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1.
Nat Mater ; 23(7): 884-889, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38671164

RESUMEN

Advances in nuclear power reactors include the use of mixed oxide fuel, containing uranium and plutonium oxides. The high-temperature behaviour and structure of PuO2-x above 1,800 K remain largely unexplored, and these conditions must be considered for reactor design and planning for the mitigation of severe accidents. Here, we measure the atomic structure of PuO2-x through the melting transition up to 3,000 ± 50 K using X-ray scattering of aerodynamically levitated and laser-beam-heated samples, with O/Pu ranging from 1.57 to 1.76. Liquid structural models consistent with the X-ray data are developed using machine-learned interatomic potentials and density functional theory. Molten PuO1.76 contains some degree of covalent Pu-O bonding, signalled by the degeneracy of Pu 5f and O 2p orbitals. The liquid is isomorphous with molten CeO1.75, demonstrating the latter as a non-radioactive, non-toxic, structural surrogate when differences in the oxidation potentials of Pu and Ce are accounted for. These characterizations provide essential constraints for modelling pertinent to reactor safety design.

2.
Inorg Chem ; 62(45): 18724-18731, 2023 Nov 13.
Artículo en Inglés | MEDLINE | ID: mdl-37917811

RESUMEN

Uranium trichloride (UCl3) has received growing interest for its use in uranium-fueled molten salt reactors and in the pyrochemical processing of used fuel. In this paper, we report for the first time the experimentally determined Raman spectra of UCl3, at both ambient condition and in situ high temperatures up to 871 K. The frequencies of five of the Raman-active vibrational modes (vi) of UCl3 exhibit a negative temperature derivative ((∂νi/∂T)P) with increasing temperature. This red-shift behavior is likely due to the elongation of U-Cl bonds. The average isobaric mode Grüneisen parameter (γiP = 0.91 ± 0.02) of UCl3 was determined through use of the coefficient of thermal expansion published in Vogel et al. (2021) and the (∂νi/∂T)P values determined in this study. These results are in general agreement with those calculated here by density functional theory (DFT+U). Finally, a comparison of the ambient band positions of UCl3 to those of isostructural lanthanide (La-Eu) and actinide chlorides (Am-Cf) has been made.

3.
Dig Dis Sci ; 68(1): 65-76, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-35459973

RESUMEN

BACKGROUND: Prospectively and systematically collected long-term real-world clinical data on ustekinumab (anti-interleukin-12/23) are still scarce. AIMS: To assess the long-term effectiveness of ustekinumab in patients with active Crohn's disease (CD). METHODS: This is a prospective multicenter study of adult patients with CD initiating ustekinumab according to recommended doses at 20 Swedish hospitals. The primary outcome was clinical remission (Harvey-Bradshaw Index (HBI) ≤ 4 points) at weeks 52 and 104. Secondary outcomes included clinical response (≥ 3-point-decrease in HBI among patients with initial HBI ≥ 5 points), treatment retention, and biomarkers (C-reactive protein (CRP), hemoglobin, fecal-calprotectin) at weeks 52 and 104 compared to baseline. We also reported Health-related Quality of Life (HRQoL) measures. RESULTS: Of 114 included patients, 107 (94%) had previously failed ≥ 1 and 58 (51%) ≥ 2 anti-tumor necrosis factor agents. Forty (35%) had failed anti-integrin agents. Ustekinumab retention rates at weeks 52 and 104 were 70% (n = 80/114) and 61% (n = 69/114), respectively. Clinical response was seen in 36% (n = 25/69) and 29% (n = 20/69) of the patients, and remission was achieved in 32% (n = 31/96) and 29% (n = 28/96) at weeks 52 and 104, respectively. Median HBI and CRP levels decreased significantly at both timepoints as compared to baseline. Significant improvements were also observed in HRQoL. Adverse events were reported in 11% (n = 13/114) of the patients, including five cases of severe adverse events. No malignancies were observed. CONCLUSIONS: In this nationwide prospective real-world 104-week-follow-up study of adult patients with active CD, ustekinumab was associated with long-term clinical effectiveness and improvement in HRQoL measures when used in routine clinical care.


