Background:
Safe and effective treatment for chronic inflammatory and neuropathic pain remains a key unmet medical need for many patients. The recent discovery and description of the transient ...receptor potential family of receptors including TRPV1 and TRPA1 has provided a number of potential new therapeutic targets for treating chronic pain. Recent reports have suggested that TRPA1 may play an important role in acute formalin and CFA induced pain. The current study was designed to further explore the therapeutic potential of pharmacological TRPA1 antagonism to treat inflammatory and neuropathic pain.
Results:
The in vitro potencies of HC-030031 versus cinnamaldehyde or allyl isothiocyanate (AITC or Mustard oil)-induced TRPA1 activation were 4.9 ± 0.1 and 7.5 ± 0.2 μM respectively (IC50). These findings were similar to the previously reported IC50 of 6.2 μM against AITC activation of TRPA1 1. In the rat, oral administration of HC-030031 reduced AITC-induced nocifensive behaviors at a dose of 100 mg/kg. Moreover, oral HC-030031 (100 mg/kg) significantly reversed mechanical hypersensitivity in the more chronic models of Complete Freunds Adjuvant (CFA)-induced inflammatory pain and the spinal nerve ligation model of neuropathic pain.
Conclusion:
Using oral administration of the selective TRPA1 antagonist HC-030031, our results demonstrated that TRPA1 plays an important role in the mechanisms responsible for mechanical hypersensitivity observed in inflammatory and neuropathic pain models. These findings suggested that TRPA1 antagonism may be a suitable new approach for the development of a potent and selective therapeutic agent to treat both inflammatory and neuropathic pain.
The angiotensin II receptors AT
R and AT
R serve as key components of the renin-angiotensin-aldosterone system. AT
R has a central role in the regulation of blood pressure, but the function of AT
R ...is unclear and it has a variety of reported effects. To identify the mechanisms that underlie the differences in function and ligand selectivity between these receptors, here we report crystal structures of human AT
R bound to an AT
R-selective ligand and to an AT
R/AT
R dual ligand, capturing the receptor in an active-like conformation. Unexpectedly, helix VIII was found in a non-canonical position, stabilizing the active-like state, but at the same time preventing the recruitment of G proteins or β-arrestins, in agreement with the lack of signalling responses in standard cellular assays. Structure-activity relationship, docking and mutagenesis studies revealed the crucial interactions for ligand binding and selectivity. Our results thus provide insights into the structural basis of the distinct functions of the angiotensin receptors, and may guide the design of new selective ligands.
BAFFLES: Bayesian Ages for Field Lower-mass Stars Stanford-Moore, S. Adam; Nielsen, Eric L.; De Rosa, Robert J. ...
Astrophysical journal/The Astrophysical journal,
07/2020, Letnik:
898, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Age is a fundamental parameter of stars, yet in many cases, ages of individual stars are presented without robust estimates of the uncertainty. We have developed a Bayesian framework, BAFFLES, to ...produce the age posterior for a star from its calcium emission strength (log( )) or lithium abundance (Li EW) and B − V color. We empirically determine the likelihood functions for calcium and lithium as functions of age from literature measurements of stars in benchmark clusters with well-determined ages. We use a uniform prior on age, which reflects a uniform star formation rate. The age posteriors we derive for several test cases are consistent with literature ages found from other methods. BAFFLES represents a robust method to determine the age posterior probability distribution for any field star with 0.45 ≤ B − V ≤ 0.9 and a measurement of and/or 0.35 ≤ B − V ≤ 1.9 and measured Li EW. We compile colors, , and Li EW from over 2630 nearby field stars from the literature, and present the derived BAFFLES age posterior for each star.
ABC transporters are a 48-member superfamily of membrane proteins that move substrates across lipid membranes and have broad biological relevance based on tissue distribution and substrate ...specificity.21 ABC transporters are known etiological drivers of rare monogenic disorders, most of which lack disease-modifying therapies; they are also genetically or mechanistically associated with susceptibility to more common and complex diseases.CFTR (ABCC7) 2mutation causes cystic fibrosis, which is effectively treated with small molecule positive functional modulators that rescue CFTR dysfunction, offering proof of principle for the druggability of ABC transporters for the treatment of other diseases.The relevance of ABC transporters to human disease and their amenability to drug discovery and development highlights their potential for the development of first-in-class therapeutics.
Adenosine triphosphate (ATP)-binding cassette (ABC) transporters are a 48-member superfamily of membrane proteins that actively transport a variety of biological substrates across lipid membranes. Their functional diversity defines an expansive involvement in myriad aspects of human biology. At least 21 ABC transporters underlie rare monogenic disorders, with even more implicated in the predisposition to and symptomology of common and complex diseases. Such broad (patho)physiological relevance places this class of proteins at the intersection of disease causation and therapeutic potential, underlining them as promising targets for drug discovery, as exemplified by the transformative CFTR (ABCC7) modulator therapies for cystic fibrosis. This review will explore the growing relevance of ABC transporters to human disease and their potential as small-molecule drug targets.
