On the action of the anti-absence drug ethosuximide in the rat and cat thalamus

The action of ethosuximide (ETX) on Na+, K+, and Ca2+ currents and on tonic and burst-firing patterns was investigated in rat and cat thalamic neurons in vitro by using patch and sharp microelectrode recordings. In thalamocortical (TC) neurons of the rat dorsal lateral geniculate nucleus (LGN), ETX (0.75-1 mM) decreased the noninactivating Na+ current, INaP, by 60% but had no effect on the transient Na+ current. In TC neurons of the rat and cat LGN, the whole-cell transient outward current was not affected by ETX (up to 1 mM), but the sustained outward current was decreased by 39% at 20 mV in the presence of ETX (0.25-0.5 mM): this reduction was not observed in a low Ca2+ (0.5 mM) and high Mg2+ (8 mM) medium or in the presence of Ni2+ (1 mM) and Cd2+ (100 µm). In addition, ETX (up to 1 mM) had no effect on the low-threshold Ca2+ current, I T, of TC neurons of the rat ventrobasal (VB) thalamus and LGN and in neurons of the rat nucleus reticularis thalami nor on the high-threshold Ca2+ current in TC neurons of the rat LGN. Sharp microelectrode recordings in TC neurons of the rat and cat LGN and VB showed that ETX did not change the resting membrane potential but increased the apparent input resistance at potentials greater than -60 mV, resulting in an increase in tonic firing. In contrast, ETX decreased the number of action potentials in the burst evoked by a low-threshold Ca2+ potential. The frequency of the remaining action potentials in a burst also was decreased, whereas the latency of the first action potential was increased. Similar effects were observed on the burst firing evoked during intrinsic δ oscillations. These results indicate an action of ETX on / NaP and on the Ca2+-activated K+ current, which explains the decrease in burst firing and the increase in tonic firing, and, together with the lack of action on low- and high-threshold Ca2+ currents, the results cast doubts on the hypothesis that a reduction of / τ in thalamic neurons underlies the therapeutic action of this anti-absence medicine

Compressibility of ferropericlase at high-temperature: evidence for the iron spin crossover in seismic tomography

The iron spin crossover in ferropericlase, the second most abundant mineral in Earth's lower mantle, causes changes in a range of physical properties, including seismic wave velocities. Understanding the effect of temperature on the spin crossover is essential to detect its signature in seismic observations and constrain its occurrence in the mantle. Here, we report the first experimental results on the spin crossover-induced bulk modulus softening at high temperatures, derived directly from time-resolved x-ray diffraction measurements during continuous compression of (Mg0.8Fe0.2)O in a resistive-heated dynamic diamond-anvil cell. We present new theoretical calculations of the spin crossover at mantle temperatures benchmarked by the experiments. Based on our results, we create synthetic seismic tomography models to investigate the signature of the spin crossover in global seismic tomography. A tomographic filter is applied to allow for meaningful comparisons between the synthetic models and data-based seismic tomography models, like SP12RTS. A negative anomaly in the correlation between Vs variations and Vc variations (S-C correlation) is found to be the most suitable measure to detect the presence of the spin crossover in tomographic models. When including the effects of the spin crossover, the misfit between the synthetic model and SP12RTS is reduced by 63%, providing strong evidence for the presence of the spin crossover, and hence ferropericlase, in the lower mantle. Future improvement of seismic resolution may facilitate a detailed mapping of spin state using the S-C correlation, providing constraints on mantle temperatures by taking advantage of the temperature sensitivity of the spin crossover

Darkness’s Descent on the American Anthropological Association: A Cautionary Tale

In September 2000, the self-styled “anthropological journalist” Patrick Tierney began to make public his work claiming that the Yanomamö people of South America had been actively—indeed brutally—harmed by the sociobiological anthropologist Napoleon Chagnon and the geneticist-physician James Neel. Following a florid summary of Tierney’s claims by the anthropologists Terence Turner and Leslie Sponsel, the American Anthropological Association (AAA) saw fit to take Tierney’s claims seriously by conducting a major investigation into the matter. This paper focuses on the AAA’s problematic actions in this case but also provides previously unpublished information on Tierney’s falsehoods. The work presented is based on a year of research by a historian of medicine and science. The author intends the work to function as a cautionary tale to scholarly associations, which have the challenging duty of protecting scholarship and scholars from baseless and sensationalistic charges in the era of the Internet and twenty-four-hour news cycles

Evaluation of the diagnostic accuracy of two point-of-care tests for COVID-19 when used in symptomatic patients in community settings in the UK primary care COVID diagnostic accuracy platform trial (RAPTOR-C19)