Asunto(s)
Enfermedad de Crohn , Ustekinumab , Adulto , Humanos , Ustekinumab/efectos adversos , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/patología , Estudios de Seguimiento , Estudios Prospectivos , Calidad de Vida , Inducción de Remisión , Interleucina-23 , Resultado del Tratamiento
4.
J Chem Phys ; 159(2)2023 Jul 14.
Artículo en Inglés | MEDLINE | ID: mdl-37428051

RESUMEN

Machine learning interatomic potentials have emerged as a powerful tool for bypassing the spatiotemporal limitations of ab initio simulations, but major challenges remain in their efficient parameterization. We present AL4GAP, an ensemble active learning software workflow for generating multicomposition Gaussian approximation potentials (GAP) for arbitrary molten salt mixtures. The workflow capabilities include: (1) setting up user-defined combinatorial chemical spaces of charge neutral mixtures of arbitrary molten mixtures spanning 11 cations (Li, Na, K, Rb, Cs, Mg, Ca, Sr, Ba and two heavy species, Nd, and Th) and 4 anions (F, Cl, Br, and I), (2) configurational sampling using low-cost empirical parameterizations, (3) active learning for down-selecting configurational samples for single point density functional theory calculations at the level of Strongly Constrained and Appropriately Normed (SCAN) exchange-correlation functional, and (4) Bayesian optimization for hyperparameter tuning of two-body and many-body GAP models. We apply the AL4GAP workflow to showcase high throughput generation of five independent GAP models for multicomposition binary-mixture melts, each of increasing complexity with respect to charge valency and electronic structure, namely: LiCl-KCl, NaCl-CaCl2, KCl-NdCl3, CaCl2-NdCl3, and KCl-ThCl4. Our results indicate that GAP models can accurately predict structure for diverse molten salt mixture with density functional theory (DFT)-SCAN accuracy, capturing the intermediate range ordering characteristic of the multivalent cationic melts.

5.
BMC Geriatr ; 23(1): 803, 2023 12 05.
Artículo en Inglés | MEDLINE | ID: mdl-38053055

RESUMEN

BACKGROUND: Worldwide, there is a large and growing group of older adults. Frailty is known as an important discriminatory factor for poor outcomes. The Clinical Frailty Scale (CFS) has become a frequently used frailty instrument in different clinical settings and health care sectors, and it has shown good predictive validity. The aims of this study were to describe and validate the translation and cultural adaptation of the CFS into Swedish (CFS-SWE), and to test the inter-rater reliability (IRR) for registered nurses using the CFS-SWE. METHODS: An observational study design was employed. The ISPOR principles were used for the translation, linguistic validation and cultural adaptation of the scale. To test the IRR, 12 participants were asked to rate 10 clinical case vignettes using the CFS-SWE. The IRR was assessed using intraclass correlation and Krippendorff's alpha agreement coefficient test. RESULTS: The Clinical Frailty Scale was translated and culturally adapted into Swedish and is presented in its final form. The IRR for all raters, measured by an intraclass correlation test, resulted in an absolute agreement value among the raters of 0.969 (95% CI: 0.929-0.991) and a consistency value of 0.979 (95% CI: 0.953-0.994), which indicates excellent reliability. Krippendorff's alpha agreement coefficient for all raters was 0.969 (95% CI: 0.917-0.988), indicating near-perfect agreement. The sensitivity of the reliability was examined by separately testing the IRR of the group of specialised registered nurses and non-specialised registered nurses respectively, with consistent and similar results. CONCLUSION: The Clinical Frailty Scale was translated, linguistically validated and culturally adapted into Swedish following a well-established standard technique. The IRR was excellent, judged by two established, separately used, reliability tests. The reliability test results did not differ between non-specialised and specialised registered nurses. However, the use of case vignettes might reduce the generalisability of the reliability findings to real-life settings. The CFS has the potential to be a common reference tool, especially when older adults are treated and rehabilitated in different care sectors.


