MSNA burst incidence was observed at -20°. CBFV were significantly diminished at -20° and -30. In the LF band, the transfer function coherence was reduced at -30° and the transfer function phase was increased at -30° and during Recovery.We found that an acute though modest increase in ICP induced by HDT was associated with an increase of sympathetic activity as assessed by MSNA, and with a reduction of CBFV with preserved CA.

BACKGROUND Renal denervation (RDN) has been proven in multiple sham-controlled trials to lower blood pressure (BP) in various forms of hypertension. RDN-mediated interruption of sympathetic signaling through its effects on renal blood flow, salt retention, and renin release are likely contributors to the BP-lowering effects. However, the impact of RDN on salt sensitivity in humans has not yet been explored. METHODS We, therefore, investigated the effect of RDN on ambulatory BP monitoring-derived salt sensitivity in a cohort of patients with uncontrolled hypertension on habitual salt intake. RDN was performed in 153 hypertensive patients, who were categorized into low intermediate and high-salt sensitivity groups, based on the ambulatory BP monitoring-derived salt sensitivity index estimated prior to (baseline) and at 3, 6 and 12 months after the procedure as previously described. Crude and adjusted mixed effects ordinal regression models were fitted to test for changes in the proportions of salt sensitivity risk during follow-up. RESULTS The proportions of individuals in the intermediate and high-salt sensitivity risk group increased after RDN and the odds for being in a higher estimated salt sensitivity risk group at 3, 6 and 12 months follow-up compared with baseline were highly significant during the 12 months follow-up period. CONCLUSION Increased salt sensitivity after RDN may represent a compensatory mechanism to maintain renal capacity for adequate salt handling. This novel finding may have implications for patient management after RDN, such as prescription of salt moderation to further optimize RDN-induced BP-lowering efficacy.

Objective. Transcutaneous vagus nerve stimulation (tVNS) is a form of non-invasive brain stimulation that delivers a sequence of electrical pulses to the auricular branch of the vagus nerve and is used increasingly in the treatment of a number of health conditions such as epilepsy and depression. Recent research has focused on the efficacy of tVNS to treat different medical conditions, but there is little conclusive evidence concerning the optimal stimulation parameters. There are relatively few studies that have combined tVNS with a neuroimaging modality, and none that have attempted simultaneous magnetoencephalography (MEG) and tVNS due to the presence of large stimulation artifacts produced by the electrical stimulation which are many orders of magnitude larger than underlying brain activity. Approach. The aim of this study is to investigate the utility of MEG to gain insight into the regions of the brain most strongly influenced by tVNS and how variation of the stimulation parameters can affect this response in healthy participants. Main results. We have successfully demonstrated that MEG can be used to measure brain response to tVNS. We have also shown that varying the stimulation frequency can lead to a difference in brain response, with the brain also responding in different anatomical regions depending on the frequency. Significance. The main contribution of this paper is to demonstrate the feasibility of simultaneous pulsed tVNS and MEG recording, allowing direct investigation of the changes in brain activity that result from different stimulation parameters. This may lead to the development of customised therapeutic approaches for the targeted treatment of different conditions.

Objective. Critical slowing features (variance and autocorrelation) of long-term continuous electroencephalography (EEG) and electrocardiography (ECG) data have previously been used to forecast epileptic seizure onset. This study tested the feasibility of forecasting non-epileptic seizures using the same methods. In doing so, we examined if long-term cycles of brain and cardiac activity are present in clinical physiological recordings of psychogenic non-epileptic seizures (PNES). Approach. Retrospectively accessed ambulatory EEG and ECG data from 15 patients with non-epileptic seizures and no background of epilepsy were used for developing the forecasting system. The median period of recordings was 161 h, with a median of 7 non-epileptic seizures per patient. The phases of different cycles (5 min, 1 h, 6 h, 12 h, 24 h) of EEG and RR interval (RRI) critical slowing features were investigated. Forecasters were generated using combinations of the variance and autocorrelation of both EEG and the RRI of the ECG at each of the aforementioned cycle lengths. Optimal forecasters were selected as those with the highest area under the receiver-operator curve (AUC). Main results. It was found that PNES events occurred in the rising phases of EEG feature cycles of 12 and 24 h in duration at a rate significantly above chance. We demonstrated that the proposed forecasters achieved performance significantly better than chance in 8/15 of patients, and the mean AUC of the best forecaster across patients was 0.79. Significance. To our knowledge, this is the first study to retrospectively forecast non-epileptic seizures using both EEG and ECG data. The significance of EEG in the forecasting models suggests that cyclic EEG features of non-epileptic seizures exist. This study opens the potential of seizure forecasting beyond epilepsy, into other disorders of episodic loss of consciousness or dissociation.

