TRPA1 is a non‐selective cation channel expressed in mammalian peripheral pain receptors, with a major role in chemonociception. TRPA1 has also been implicated in noxious cold and mechanical pain ...sensation. TRPA1 has an ancient origin and plays important functions in lower organisms, including thermotaxis, mechanotransduction and modulation of lifespan. Here we highlight the role of TRPA1 as a multipurpose sensor of harmful signals, including toxic bacterial products and UV light, and as a sensor of stress and tissue damage. Sensing roles span beyond the peripheral nervous system to include major barrier tissues: gut, skin and lung. Tissue injury, environmental irritants and microbial pathogens are danger signals that can threaten the health of organisms. These signals lead to the coordinated activation of the nociceptive and the innate immune system to provide a homeostatic response trying to re‐establish physiological conditions including tissue repair. Activation of TRPA1 participates in protective neuroimmune interactions at multiple levels, sensing ROS and bacterial products and triggering the release of neuropeptides. However, an exaggerated response to danger signals is maladaptive and can lead to the development of chronic inflammatory conditions.
TRPA1 is emerging as an important therapeutic target to treat different pathologies, including pain, asthma and chronic itch. However, the broad expression profile of TRPA1 and the fine balance between physiological and maladaptive responses of TRPA1 suggest potential complications. Therefore, a better understanding of TRPA1 function is essential before we can realize the hope of targeting it safely and effectively to treat disease.
AbstractObjectivesTo determine rates of stroke or transient ischaemic attack (TIA) and all cause mortality in patients with a diagnosis of “resolved” atrial fibrillation compared to patients with ...unresolved atrial fibrillation and without atrial fibrillation.DesignTwo retrospective cohort studies.SettingGeneral practices contributing to The Health Improvement Network, 1 January 2000 to 15 May 2016.ParticipantsAdults aged 18 years or more with no previous stroke or TIA: 11 159 with resolved atrial fibrillation, 15 059 controls with atrial fibrillation, and 22 266 controls without atrial fibrillation.Main outcome measuresPrimary outcome was incidence of stroke or TIA. Secondary outcome was all cause mortality.ResultsAdjusted incidence rate ratios for stroke or TIA in patients with resolved atrial fibrillation were 0.76 (95% confidence interval 0.67 to 0.85, P<0.001) versus controls with atrial fibrillation and 1.63 (1.46 to 1.83, P<0.001) versus controls without atrial fibrillation. Adjusted incidence rate ratios for mortality in patients with resolved atrial fibrillation were 0.60 (0.56 to 0.65, P<0.001) versus controls with atrial fibrillation and 1.13 (1.06 to 1.21, P<0.001) versus controls without atrial fibrillation. When patients with resolved atrial fibrillation and documented recurrent atrial fibrillation were excluded the adjusted incidence rate ratio for stroke or TIA was 1.45 (1.26 to 1.67, P<0.001) versus controls without atrial fibrillation.ConclusionPatients with resolved atrial fibrillation remain at higher risk of stroke or TIA than patients without atrial fibrillation. The risk is increased even in those in whom recurrent atrial fibrillation is not documented. Guidelines should be updated to advocate continued use of anticoagulants in patients with resolved atrial fibrillation.
This article represents the update of the European Stroke Initiative Recommendations for Stroke Management. These guidelines cover both ischaemic stroke and transient ischaemic attacks, which are now ...considered to be a single entity. The article covers referral and emergency management, Stroke Unit service, diagnostics, primary and secondary prevention, general stroke treatment, specific treatment including acute management, management of complications, and rehabilitation.
Abstract We present a public catalog of transients from the Zwicky Transient Facility (ZTF) Bright Transient Survey, a magnitude-limited ( m < 19 mag in either the g or r filter) survey for ...extragalactic transients in the ZTF public stream. We introduce cuts on survey coverage, sky visibility around peak light, and other properties unconnected to the nature of the transient, and show that the resulting statistical sample is spectroscopically 97% complete at <18 mag, 93% complete at <18.5 mag, and 75% complete at <19 mag. We summarize the fundamental properties of this population, identifying distinct duration–luminosity correlations in a variety of supernova (SN) classes and associating the majority of fast optical transients with well-established spectroscopic SN types (primarily SN Ibn and II/IIb). We measure the Type Ia SN and core-collapse (CC) SN rates and luminosity functions, which show good consistency with recent work. About 7% of CC SNe explode in very low-luminosity galaxies ( M i > −16 mag), 10% in red-sequence galaxies, and 1% in massive ellipticals. We find no significant difference in the luminosity or color distributions between the host galaxies of SNe Type II and SNe Type Ib/c, suggesting that line-driven wind stripping does not play a major role in the loss of the hydrogen envelope from their progenitors. Future large-scale classification efforts with ZTF and other wide-area surveys will provide high-quality measurements of the rates, properties, and environments of all known types of optical transients and limits on the existence of theoretically predicted but as yet unobserved explosions.