To explore the optical and physiologic properties of normal and lesion-bearing breasts by using a combined optical and digital breast tomosynthesis (DBT) imaging system.
Institutional review board ...approval and patient informed consent were obtained for this HIPAA-compliant study. Combined optical and tomosynthesis imaging analysis was performed in 189 breasts from 125 subjects (mean age, 56 years ± 13 standard deviation), including 138 breasts with negative findings and 51 breasts with lesions. Three-dimensional (3D) maps of total hemoglobin concentration (Hb(T)), oxygen saturation (So(2)), and tissue reduced scattering coefficients were interpreted by using the coregistered DBT images. Paired and unpaired t tests were performed between various tissue types to identify significant differences.
The estimated average bulk Hb(T) from 138 normal breasts was 19.2 μmol/L. The corresponding mean So(2) was 0.73, within the range of values in the literature. A linear correlation (R = 0.57, P < .0001) was found between Hb(T) and the fibroglandular volume fraction derived from the 3D DBT scans. Optical reconstructions of normal breasts revealed structures corresponding to chest-wall muscle, fibroglandular, and adipose tissues in the Hb(T), So(2), and scattering images. In 26 malignant tumors of 0.6-2.5 cm in size, Hb(T) was significantly greater than that in the fibroglandular tissue of the same breast (P = .0062). Solid benign lesions (n = 17) and cysts (n = 8) had significantly lower Hb(T) contrast than did the malignant lesions (P = .025 and P = .0033, respectively).
The optical and DBT images were structurally consistent. The malignant tumors and benign lesions demonstrated different Hb(T) and scattering contrasts, which can potentially be exploited to reduce the false-positive rate of conventional mammography and unnecessary biopsies.
IMPORTANCE: Lebrikizumab (LEB), a high-affinity monoclonal antibody targeting interleukin (IL)-13, demonstrated efficacy and safety in patients with moderate-to-severe atopic dermatitis (AD) during ...16 weeks of monotherapy in a phase 2b trial, and two 52-week phase 3 trials. OBJECTIVE: To evaluate efficacy and safety of LEB combined with low- to mid-potency topical corticosteroids (TCS) in patients with moderate-to-severe AD. DESIGN, SETTING, AND PARTICIPANTS: The ADhere trial was a 16-week randomized, double-blinded, placebo (PBO)-controlled, multicenter, phase 3 clinical trial conducted from February 3, 2020, to September 16, 2021. The study was conducted at 54 outpatient sites across Germany, Poland, Canada, and the US and included adolescent (aged ≥12 to <18 years weighing ≥40 kg) and adult patients with moderate-to-severe AD. The treatment allocation ratio was 2:1 (LEB:PBO). INTERVENTIONS: Overall, 211 patients were randomized to subcutaneous LEB (loading dose of 500 mg at baseline and week 2, followed by 250 mg every 2 weeks Q2W thereafter) or PBO Q2W in combination with TCS for 16 weeks. MAIN OUTCOMES AND MEASURES: Efficacy analyses at week 16 included proportions of patients achieving Investigator’s Global Assessment score of 0 or 1 (IGA 0,1) with 2 or more points improvement from baseline, and 75% improvement in the Eczema Area and Severity Index (EASI-75). Key secondary end points included evaluation of itch, itch interference on sleep, and quality of life. Safety assessments included monitoring adverse events (AEs). RESULTS: The mean (SD) age of patients was 37.2 (19.3) years, 103 (48.8%) patients were women, 31 (14.7%) patients were Asian, and 28 (13.3%) patients were Black/African American. At week 16, IGA (0,1) was achieved by 145 (41.2%) patients in the LEB+TCS group vs 66 (22.1%) receiving PBO+TCS (P = .01); corresponding proportions of patients achieving EASI-75 were 69.5% vs 42.2% (P < .001). The LEB+TCS group showed statistically significant improvements in all key secondary end points. Most treatment-emergent adverse events (TEAEs) were nonserious, mild or moderate in severity, and did not lead to study discontinuation. The TEAEs frequently reported in the LEB+TCS group included conjunctivitis (7 4.8%), headache (7 4.8%), hypertension (4 2.8%), injection site reactions (4 2.8%), and herpes infection (5 3.4%) vs 1.5% or less patient-reported frequencies in the PBO+TCS group. Similar frequencies of patient-reported serious AEs following LEB+TCS (n = 2, 1.4%) and PBO+TCS (n = 1, 1.5%). CONCLUSIONS AND RELEVANCE: In this randomized phase 3 clinical trial, LEB+TCS was associated with improved outcomes in adolescents and adults with moderate-to-severe AD compared with TCS alone, and safety was consistent with previously reported AD trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04250337
Guidelines currently indicate the use of surgical aortic valve replacement (SAVR) to treat severe cases of aortic stenosis, particularly for low- to medium-risk patients. Although several studies ...have compared health outcomes of tissue and mechanical SAVR, this economic simulation model estimates the difference in long-term healthcare costs associated with tissue relative to mechanical SAVR.