Asunto(s)
Fragilidad , Humanos , Anciano , Fragilidad/diagnóstico , Suecia , Reproducibilidad de los Resultados , Comparación Transcultural
6.
Pain Med ; 23(12): 1928-1938, 2022 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-35652761

RESUMEN

BACKGROUND: Fibromyalgia syndrome (FMS) is a chronic widespread pain condition with mixed peripheral and central contributions. Patients display hypersensitivities to a spectrum of stimuli. Patients' blunt pressure pain thresholds are typically reduced, and sometimes (∼15%) gentle brushstroke induces allodynia. However, aftersensations after these stimuli have not, to our knowledge, been reported. METHODS: We examined the perception of blunt pressure and "pleasant touch" in FMS. Patients were first interviewed and completed standard psychometric questionnaires. We then measured their sensitivity to blunt pressure and perception of pleasant touch, including aftersensations; patients were followed up for 5 days to evaluate lingering pain from blunt pressure. RESULTS: We recruited 51 patients with FMS and 16 pain-free healthy controls (HCs) at a UK Pain Management Centre. Forty-four patients completed the aftersensation protocol. Most patients reported pain after the application of less mechanical pressure than the level of pressure at which HCs reported pain; median arm and leg thresholds for the patients with FMS were 167 kPa and 233 kPa, respectively. Eighty-four percent (31/37) of patients reported ongoing pain at the site of pressure application 1 day after testing, and 49% (18/37) still perceived pain at 5 days. Aftersensations after brushstroke were common in the FMS group, reported by 77% (34/44) of patients with FMS vs 25% (4/16) of HCs; 34% (15/44) of patients, but no HCs, perceived these aftersensations as uncomfortable. For patients with FMS who experienced aftersensations, brushstroke pleasantness ratings were reduced, and the skin was often an important site of pain. CONCLUSION: Pain after blunt pressure assessment typically lingers for several days. Aftersensations after brushstroke stimulation are a previously unreported FMS phenomenon. They are associated with tactile anhedonia and might identify a clinically distinct subgroup.


Asunto(s)
Dolor Crónico , Fibromialgia , Humanos , Fibromialgia/diagnóstico , Dimensión del Dolor/métodos , Umbral del Dolor/fisiología , Dolor Crónico/complicaciones , Hiperalgesia/complicaciones
7.
Pain Med ; 23(6): 1084-1094, 2022 05 30.
Artículo en Inglés | MEDLINE | ID: mdl-34850195

RESUMEN

BACKGROUND: Fibromyalgia syndrome (FMS) is the most common chronic widespread pain condition in rheumatology. Until recently, no clear pathophysiological mechanism for fibromyalgia had been established, resulting in management challenges. Recent research has indicated that serum immunoglobulin Gs (IgGs) may play a role in FMS. We undertook a research prioritisation exercise to identify the most pertinent research approaches that may lead to clinically implementable outputs. METHODS: Research priority setting was conducted in five phases: situation analysis; design; expert group consultation; interim recommendations; consultation and revision. A dialogue model was used, and an international multi-stakeholder expert group was invited. Clinical, patient, industry, funder, and scientific expertise was represented throughout. Recommendation-consensus was determined via a voluntary closed eSurvey. Reporting guideline for priority setting of health research were employed to support implementation and maximise impact. RESULTS: Arising from the expert group consultation (n = 29 participants), 39 interim recommendations were defined. A response rate of 81.5% was achieved in the consensus survey. Six recommendations were identified as high priority- and 15 as medium level priority. The recommendations range from aspects of fibromyalgia features that should be considered in future autoantibody research, to specific immunological investigations, suggestions for trial design in FMS, and therapeutic interventions that should be assessed in trials. CONCLUSIONS: By applying the principles of strategic priority setting we directed research towards that which is implementable, thereby expediating the benefit to the FMS patient population. These recommendations are intended for patients, international professionals and grant-giving bodies concerned with research into causes and management of patients with fibromyalgia syndrome.