Background and objective Point-of-care lateral flow device antigen testing has been used extensively to identify individuals with active SARS-CoV-2 infection in the community. This study aimed to evaluate the diagnostic accuracy of two point-of-care tests (POCTs) for SARS-CoV-2 in routine community care. Methods Adults and children with symptoms consistent with suspected current COVID-19 infection were prospectively recruited from 19 UK general practices and two COVID-19 testing centres between October 2020 and October 2021. Participants were tested by trained healthcare workers using at least one of two index POCTs (Roche-branded SD Biosensor Standard™ Q SARS-CoV-2 Rapid Antigen Test and/or BD Veritor™ System for Rapid Detection of SARS-CoV-2). The reference standard was laboratory triplex reverse transcription quantitative PCR (RT-PCR) using a combined nasal/oropharyngeal swab. Diagnostic accuracy parameters were estimated, with 95% confidence intervals (CIs), overall, in relation to RT-PCR cycle threshold and in pre-specified subgroups. Results Of 663 participants included in the primary analysis, 39.2% (260/663, 95% CI 35.5% to 43.0%) had a positive RT-PCR result. The SD Biosensor POCT had sensitivity 84.0% (178/212, 78.3% to 88.6%) and specificity 98.5% (328/333, 96.5% to 99.5%), and the BD Veritor POCT had sensitivity 76.5% (127/166, 69.3% to 82.7%) and specificity 98.8% (249/252, 96.6% to 99.8%) compared with RT-PCR. Sensitivity of both devices dropped substantially at cycle thresholds ≥30 and in participants more than 7 days after onset of symptoms. Conclusions Both POCTs assessed exceed the Medicines and Healthcare products Regulatory Agency target product profile’s minimum acceptable specificity of 95%. Confidence intervals for both tests include the minimum acceptable sensitivity of 80%. In symptomatic patients, negative results on these two POCTs do not preclude the possibility of infection. Tests should not be expected to reliably detect disease more than a week after symptom onset, when viral load may be reduced. Registration ISRCTN142269

"<i>I've made this my lifestyle now</i>":a prospective qualitative study of motivation for lifestyle change among people with newly diagnosed type two diabetes mellitus

Abstract Background Diagnosis with Type 2 Diabetes is an opportunity for individuals to change their physical activity and dietary behaviours. Diabetes treatment guidelines recommend theory-based, patient-centred care and advocate the provision of support for patient motivation but the motivational experiences of people newly diagnosed with diabetes have not been well studied. Framed in self-determination theory, this study aimed to qualitatively explore how this patient group articulate and experience different types of motivation when attempting lifestyle change. Methods A secondary analysis of semi-structured interview data collected with 30 (n female = 18, n male = 12) adults who had been newly diagnosed with type two diabetes and were participants in the Early ACTID trial was undertaken. Deductive directed content analysis was performed using NVivo V10 and researcher triangulation to identify and describe patient experiences and narratives that reflected the motivation types outlined in self-determination theory and if/how these changed over time. Results The findings revealed the diversity in motivation quality both between and within individuals over time and that patients with newly-diagnosed diabetes have multifaceted often competing motivations for lifestyle behaviour change. Applying self-determination theory, we identified that many participants reported relatively dominant controlled motivation to comply with lifestyle recommendations, avoid their non-compliance being “found out” or supress guilt following lapses in behaviour change attempts. Such narratives were accompanied by experiences of frustrating slow behaviour change progress. More autonomous motivation was expressed as something often achieved over time and reflected goals to improve health, quality of life or family time. Motivational internalisation was evident and some participants had integrated their behaviour change to a new way of life which they found resilient to common barriers. Conclusions Motivation for lifestyle change following diagnosis with type two diabetes is complex and can be relatively low in self-determination. To achieve the patient empowerment aspirations of current national health care plans, intervention developers, and clinicians would do well to consider the quality not just quantity of their patients’ motivation. Trial registration ISRCTN ISRCTN92162869. Retrospectively registere

Regulation of Respiration and Apoptosis by Cytochrome c Threonine 58 Phosphorylation

Cytochrome c (cytc) is a multifunctional protein, acting as an electron carrier in the electron transport chain (ETC), where it shuttles electrons from bc1 complex to cytochrome c oxidase (COX), and as a trigger of type II apoptosis when released from the mitochondria. We previously showed that cytc is regulated in a highly tissue-specific manner: Cytc isolated from heart, liver, and kidney is phosphorylated on Y97, Y48, and T28, respectively. Here, we have analyzed the effect of a new Cytc phosphorylation site, threonine 58, which we mapped in rat kidney Cytc by mass spectrometry. We generated and overexpressed wild-type, phosphomimetic T58E, and two controls, T58A and T58I cytc; the latter replacement is found in human and testis-specific Cytc. In vitro, COX activity, caspase-3 activity, and heme degradation in the presence of H2o2 were decreased with phosphomimetic Cytc compared to wild-type. Cytc-knockout cells expressing T58E or T58I Cytc showed a reduction in intact cell respiration, mitochondrial membrane potential (∆Ψm), ROS production, and apoptotic activity compared to wild-type. We propose that, under physiological conditions, Cytc is phosphorylated, which controls mitochondrial respiration and apoptosis. Under conditions of stress Cytc phosphorylations are lost leading to maximal respiration rates, ∆Ψm hyperpolarization, ROS production, and apoptosis