Cerebral microbleeds are a neuroimaging biomarker of stroke risk. A crucial clinical question is whether cerebral microbleeds indicate patients with recent ischaemic stroke or transient ischaemic ...attack in whom the rate of future intracranial haemorrhage is likely to exceed that of recurrent ischaemic stroke when treated with antithrombotic drugs. We therefore aimed to establish whether a large burden of cerebral microbleeds or particular anatomical patterns of cerebral microbleeds can identify ischaemic stroke or transient ischaemic attack patients at higher absolute risk of intracranial haemorrhage than ischaemic stroke.
We did a pooled analysis of individual patient data from cohort studies in adults with recent ischaemic stroke or transient ischaemic attack. Cohorts were eligible for inclusion if they prospectively recruited adult participants with ischaemic stroke or transient ischaemic attack; included at least 50 participants; collected data on stroke events over at least 3 months follow-up; used an appropriate MRI sequence that is sensitive to magnetic susceptibility; and documented the number and anatomical distribution of cerebral microbleeds reliably using consensus criteria and validated scales. Our prespecified primary outcomes were a composite of any symptomatic intracranial haemorrhage or ischaemic stroke, symptomatic intracranial haemorrhage, and symptomatic ischaemic stroke. We registered this study with the PROSPERO international prospective register of systematic reviews, number CRD42016036602.
Between Jan 1, 1996, and Dec 1, 2018, we identified 344 studies. After exclusions for ineligibility or declined requests for inclusion, 20 322 patients from 38 cohorts (over 35 225 patient-years of follow-up; median 1·34 years IQR 0·19–2·44) were included in our analyses. The adjusted hazard ratio aHR comparing patients with cerebral microbleeds to those without was 1·35 (95% CI 1·20–1·50) for the composite outcome of intracranial haemorrhage and ischaemic stroke; 2·45 (1·82–3·29) for intracranial haemorrhage and 1·23 (1·08–1·40) for ischaemic stroke. The aHR increased with increasing cerebral microbleed burden for intracranial haemorrhage but this effect was less marked for ischaemic stroke (for five or more cerebral microbleeds, aHR 4·55 95% CI 3·08–6·72 for intracranial haemorrhage vs 1·47 1·19–1·80 for ischaemic stroke; for ten or more cerebral microbleeds, aHR 5·52 3·36–9·05 vs 1·43 1·07–1·91; and for ≥20 cerebral microbleeds, aHR 8·61 4·69–15·81 vs 1·86 1·23–2·82). However, irrespective of cerebral microbleed anatomical distribution or burden, the rate of ischaemic stroke exceeded that of intracranial haemorrhage (for ten or more cerebral microbleeds, 64 ischaemic strokes 95% CI 48–84 per 1000 patient-years vs 27 intracranial haemorrhages 17–41 per 1000 patient-years; and for ≥20 cerebral microbleeds, 73 ischaemic strokes 46–108 per 1000 patient-years vs 39 intracranial haemorrhages 21–67 per 1000 patient-years).
In patients with recent ischaemic stroke or transient ischaemic attack, cerebral microbleeds are associated with a greater relative hazard (aHR) for subsequent intracranial haemorrhage than for ischaemic stroke, but the absolute risk of ischaemic stroke is higher than that of intracranial haemorrhage, regardless of cerebral microbleed presence, antomical distribution, or burden.
British Heart Foundation and UK Stroke Association.
Sensory TRP Channels in Three Dimensions Diver, Melinda M; Lin King, John V; Julius, David ...
Annual review of biochemistry,
06/2022, Letnik:
91
Journal Article
Recenzirano
Transient receptor potential (TRP) ion channels are sophisticated signaling machines that detect a wide variety of environmental and physiological signals. Every cell in the body expresses one or ...more members of the extended TRP channel family, which consists of over 30 subtypes, each likely possessing distinct pharmacological, biophysical, and/or structural attributes. While the function of some TRP subtypes remains enigmatic, those involved in sensory signaling are perhaps best characterized and have served as models for understanding how these excitatory ion channels serve as polymodal signal integrators. With the recent resolution revolution in cryo-electron microscopy, these and other TRP channel subtypes are now yielding their secrets to detailed atomic analysis, which is beginning to reveal structural underpinnings of stimulus detection and gating, ion permeation, and allosteric mechanisms governing signal integration. These insights are providing a framework for designing and evaluating modality-specific pharmacological agents for treating sensory and other TRP channel-associated disorders.