Asunto(s)
Dolor Crónico , Fibromialgia , Autoanticuerpos , Fibromialgia/terapia , Humanos , Inmunoglobulina G , Encuestas y Cuestionarios
8.
Scand J Gastroenterol ; 56(6): 680-686, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33794731

RESUMEN

BACKGROUND: Prospectively and systematically collected real-world data on the effectiveness of ustekinumab (anti-interleukin-12/23) for treating Crohn's disease (CD) are still limited. AIM: To assess the short-term real-world effectiveness of ustekinumab in Swedish patients with active CD. METHODS: Prospective multicentre study of adult CD patients initiating ustekinumab according to recommended doses at 20 hospitals, between January 2017 and November 2018. Data were collected through an electronic case report form (eCRF) linked to the Swedish Inflammatory Bowel Disease Registry (SWIBREG). The primary outcomes were clinical response (≥3-point-decrease of Harvey-Bradshaw index (HBI)) and remission (HBI ≤4 points) at week 16. Secondary outcomes included C-reactive protein (CRP) and haemoglobin (Hb) at baseline compared to week 16. RESULTS: Of 114 included patients, 107 (94%) had failed ≥ 1 and 58 (51%) ≥ 2 biological agents (anti-tumour necrosis factor [aTNF] agents or vedolizumab). The 16-week ustekinumab retention rate was 105 (92%). Data on HBI at baseline were available for 96 patients. At week 16, response or remission was achieved in 38/96 (40%) patients (25/96 (26%) achieving clinical remission and 23/96 (24%) showing a clinical response). The median CRP concentration (N = 65) decreased from 6 to 4 mg/l (p = .006). No significant changes in Hb were observed. No incident malignancies or infections, requiring antibiotic treatment, were reported. CONCLUSIONS: In this nation-wide prospective real-world study of adult patients with CD, ustekinumab was associated with clinical effectiveness when administered according to clinical practice and seemed to represent a safe treatment option.


Asunto(s)
Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Adulto , Enfermedad de Crohn/tratamiento farmacológico , Estudios de Seguimiento , Humanos , Estudios Prospectivos , Inducción de Remisión , Resultado del Tratamiento , Ustekinumab/uso terapéutico
9.
J Neurosci ; 39(40): 7840-7852, 2019 10 02.
Artículo en Inglés | MEDLINE | ID: mdl-31451581

RESUMEN

Transient receptor potential melastatin 3 (TRPM3) is a nonselective cation channel that is inhibited by Gßγ subunits liberated following activation of Gαi/o protein-coupled receptors. Here, we demonstrate that TRPM3 channels are also inhibited by Gßγ released from Gαs and Gαq Activation of the Gs-coupled adenosine 2B receptor and the Gq-coupled muscarinic acetylcholine M1 receptor inhibited the activity of TRPM3 heterologously expressed in HEK293 cells. This inhibition was prevented when the Gßγ sink ßARK1-ct (C terminus of ß-adrenergic receptor kinase-1) was coexpressed with TRPM3. In neurons isolated from mouse dorsal root ganglion (DRG), native TRPM3 channels were inhibited by activating Gs-coupled prostaglandin-EP2 and Gq-coupled bradykinin B2 (BK2) receptors. The Gi/o inhibitor pertussis toxin and inhibitors of PKA and PKC had no effect on EP2- and BK2-mediated inhibition of TRPM3, demonstrating that the receptors did not act through Gαi/o or through the major protein kinases activated downstream of G-protein-coupled receptor (GPCR) activation. When DRG neurons were dialyzed with GRK2i, which sequesters free Gßγ protein, TRPM3 inhibition by EP2 and BK2 was significantly reduced. Intraplantar injections of EP2 or BK2 agonists inhibited both the nocifensive response evoked by TRPM3 agonists, and the heat hypersensitivity produced by Freund's Complete Adjuvant (FCA). Furthermore, FCA-induced heat hypersensitivity was completely reversed by the selective TRPM3 antagonist ononetin in WT mice and did not develop in Trpm3-/- mice. Our results demonstrate that TRPM3 is subject to promiscuous inhibition by Gßγ protein in heterologous expression systems, primary neurons and in vivo, and suggest a critical role for this ion channel in inflammatory heat hypersensitivity.SIGNIFICANCE STATEMENT The ion channel TRPM3 is widely expressed in the nervous system. Recent studies showed that Gαi/o-coupled GPCRs inhibit TRPM3 through a direct interaction between Gßγ subunits and TRPM3. Since Gßγ proteins can be liberated from other Gα subunits than Gαi/o, we examined whether activation of Gs- and Gq-coupled receptors also influence TRPM3 via Gßγ. Our results demonstrate that activation of Gs- and Gq-coupled GPCRs in recombinant cells and sensory neurons inhibits TRPM3 via Gßγ liberation. We also demonstrated that Gs- and Gq-coupled receptors inhibit TRPM3 in vivo, thereby reducing pain produced by activation of TRPM3, and inflammatory heat hypersensitivity. Our results identify Gßγ inhibition of TRPM3 as an effector mechanism shared by the major Gα subunits.