Sex- differences in alpha-1 antitrypsin deficiency:Data from the EARCO Registry

Background: Sex and gender influence many aspects of chronic obstructive pulmonary disease (COPD). Limited data are available on this topic in alpha-1 antitrypsin deficiency (AATD). We therefore aimed to investigate sex issues in the EARCO registry, a prospective, international, observational cohort study.Methods: Baseline data from PiZZ individuals, enrolled in the registry with complete data on sex and smoking history were analysed by group comparisons and binary logistic regression analyses.Results: 1283 patients with AATD, 49.3% women were analysed. Females reported less tobacco consumption (16.8 ± 12.2 vs. 19.6 ± 14.5 PY, p = 0.006), occupational exposures towards gases, dusts or asbestos (p &lt; 0.005 each) and consumed less alcohol (5.5 ± 7.6 vs. 8.4 ± 10.3 u/week, p &lt; 0.001). Females reported COPD (41% vs. 57%, p &lt; 0.001) and liver disease (11% vs. 20%, p &lt; 0.001) less often. However, they had a higher prevalence of bronchiectasis (24% vs. 13%, p &lt; 0.001). Despite better lung function (FEV1%pred. 73.6 ± 29.9 vs. 62.7 ± 29.5, p &lt; 0.001) females reported a similar symptom burden (CAT 13.4 ± 9.5 vs. 12.5 ± 8.9, p = ns) and exacerbation frequency (at least one in the previous year 30% vs. 26%, p = ns) compared to males. In multivariate analyses, female sex was an independent risk factor for exacerbations in the previous year OR 1.6 p = 0.001 in addition to smoking history, COPD, asthma and bronchiectasis and was also identified as risk factors for symptom burden (CAT ≥ 10) OR 1.4 p = 0.014 besides age, BMI, COPD and smoking history.Conclusion: Men had higher rates of COPD and liver disease, women were more likely to have bronchiectasis. Women's higher symptom burden and exacerbation frequency suggest they may need tailored treatment approaches

Anthropogenic, direct pressures on coastal wetlands

Coastal wetlands, such as saltmarshes and mangroves that fringe transitional waters, deliver important ecosystem services that support human development. Coastal wetlands are complex social-ecological systems that occur at all latitudes, from polar regions to the tropics. This overview covers wetlands in five continents. The wetlands are of varying size, catchment size, human population and stages of economic development. Economic sectors and activities in and around the coastal wetlands and their catchments exert multiple, direct pressures.Chinese Academy of Sciences (CAS-YIC) scholarship and SKLECECNU project 111 scholarship<, Natural Resources Canada contribution no. 20200070; Fundação para a Ciência e a Tecnologia (FCT) Scientific Employment Stimulus Programme (CEECIND/01635/2017). and (CEECIND/00095/2017), (UID/MAR/00350/2019CIMA) and (UID/MAR/04292/2019)info:eu-repo/semantics/publishedVersio

Phenotypic screen for oxygen consumption rate identifies an anti-cancer naphthoquinone that induces mitochondrial oxidative stress.

A hallmark of cancer cells is their ability to reprogram nutrient metabolism. Thus, disruption to this phenotype is a potential avenue for anti-cancer therapy. Herein we used a phenotypic chemical library screening approach to identify molecules that disrupted nutrient metabolism (by increasing cellular oxygen consumption rate) and were toxic to cancer cells. From this screen we discovered a 1,4-Naphthoquinone (referred to as BH10) that is toxic to a broad range of cancer cell types. BH10 has improved cancer-selective toxicity compared to doxorubicin, 17-AAG, vitamin K3, and other known anti-cancer quinones. BH10 increases glucose oxidation via both mitochondrial and pentose phosphate pathways, decreases glycolysis, lowers GSH:GSSG and NAPDH/NAPD+ ratios exclusively in cancer cells, and induces necrosis. BH10 targets mitochondrial redox defence as evidenced by increased mitochondrial peroxiredoxin 3 oxidation and decreased mitochondrial aconitase activity, without changes in markers of cytosolic or nuclear damage. Over-expression of mitochondria-targeted catalase protects cells from BH10-mediated toxicity, while the thioredoxin reductase inhibitor auranofin synergistically enhances BH10-induced peroxiredoxin 3 oxidation and cytotoxicity. Overall, BH10 represents a 1,4-Naphthoquinone with an improved cancer-selective cytotoxicity profile via its mitochondrial specificity