Transient receptor potential mucolipin 1 (TRPML1) is a Ca
-releasing cation channel that mediates the calcium signalling and homeostasis of lysosomes. Mutations in TRPML1 lead to mucolipidosis type ...IV, a severe lysosomal storage disorder. Here we report two electron cryo-microscopy structures of full-length human TRPML1: a 3.72-Å apo structure at pH 7.0 in the closed state, and a 3.49-Å agonist-bound structure at pH 6.0 in an open state. Several aromatic and hydrophobic residues in pore helix 1, helices S5 and S6, and helix S6 of a neighbouring subunit, form a hydrophobic cavity to house the agonist, suggesting a distinct agonist-binding site from that found in TRPV1, a TRP channel from a different subfamily. The opening of TRPML1 is associated with distinct dilations of its lower gate together with a slight structural movement of pore helix 1. Our work reveals the regulatory mechanism of TRPML channels, facilitates better understanding of TRP channel activation, and provides insights into the molecular basis of mucolipidosis type IV pathogenesis.
This paper investigates the accelerating up transient vibrations of a rotor system under both the random and uncertain-but-bounded parameters. The Polynomial Chaos Expansion (PCE) coupled with the ...Chebyshev Surrogate Method (CSM) is used to analyses the propagations of the two categorizes of uncertainties. The output responses will possess the characteristics of both bounded quantities and statistical moments. As a hybrid non-intrusive uncertainty quantification (UQ) procedure, the deterministic rotor model is taken as a black box and will only be executed at some parameter points. A number of uncertain physical parameters are studied and the corresponding transient responses are presented. The accuracy and efficiency are verified by the Monte Carlo simulations (MCS) in combination with the scanning scheme and also other hybrid analysis framework. It will provide guidance for the accurate transient dynamic analysis of engineering problems with hybrid uncertainties.
•Treatment of both random and interval uncertainties in speed-varying rotor system.•Statistical response moments are obtained by the PCE considering random uncertainty.•Bounds of the stochastic response are derived by the surrogate with interval uncertainty.•Verification of the hybrid analysis procedure and numerical investigations are performed.
Summary More than 50 years after its initial description, transient global amnesia (TGA) remains one of the most enigmatic syndromes in clinical neurology. Recent MRI data suggest that a transient ...perturbation of hippocampal function is the functional correlate of TGA because focal diffusion lesions can be selectively detected in the CA1 field of the hippocampal cornu ammonis. Although various factors, such as migraine, focal ischaemia, venous flow abnormalities, and epileptic phenomena, have been suggested to be involved in the pathophysiology of TGA, the factors triggering the emergence of these lesions are still elusive. Recent data suggest that the vulnerability of CA1 neurons to metabolic stress plays a pivotal part in the pathophysiological cascade, leading to an impairment of hippocampal function during TGA. In this Review, we discuss clinical aspects, new imaging findings, and recent clinical–epidemiological data with regard to the phenotype, functional anatomy, and putative cellular mechanisms of TGA.
Compact low dropout (LDO) with high current handling capability and superior transient response is gaining increasing attention for the battery-powered 5G mobile applications. In this article, a new ...multiple-loop design technique for fast-transient response LDO regulator design has been proposed and successfully implemented in a 0.13-<inline-formula> <tex-math notation="LaTeX">\mu \text{m} </tex-math></inline-formula> SOI CMOS process for portable smartphone and tablet PC applications. Its supply current capacity is more than 1 A, and its output voltage is from 1.2 to 1.8 V. The proposed LDO features a 10-mV undershoot and overshoot with 1-A/100-ns load current on a 1-<inline-formula> <tex-math notation="LaTeX">\mu \text{F} </tex-math></inline-formula> output capacitor. This superior transient performance is achieved by embodying a novel frequency compensation scheme without penalty of dc loop gain drop in large load current conditions. The dc loop gain is 60 dB and constant regardless of the fact that the load current varies from 0 to 1 A. This contributes to a small load regulation and line regulation of 0.6 <inline-formula> <tex-math notation="LaTeX">\mu \text{V} </tex-math></inline-formula>/A and 0.23 mV/V, respectively. The LDO consumes 35-<inline-formula> <tex-math notation="LaTeX">\mu \text{A} </tex-math></inline-formula> quiescent current in the mission mode and 5 <inline-formula> <tex-math notation="LaTeX">\mu \text{A} </tex-math></inline-formula> in the standby mode. The LDO silicon size is 325 <inline-formula> <tex-math notation="LaTeX">\mu \text{m}\,\,\times </tex-math></inline-formula> 106 <inline-formula> <tex-math notation="LaTeX">\mu \text{m} </tex-math></inline-formula>.
PDF