Asunto(s)
Subunidades beta de la Proteína de Unión al GTP/fisiología , Subunidades gamma de la Proteína de Unión al GTP/fisiología , Receptores Acoplados a Proteínas G/fisiología , Canales Catiónicos TRPM/fisiología , Animales , Conducta Animal , Femenino , Subunidades beta de la Proteína de Unión al GTP/antagonistas & inhibidores , Subunidades gamma de la Proteína de Unión al GTP/antagonistas & inhibidores , Ganglios Espinales/citología , Ganglios Espinales/fisiología , Células HEK293 , Humanos , Hiperalgesia/inducido químicamente , Hiperalgesia/fisiopatología , Hiperalgesia/psicología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/fisiología , Nociceptores/efectos de los fármacos , Toxina del Pertussis/farmacología , Receptor de Adenosina A2B/fisiología , Receptor Muscarínico M1/fisiología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Transducción de Señal/fisiología , Canales Catiónicos TRPM/antagonistas & inhibidores , Canales Catiónicos TRPM/genética
10.
Biochemistry ; 58(32): 3408-3412, 2019 08 13.
Artículo en Inglés | MEDLINE | ID: mdl-31339702

RESUMEN

As a key molecule in biology, adenosine triphosphate (ATP) has numerous crucial functions in, for instance, energetics, post-translational modifications, nucleotide biosynthesis, and cofactor metabolism. Here, we have discovered an intricate interplay between the enzyme adenylate kinase and its substrate ATP. The side chain of an arginine residue was found to be an efficient sensor of the aromatic moiety of ATP through the formation of a strong cation-π interaction. In addition to recognition, the interaction was found to have dual functionality. First, it nucleates the activating conformational transition of the ATP binding domain and also affects the specificity in the distant AMP binding domain. In light of the functional consequences resulting from the cation-π interaction, it is possible that the mode of ATP recognition may be a useful tool in enzyme design.


Asunto(s)
Adenosina Trifosfato/metabolismo , Adenilato Quinasa/metabolismo , Adenosina Trifosfato/química , Adenilato Quinasa/química , Modelos Moleculares , Unión Proteica , Conformación Proteica
11.
J Neurosci ; 36(45): 11435-11439, 2016 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-27911746

RESUMEN

Cold temperature detection involves the process of sensory transduction in cutaneous primary sensory nerve terminals, which converts thermal stimuli into depolarizations of the membrane. This transformation into electrical signals is followed by the subsequent propagation of action potentials in cold-sensitive afferent nerve fibers. A large array of ion channels shapes this process; however, the precise contribution of specific ion channel subtypes to cold perception and cold pain remains elusive. This review aims at giving an update on our current understanding of the role played by TRPs, leak K+ and voltage-gated Na+ and K+ channels in the transduction of cold by nociceptors and in cold-induced pain.


Asunto(s)
Frío , Canales Iónicos/metabolismo , Nociceptores/fisiología , Percepción del Dolor/fisiología , Dolor/fisiopatología , Sensación Térmica/fisiología , Animales , Medicina Basada en la Evidencia , Humanos , Activación del Canal Iónico/fisiología , Plasticidad Neuronal/fisiología
12.
Inorg Chem ; 56(1): 125-137, 2017 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-27983828

