The timing of proton migration in membrane-reconstituted cytochrome c oxidase

In mitochondria and aerobic bacteria energy conservation involves electron transfer through a number of membrane-bound protein complexes to O2. The reduction of O2, accompanied by the uptake of substrate protons to form H2O, is catalyzed by cytochrome c oxidase (CcO). This reaction is coupled to proton translocation (pumping) across the membrane such that each electron transfer to the catalytic site is linked to the uptake of two protons from one side and the release of one proton to the other side of the membrane. To address the mechanism of vectorial proton translocation, in this study we have investigated the solvent deuterium isotope effect of proton-transfer rates in CcO oriented in small unilamellar vesicles. Although in H2O the uptake and release reactions occur with the same rates, in D2O the substrate and pumped protons are taken up first (tau(D) congruent with 200 micros, "peroxy" to "ferryl" transition) followed by a significantly slower proton release to the other side of the membrane (tau(D) congruent with 1 ms). Thus, the results define the order and timing of the proton transfers during a pumping cycle. Furthermore, the results indicate that during CcO turnover internal electron transfer to the catalytic site is controlled by the release of the pumped proton, which suggests a mechanism by which CcO orchestrates a tight coupling between electron transfer and proton translocation.     

Smell disorders in COVID-19 patients: role of olfactory training: A protocol for systematic review and meta-analysis

Background:As the coronavirus disease 2019 (COVID-19) spread around the world, a surge of evidence suggests that smell disorders are common symptoms in COVID-19 infection. This dysfunction may cause loss of appetite, malnutrition, poisoning, and depression. Obviously, the impairment has a strong impact on the quality of life. Therefore, there is an urgent need to identify effective treatments. Various therapies have been studied to treat smell disorders after infection, and olfactory training (OT) is considered a promising treatment option. Assessing the effectiveness and safety of olfactory training for COVID-19 patients with smell disorders is the main purpose of this systematic review protocol.Methods:PubMed, EMBASE, MEDLINE, the Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature Database, Wanfang Database, ClinicalTrials.gov trials registry, and Chinese Clinical Trial Registry will be searched from January 2019 to January 2021. A combination of subject words and free text words will be applied in the searches. The language is limited to Chinese and English. The complete process will include study selection, data extraction, risk of bias assessment, and meta-analyses. Endnote X9.3 will be used to manage data screening. The statistical analysis will be completed by Review Manager V.5.3 (Cochrane Collaboration) or Stata V.16.0 software.Results:This proposed study will assess the effectiveness and safety of OT for COVID-19 patients with smell disorders.Conclusion:The conclusion of this study will provide evidence to prove the effectiveness and safety of olfactory training for COVID-19 patients with smell disorders.Ethics and dissemination:This protocol will not evaluate individual patient information or infringe patient rights and therefore does not require ethical approval.Registration:PEROSPERO CRD42020218009.     

m6A regulators are associated with osteosarcoma metastasis and have prognostic significance: A study based on public databases

Background:Osteosarcoma represents the most common malignant bone tumor with high metastatic potential and inferior prognosis. RNA methylation (N6-methyladenosine [m6A]) is a prevalent RNA modification that epigenetically influences numerous biological processes including tumorigenesis. This study aims to determine that m6A regulators are significant biomarkers for osteosarcoma, and establish a prognostic model to predict the survival of patients.Methods:In this study, we comprehensively analyzed the underlying associations between m6A regulators’ mRNA expressions and metastasis as well as prognosis of osteosarcoma patients in the Cancer Genome Atlas. Multivariate Cox-regression analysis was used to screen regulators that were significantly associated with overall survival of osteosarcoma patients. Least absolute shrinkage and selection operator (LASSO) Cox-regression analysis was used for constructing m6A regulator-based osteosarcoma prognostic signature.Results:Some of the regulators exhibited aberrant mRNA levels between osteosarcoma samples with and without metastasis. Multivariate Cox-regression analysis identified several regulators with potential prognostic significance. A risk score formula consisted of methyltransferase-like 3, YTH domains of Homo sapiens, and fat mass and obesity-associated protein was obtained through which patients could be prognostically stratified independently of potential confounding factors. The signature was also significantly associated with the metastatic potential of osteosarcoma. All the analyses could be well reproduced in another independent osteosarcoma cohort from the Gene Expression Omnibus.Conclusions:In conclusion, this study first revealed potential roles of m6A regulators in osteosarcoma metastasis and prognosis, which should be helpful for its clinical decision-making.     