Transport of lipids across membranes is fundamental for diverse biological pathways in cells. Multiple ion-coupled transporters participate in lipid translocation, but their mechanisms remain largely unknown. Major facilitator superfamily (MFS) lipid transporters play central roles in cell wall synthesis, brain development and function, lipids recycling, and cell signaling. Recent structures of MFS lipid transporters revealed overlapping architectural features pointing towards a common mechanism. Here we used cysteine disulfide trapping, molecular dynamics simulations, mutagenesis analysis, and transport assays in vitro and in vivo, to investigate the mechanism of LtaA, a proton-dependent MFS lipid transporter essential for lipoteichoic acids synthesis in the pathogen Staphylococcus aureus. We reveal that LtaA displays asymmetric lateral openings with distinct functional relevance and that cycling through outward- and inward-facing conformations is essential for transport activity. We demonstrate that while the entire amphipathic central cavity of LtaA contributes to lipid binding, its hydrophilic pocket dictates substrate specificity. We propose that LtaA catalyzes lipid translocation by a ‘trap-and-flip’ mechanism that might be shared among MFS lipid transporters.

Cardiovascular complications have been demonstrated in patients with anorexia nervosa (AN) in both the state of starvation and during weight restoration, however, the underlying mechanisms remain unclear. The current study aimed to assess arterial stiffness via carotid-femoral pulse wave velocity (cfPWV) in the acute and weight-restored states of AN. The study also aimed to determine the association between psychological distress and cfPWV. The sample included 37 participants; 10 participants with AN, 17 who were weight-restored (AN-WR; minimum body mass index >18.5 for at least 12 months) and 10 healthy controls (HCs). cfPWV via applanation tonometry was conducted to assess arterial stiffness. Psychological distress was assessed using the depression anxiety stress scale (DASS-21) and the state-trait anxiety inventory (STAI). Between-group comparisons were performed to determine differences between groups, a two-stage hierarchical regression model was performed to determine the contribution of physiological and psychological variables on cfPWV and correlation analyses were also performed. Vascular stiffness was significantly increased in the AN and AN-WR groups, relative to HCs. The total DASS score was the only significant predictor of cfPWV across the sample. There were positive associations between cfPWV and depression, anxiety and stress, as assessed by the DASS. Furthermore, cfPWV was positively associated with STAI trait anxiety. Arterial stiffness was increased in individuals in the acute and weight-restored states of AN, demonstrating early signs of the development of arteriosclerotic cardiovascular disease. Increased arterial stiffness was associated with increased psychological distress, which may be a contributing mechanism to the increased cardiovascular risk in AN.

The volume of data in the field of Earth data observation has increased considerably, especially with the emergence of new generations of satellites and models providing much more precise measures and thus voluminous data and files. One of the most traditional and popular data formats used in scientific and education communities (reference) is the NetCDF format. However, it was designed before the development of cloud storage and parallel processing in big data architectures. Alternative solutions, under open source or under proprietary licences, appeared in the past few years (See Rasdaman, Opendatacube). These data cubes are managing the storage and the services for an easy access to the data but they are also altering the input information applying conversions and/or reprojections to homogenize their internal data structure, introducing a bias in the scientific value of the data. The consequence is that it drives the users in a closed infrastructure, made of customized storage and access services. The objective of this study is to propose a light new open source solution which is able to store gridded datasets into a native big data format and make data available for parallel processing, analytics or artificial intelligence learning. There is a demand for developing a unique storage solution that would be opened to different users: Scientists, setting up their prototypes and models in their customized environment and qualifying their data to publish as Copernicus datatsets for instance; Operational teams, in charge of the daily processing of data which can be run in another environment, to ingest the product in an archive and make it available to end-users for additional model and data science processing. Data ingestion and storage are key factors to study to ensure good performances in further subsetting access services and parallel processing. Through typical end users’ use cases, four storage and services implementations are compared through benchmarks: Unidata's THREDDS Data Server (TDS) which is a traditional NetCDF data access service solution built on the NetCDF-Java, an extension of the THREDDS Data Server using object store, pangeo/Dask/Python ecosystem, and the alternative Hadoop/Spark/Parquet solution, driven by CLS technical and business requirements.