RESUMEN

We present a study of the diffusion of krypton in UO2 using atomic scale calculations combined with diffusion models adapted to the system studied. The migration barriers of the elementary mechanisms for interstitial or vacancy assisted migration are calculated in the DFT+U framework using the nudged elastic band method. The attempt frequencies are obtained from the phonon modes of the defect at the initial and saddle points using empirical potential methods. The diffusion coefficients of Kr in UO2 are then calculated by combining this data with diffusion models accounting for the concentration of vacancies and the interaction of vacancies with Kr atoms. We determined the preferred mechanism for Kr migration and the corresponding diffusion coefficient as a function of the oxygen chemical potential µO or nonstoichiometry. For very hypostoichiometric (or U-rich) conditions, the most favorable mechanism is interstitial migration. For hypostoichiometric UO2, migration is assisted by the bound Schottky defect and the charged uranium vacancy, VU4-. Around stoichiometry, migration assisted by the charged uranium-oxygen divacancy (VUO2-) and VU4- is the favored mechanism. Finally, for hyperstoichiometric or O-rich conditions, the migration assisted by two VU4- dominates. Kr migration is enhanced at higher µO, and in this regime, the activation energy will be between 4.09 and 0.73 eV depending on nonstoichiometry. The experimental values available are in the latter interval. Since it is very probable that these values were obtained for at least slightly hyperstoichiometric samples, our activation energies are consistent with the experimental data, even if further experiments with precisely controlled stoichiometry are needed to confirm these results. The mechanisms and trends with nonstoichiometry established for Kr are similar to those found in previous studies of Xe.

13.
Respirology ; 22(3): 460-465, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-27859946

RESUMEN

BACKGROUND AND OBJECTIVE: Understanding the associations between childhood asthma and growth in early adolescence by accounting for the heterogeneity of growth during puberty has been largely unexplored. The objective was to identify sex-specific classes of growth trajectories during early adolescence, using a method which takes the heterogeneity of growth into account and to evaluate the association between childhood asthma and different classes of growth trajectories in adolescence. METHODS: Our longitudinal study included participants with a family history of asthma born during 1997-1999 in Sydney, Australia. Hence, all participants were at high risk for asthma. Asthma status was ascertained at 8 years of age using data from questionnaires and lung function tests. Growth trajectories between 11 and 14 years of age were classified using a latent basis growth mixture model. Multinomial regression analyses were used to evaluate the association between asthma and the categorized classes of growth trajectories. RESULTS: In total, 316 participants (51.6% boys), representing 51.3% of the entire cohort, were included. Sex-specific classes of growth trajectories were defined. Among boys, asthma was not associated with the classes of growth trajectories. Girls with asthma were more likely than girls without asthma to belong to a class with later growth (OR: 3.79, 95% CI: 1.33, 10.84). Excluding participants using inhaled corticosteroids or adjusting for confounders did not significantly change the results for either sex. CONCLUSION: We identified sex-specific heterogeneous classes of growth using growth mixture modelling. Associations between childhood asthma and different classes of growth trajectories were found for girls only.


Asunto(s)
Asma/fisiopatología , Desarrollo Infantil , Adolescente , Asma/tratamiento farmacológico , Australia , Estatura , Niño , Femenino , Humanos , Estudios Longitudinales , Masculino , Modelos Biológicos , Pubertad , Pruebas de Función Respiratoria , Factores Sexuales , Encuestas y Cuestionarios
14.
J Biol Chem ; 290(24): 15185-96, 2015 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-25903127

RESUMEN

Streptozotocin (STZ)-induced diabetes is the most commonly used animal model of diabetes. Here, we have demonstrated that intraplantar injections of low dose STZ evoked acute polymodal hypersensitivities in mice. These hypersensitivities were inhibited by a TRPA1 antagonist and were absent in TRPA1-null mice. In wild type mice, systemic STZ treatment (180 mg/kg) evoked a loss of cold and mechanical sensitivity within an hour of injection, which lasted for at least 10 days. In contrast, Trpa1(-/-) mice developed mechanical, cold, and heat hypersensitivity 24 h after STZ. The TRPA1-dependent sensory loss produced by STZ occurs before the onset of diabetes and may thus not be readily distinguished from the similar sensory abnormalities produced by the ensuing diabetic neuropathy. In vitro, STZ activated TRPA1 in isolated sensory neurons, TRPA1 cell lines, and membrane patches. Mass spectrometry studies revealed that STZ oxidizes TRPA1 cysteines to disulfides and sulfenic acids. Furthermore, incubation of tyrosine with STZ resulted in formation of dityrosine, suggesting formation of peroxynitrite. Functional analysis of TRPA1 mutants showed that cysteine residues that were oxidized by STZ were important for TRPA1 responsiveness to STZ. Our results have identified oxidation of TRPA1 cysteine residues, most likely by peroxynitrite, as a novel mechanism of action of STZ. Direct stimulation of TRPA1 complicates the interpretation of results from STZ models of diabetic sensory neuropathy and strongly argues that more refined models of diabetic neuropathy should replace the use of STZ.