Melatonin antagonizes the intrinsic pathway of apoptosis via mitochondrial targeting of Bcl-2

Abstract:  We have recently shown that melatonin antagonizes damage-induced apoptosis by interaction with the MT-1/MT-2 plasma membrane receptors. Here, we show that melatonin interferes with the intrinsic pathway of apoptosis at the mitochondrial level. In response to an apoptogenic stimulus, melatonin allows mitochondrial translocation of the pro-apoptotic protein Bax, but it impairs its activation/dimerization The downstream apoptotic events, i.e. cytochrome c release, caspase 9 and 3 activation and nuclear vesiculation are equally impaired, indicating that melatonin interferes with Bax activation within mitochondria. Interestingly, we found that melatonin induces a strong re-localization of Bcl-2, the main Bax antagonist to mitochondria, suggesting that Bax activation may in fact be antagonized by Bcl-2 at the mitochondrial level. Indeed, we inhibit the melatonin anti-apoptotic effect (i) by silencing Bcl-2 with small interfering RNAs, or with small-molecular inhibitors targeted at the BH3 binding pocket in Bcl-2 (i.e. the one interacting with Bax); and (ii) by inhibiting melatonin-induced Bcl-2 mitochondrial re-localization with the MT1/MT2 receptor antagonist luzindole. This evidence provides a mechanism that may explain how melatonin through interaction with the MT1/MT2 receptors, elicits a pathway that interferes with the Bcl-2 family, thus modulating the cell life/death balance.     

Suprasellar granular cell tumor of the neurohypophysis: surgical outcome of a very rare tumor

Purpose

Granular cell tumors of the neurohypophysis are rare, solitary lesions, mostly presenting in the adult age. They rarely grow to a sufficient size to cause mass effect related symptoms and they may be found in most cases incidentally at autopsy. Because of their rarity as of now they have been described only as case reports or included in small clinical series.

Methods

We report a series of 11 patients, who underwent surgery for granular cell tumors of the neurohypophysis between 1996 and 2013 in a single center.

Results

Mean follow-up time after treatment was 92.2 months (range 9–231 months). Mean age at surgery was 40.7 years (range 12–66 years). There were 7 males (63.6 %) and 4 females (36.4 %). Main symptoms at presentation were: hyperprolactinemia (72.7 %), visual impairment (45.5 %) and headache (36 %). Except for 2 patients, all the others underwent surgery as primary treatment at our Institution, through a transsphenoidal (54.5 %) or a transcranial approach (45.5 %). Overall- and progression-free survival times for the entire series (calculated from the time of diagnosis) were 112.9 and 100.5 months respectively. There was one case of perioperative death in a patient who had undergone repeat transcranial surgery for residual tumor.

Conclusions

Although extremely rare, granular cell tumors of the neurohypophysis have to be considered in the differential diagnosis of suprasellar masses, to avoid misleading interpretation and consequent wrong therapeutic management. Early diagnosis, extensive tumor removal, opportune indication of adjuvant radiotherapy are the keys to manage these cases.

     

Research into the reaction process and the effect of reaction conditions on the simultaneous removal of H2S,COS and CS2 at low temperature

In this work, tobacco stem active carbon (TSAC) catalysts loaded on to CuO and Fe₂O₃ were prepared by a sol–gel method and used for the simultaneous removal of hydrogen sulfide (H₂S), carbonyl sulfide (COS) and carbon disulfide (CS₂). The influences of the operating conditions such as reaction temperature, relative humidity (RH), O₂ concentration, and gas hourly space velocity (GHSV) were discussed. DRIFTS results showed that the deactivation was attributed to the generation of S and sulfates. H₂O promoted the generation of sulfate. The enhancement of the hydrolysis of COS/CS₂ was due to the promotion of H₂S oxidation by O₂. A high GHSV decreased the contact time between the gases and the catalyst. Meanwhile, a high GHSV was not conducive to the adsorption of gases on the surface of the catalyst. XPS results indicated that the deactivation of the catalyst was attributable to the formation of S containing components, such as thiol/thioether, S, –SO– and sulfate. BET results indicated that the adsorptive ability of the catalyst was related to the microporous volume and surface area.

The removal processes of COS, CS₂ and H₂S could be divided into two parts: a catalytic hydrolysis reaction and a catalytic oxidation reaction.     

A cross-sectional survey of factors associated with the uptake of smoking cessation aids among smokers and ex-smokers

Background: A cross-sectional survey was conducted in Germany via the online panel PsyWeb with the aim of assessing factors associated with the uptake of smoking cessation aids among smokers and ex-smokers.

Methods: Of the 10,000 panel members invited to participate in the survey, 624 took part.

Main Outcome Measures: Outcomes were measured via questionnaires to assess the uptake of smoking cessation aids, health literacy, readiness to change smoking behavior, and the Fagerström Test for Nicotine Dependence.

Results: There was no association between gender or educational status and use of smoking cessation aids according to chi-square tests of independence. Logistic regression showed that health literacy, degree of tobacco dependence, and readiness to change were significantly associated with the uptake of smoking cessation aids. Smokers with a high degree of nicotine dependence, high readiness to change, and low health literacy were more likely to use aids.

Conclusion: The survey results can be used to develop psychological approaches and interventions to promote smoking cessation, e.g., interventions to increase readiness to change among smokers may increase the uptake of aids. Moreover, the results may help to improve patient care by disseminating information on effective aids and thereby promoting smoking cessation among relevant patient groups.     

Combination Immunotherapy of MUC1 mRNA Nano-vaccine and CTLA-4 Blockade Effectively Inhibits Growth of Triple Negative Breast Cancer

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