The deterministic and Monte Carlo simulation models used literature-based epidemiologic and cost inputs to calculate annual expenditures related to SAVR for up to 25 years after initial surgery. A series of 3 cohort studies across different age groups provided the health outcome probabilities for tissue valve patients. Outcome probabilities for mechanical valve patients were based on relative risks reported in comparative meta-analyses or large cohort studies.
Relative to mechanical SAVR the expected net discounted savings for a patient receiving tissue SAVR at ages 45, 55, and 65 years were $12,266, $15,462, and $16,008, respectively (based on 2018 US dollars) over a 25-year horizon (95% confidence intervals exceed $0). For a 45-year-old tissue SAVR patient, the estimated per-patient cost difference (relative to mechanical SAVR) of reoperation over 25 years ($16,201) were offset by expected savings on anticoagulation monitoring ($26,257) over the same period. In a sensitivity analysis in which mortality risk was assumed equal, significant long-term savings associated with tissue SAVR still accrued in each of the 3 age cohorts.
Payers, providers, and the healthcare system may financially benefit from the use of tissue valves because significant savings were associated with the use of tissue valves relative to mechanical valves for SAVR.
Solar-powered electrochemical production of hydrogen through water electrolysis is an active and important research endeavor. However, technologies and roadmaps for implementation of this process do ...not exist. In this perspective paper, we describe potential pathways for solar-hydrogen technologies into the marketplace in the form of photoelectrochemical or photovoltaic-driven electrolysis devices and systems. We detail technical approaches for device and system architectures, economic drivers, societal perceptions, political impacts, technological challenges, and research opportunities. Implementation scenarios are broken down into short-term and long-term markets, and a specific technology roadmap is defined. In the short term, the only plausible economical option will be photovoltaic-driven electrolysis systems for niche applications. In the long term, electrochemical solar-hydrogen technologies could be deployed more broadly in energy markets but will require advances in the technology, significant cost reductions, and/or policy changes. Ultimately, a transition to a society that significantly relies on solar-hydrogen technologies will benefit from continued creativity and influence from the scientific community.
Several application fields can benefit from solar-hydrogen technologies
via
specific short-term and long-term pathways.
The clinical effectiveness of antagonizing the calcitonin gene‐related peptide (CGRP) receptor for relief of migraine pain has been clearly demonstrated, but the road to the development of these ...small molecule antagonists has been daunting. The key hurdle that needed to be overcome was the CGRP receptor itself. The vast majority of the current antagonists recognize similar epitopes on the calcitonin receptor‐like receptor (CLR) and receptor activity‐modifying protein 1 (RAMP1). RAMP1 is a relatively small, single, transmembrane‐spanning protein and along with the G‐protein‐coupled receptor CLR comprise a functional CGRP receptor. The tri‐helical extracellular domain of RAMP1 plays a key role in the high affinity binding of CGRP receptor antagonists and drives their species‐selective pharmacology. Over the years, a significant amount of mutagenesis data has been generated to identify specific amino acids or regions within CLR and RAMP1 that are critical to antagonist binding and has directed attention to the CLR/RAMP1 extracellular domain (ECD) complex. Recently, the crystal structure of the CGRP receptor ECD has been elucidated and not only reinforces the early mutagenesis data, but provides critical insight into the molecular mechanism of CGRP receptor antagonism. This review will highlight the drug design hurdles that must be overcome to meet the desired potency, selectivity and pharmacokinetic profile while retaining drug‐like properties. Although the development of these antagonists has proved challenging, blocking the CGRP receptor may one day represent a new way to manage migraine and offer hope to migraine sufferers.
LINKED ARTICLES This article is part of a themed section on Secretin Family (Class B) G Protein‐Coupled Receptors. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.166.issue‐1
Laser capture microdissection (LCM)-enabled region-specific tissue analyses are critical to better understand complex multicellular processes. However, current proteomics workflows entail several ...manual sample preparation steps and are challenged by the microscopic mass-limited samples generated by LCM, impacting measurement robustness, quantification and throughput. Here, we coupled LCM with a proteomics workflow that provides fully automated analysis of proteomes from microdissected tissues. Benchmarking against the current state-of-the-art in ultrasensitive global proteomics (FASP workflow), our approach demonstrated significant improvements in quantification (~2-fold lower variance) and throughput (>5 times faster). Using our approach we for the first time characterized, to a depth of >3,400 proteins, the ontogeny of protein changes during normal lung development in microdissected alveolar tissue containing only 4,000 cells. Our analysis revealed seven defined modules of coordinated transcription factor-signaling molecule expression patterns, suggesting a complex network of temporal regulatory control directs normal lung development with epigenetic regulation fine-tuning pre-natal developmental processes.
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