Asunto(s)
Ácido Peroxinitroso/metabolismo , Estreptozocina/farmacología , Canales de Potencial de Receptor Transitorio/efectos de los fármacos , Analgésicos/farmacología , Animales , Espectrometría de Masas , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Oxidación-Reducción , Canal Catiónico TRPA1 , Canales de Potencial de Receptor Transitorio/química , Canales de Potencial de Receptor Transitorio/genética
15.
Anal Chem ; 88(8): 4169-73, 2016 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-27008406

RESUMEN

A systematic X-ray absorption study at actinide N6,7 (4f → 6d transitions) edges was performed for light-actinide oxides including data obtained for the first time for NpO2, PuO2, and UO3. The measurements were supported by ab initio calculations based on local-density-approximation with added 5f-5f Coulomb interaction (LDA+U). Improved energy resolution compared to common experiments at actinide L(2,3) (2p → 6d transitions) edges allowed us to resolve the major structures of the unoccupied 6d density of states (DOS) and estimate the crystal-field splittings in the 6d shell directly from the spectra of light-actinide dioxides. The measurements demonstrated an enhanced sensitivity of the N(6,7) spectral shape to changes in the compound crystal structure. For nonstoichiometric NpO(2-x), the filling of the entire band gap with Np 6d states was observed thus supporting a phase coexistence of Np metal and stoichiometric NpO2 which is in agreement with the tentative Np-O phase diagram.

17.
Handb Exp Pharmacol ; 222: 207-45, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24756708

RESUMEN

TRPV1 is a well-characterised channel expressed by a subset of peripheral sensory neurons involved in pain sensation and also at a number of other neuronal and non-neuronal sites in the mammalian body. Functionally, TRPV1 acts as a sensor for noxious heat (greater than ~42 °C). It can also be activated by some endogenous lipid-derived molecules, acidic solutions (pH < 6.5) and some pungent chemicals and food ingredients such as capsaicin, as well as by toxins such as resiniferatoxin and vanillotoxins. Structurally, TRPV1 subunits have six transmembrane (TM) domains with intracellular N- (containing 6 ankyrin-like repeats) and C-termini and a pore region between TM5 and TM6 containing sites that are important for channel activation and ion selectivity. The N- and C- termini have residues and regions that are sites for phosphorylation/dephosphorylation and PI(4,5)P2 binding, which regulate TRPV1 sensitivity and membrane insertion. The channel has several interacting proteins, some of which (e.g. AKAP79/150) are important for TRPV1 phosphorylation. Four TRPV1 subunits form a non-selective, outwardly rectifying ion channel permeable to monovalent and divalent cations with a single-channel conductance of 50-100 pS. TRPV1 channel kinetics reveal multiple open and closed states, and several models for channel activation by voltage, ligand binding and temperature have been proposed. Studies with TRPV1 agonists and antagonists and Trpv1 (-/-) mice have suggested a role for TRPV1 in pain, thermoregulation and osmoregulation, as well as in cough and overactive bladder. TRPV1 antagonists have advanced to clinical trials where findings of drug-induced hyperthermia and loss of heat sensitivity have raised questions about the viability of this therapeutic approach.