Background High blood pressure is an independent risk factor of cardiovascular disease (CVD) and is a major cause of disability and death. Managing a healthy lifestyle has been shown to reduce blood pressure and improve health outcomes. We aim to investigate the effectiveness of a lifestyle modification intervention program for lowering blood pressure in a rural area of Bangladesh. Methods A single-center cluster randomized controlled trial (RCT). The study will be conducted for 6 months, a total of 300 participants of age 30 to 75 years with 150 adults in each of the intervention and the control arms. The intervention arm will involve the delivery of a blended learning education program on lifestyle changes for the management of high blood pressure. The education program comprises evidence-based information with pictures, fact sheets, and published literature about the effects of high blood pressure on CVD development, increased physical activity, and the role of a healthy diet in blood pressure management. The control group involves providing information booklets and general advice at the baseline data collection point. The primary outcome will be the absolute difference in clinic SBP and DBP. Secondary outcomes include the difference in the percentage of people adopting regular exercise habits, cessation of smoking and reducing sodium chloride intake, health literacy of all participants, and the perceived barriers and enablers to adopt behavior changes by collecting qualitative data. Analyses will include analysis of covariance to report the mean difference in blood pressure between the control and the intervention group and the difference in change in blood pressure due to the intervention. Discussion The study will assess the effects of physical activity and lifestyle modification in controlling high blood pressure. This study will develop new evidence as to whether a simple lifestyle program implemented in a rural region of a low- and middle-income country will improve blood pressure parameters for people with different chronic diseases by engaging community people. Trial registration ClinicalTrials.gov NCT04505150. Registered on 7 August 2020

BACKGROUND The impact of the 2017 American College Cardiology/American Heart Association guidelines on reclassification of white coat hypertension (WCH) and white coat uncontrolled hypertension (WUCH) phenotypes has not been thoroughly investigated, so far. The aim of the present analysis was to compare the prevalence rates of WCH and WUCH according to either 2018 European Society Hypertension/European Society Cardiology and 2017 ACC/AHA hypertension guidelines. METHODS A large database of individual 24-hour ambulatory blood pressure (BP) recordings from untreated and treated hypertensive individuals with office BP ≥140 and/or 90 mm Hg was analyzed. RESULTS As many as 3,223 (39% men) out of 7,353 (47% men) fulfilled diagnostic criteria for WCH (n = 1,281) and WUCH (n = 1,942) according to the 2018 ESH/ESC guidelines (mean 24-hour BP

Sympathetic overdrive contributes to the derangement of glucose metabolism evident in clinical conditions, such as obesity, metabolic syndrome, type 2 diabetes, obstructive sleep apnea, and others. Targeting the sympathetic nervous system directly therefore appears as an attractive therapeutic approach to restore impaired glucose metabolism. Indeed, lifestyle interventions, including healthier diets and exercise, have been shown to exert their beneficial effects at least in part by reducing sympathetic nervous system activity. Pharmacologic inhibition of exaggerated central sympathetic outflow has also been demonstrated to beneficially impact on body weight and glucose and lipid metabolism. More recently, catheter-based renal denervation, an intervention applied predominantly to lower elevated blood pressure in patients with resistant hypertension, revealed salutary effects on glucose metabolism. Here, we review the mechanisms that contribute to the beneficial effects of targeting the sympathetic nervous system directly and discuss how these approaches may best be embedded in routine clinical practice.