Asunto(s)
Canales Catiónicos TRPV/metabolismo , Animales , Regulación de la Expresión Génica , Genotipo , Humanos , Activación del Canal Iónico , Potenciales de la Membrana , Ratones , Ratones Noqueados , Fenotipo , Fosfatidilinositoles/metabolismo , Fosforilación , Conformación Proteica , Procesamiento Proteico-Postraduccional , Transporte de Proteínas , Transducción de Señal , Relación Estructura-Actividad , Canales Catiónicos TRPV/química , Canales Catiónicos TRPV/deficiencia , Canales Catiónicos TRPV/genética
18.
Int J Health Serv ; 44(1): 169-84, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24684090

RESUMEN

The objective of this article was to investigate the existence of horizontal inequality in access to care for six categories of elective surgery in a publicly funded system, when care is rationed through waiting lists. Administrative waiting time data on all elective surgeries (n = 4,634) performed in Ostergötland, Sweden, in 2007 were linked to national registers containing variables on socioeconomic indicators. Using multiple regression, we tested five hypotheses reflecting that more resourceful groups receive priority when rationing by waiting lists. Low disposable household income predicted longer waiting times for orthopedic surgery (27%, p < 0.01) and general surgery (34%, p < 0.05). However, no significant differences on the basis of ethnicity and gender were detected. A particularly noteworthy finding was that disposable household income appeared to be an increasingly influential factor when the waiting times were longer. Our findings reveal horizontal inequalities in access to elective surgeries, but only to a limited extent. Whether this is good or bad depends on one's moral inclination. From a policymaker's perspective, it is nevertheless important to recognize that horizontal inequalities arise even though care is not rationed through ability to pay.


Asunto(s)
Accesibilidad a los Servicios de Salud , Disparidades en Atención de Salud , Listas de Espera , Adolescente , Adulto , Anciano , Procedimientos Quirúrgicos Electivos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sistema de Registros , Análisis de Regresión , Estudios Retrospectivos , Medicina Estatal , Suecia , Adulto Joven
19.
Sci Rep ; 14(1): 16116, 2024 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-38997410

RESUMEN

The study of rapid and stochastic events that involve multiple species, such as chemical reactions and plasma dynamics, requires means to capture multispectral information in two dimensions at both high temporal- and spatial resolution. Commercially available cameras that provide high temporal resolution are based on either signal intensification or rapid data acquisition. Intensified cameras provide extremely short acquisition times using intensification by means of micro channel plates, but the conversion between electrons and photons makes these cameras inherently monochrome. In contrast, high-speed cameras can achieve color-sensitivity through integrated Bayer filters but suffer from a reduced light collection efficiency and a fixed spectral composition. In this article we present a non-integrated optical arrangement for instantaneous multispectral imaging based on FRAME image multiplexing. By spectrally separating the signal using lossless dichroic mirrors, a 16-fold increase in light-collection efficiency is gained (compared to past solutions), resulting in an equivalent increase in temporal resolution. This improvement provides new avenues for multispectral imaging of rapid events. We demonstrate the system's versatility and suitability for studies of such processes by applying it for (i) temperature mapping using a high-resolution CCD camera, (ii) high-speed videography up to 10 kHz at four spectral channels and (iii) dual-species visualization in a plasma discharge using an intensified sCMOS camera.

20.
Med Decis Making ; : 272989X241258195, 2024 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-38912645

RESUMEN

BACKGROUND: The use of policies in medical treatment reimbursement decisions, in which only future patients are affected, prompts a moral dilemma: is there an ethical difference between withdrawing and withholding treatment? DESIGN: Through a preregistered behavioral experiment involving 1,067 participants, we tested variations in public attitudes concerning withdrawing and withholding treatments at both the bedside and policy levels. RESULTS: In line with our first hypothesis, participants were more supportive of rationing decisions presented as withholding treatments compared with withdrawing treatments. Contrary to our second prestated hypothesis, participants were more supportive of decisions to withdraw treatment made at the bedside level compared with similar decisions made at the policy level. IMPLICATIONS: Our findings provide behavioral insights that help explain the common use of policies affecting only future patients in medical reimbursement decisions, despite normative concerns of such policies. In addition, our results may have implications for communication strategies when making decisions regarding treatment reimbursement. HIGHLIGHTS: We explore public' attitudes toward withdrawing and withholding treatments and how the decision level (bedside or policy level) matters.People were more supportive of withholding medical treatment than of withdrawing equivalent treatment.People were more supportive of treatment withdrawal made at the bedside than at the policy level.Our findings help clarify why common-use policies, which impact only future patients in medical reimbursement decision, are implemented despite the normative concerns associted with thesepolicies.

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