Nonsense CD247 mutations show dominant-negative features in TCR expression and function.

BACKGROUND: The invariant TCRζ/CD247 homodimer is crucial for TCR/CD3 expression and signaling through its three immunoreceptor tyrosine-based activation motifs (ITAMs). Homozygous null mutations in CD247 lead to immunodeficiency, while carriers exhibit 50% reduced surface CD3. It is unclear whether carriers of other CD247 variants show dominant-negative effects. OBJECTIVE: To analyze and model the potential impact on TCR expression and function of heterozygous nonsense CD247 mutations found in patients with signs of immunodeficiency or autoimmunity. METHODS: Jurkat T cells, either wild-type (WT) or CRISPR/Cas9-edited CD247-deficient (ZKO), were lentivirally transduced with wild-type CD247 or mutations ablating one (Q142X), two (Q101X), or three (Q70X) ITAMs. RESULTS: Three patients from unrelated families were studied. Two heterozygous nonsense CD247 mutations were identified (p.Y152X and p.Q101X), which affected ITAM-3 and ITAM-2+3, respectively. Both mutations were associated with low surface CD3 expression, normal intracellular CD247 levels using a transmembrane-specific antibody but very low intracellular CD247 levels using an ITAM-3-specific one, suggesting the presence of truncated variants in T cells. Transduction of the mutations lacking 1, 2, or 3 ITAMs into ZKO could not restore normal surface CD3 expression (only 60%, 22% and 10%, respectively), whereas in WT they reduced it (to 39%, 19% and 9% of normal levels), and both effects were ITAM number dependent. All six transfectants showed reduced CD69 induction (25-50%), indicating that they were unable to signal downstream properly neither isolated nor associated with wild-type CD247. CONCLUSION: Our results suggest that CD247 variants lacking ITAMs due to nonsense, but not null, mutations are defective for normal TCR assembly and exert a dominant-negative effect on TCR expression and signaling in vitro. This, in turn, may correlate with clinical features in vivo.

Smartphone-based inertial measurements during Chester step test as a predictor of length of hospital stay in abdominopelvic cancer postoperative period: a prospective cohort study.

BACKGROUND: Objective assessment of pre-operative functional capacity in cancer patients using the smartphone gyroscope during the Chester step (CST) test may allow greater sensitivity of test results. This study has investigated whether the CST is a postoperative hospital permanence predictor in cancer patients undergoing abdominopelvic surgery through work, VO2MAX and gyroscopic movement analysis. METHODS: Prospective, quantitative, descriptive and inferential observational cohort study. Fifty-one patients were evaluated using CST in conjunction with a smartphone gyroscope. Multivariate linear regression analysis was used to examine the predictive value of the CST. RESULTS: The duration of hospital permanence 30 days after surgery was longer when patients who performed stage 1 showed lower RMS amplitude and higher peak power. The work increased as the test progressed in stage 3. High VO2MAX seemed to be a predictor of hospital permanence in those who completed levels 3 and 4 of the test. CONCLUSION: The use of the gyroscope was more accurate in detecting mobility changes, which predicted a less favorable result for those who met at level 1 of the CST. VO2MAX was a predictor of prolonged hospitalization from level 3 of the test. The work was less accurate to determine the patient's true functional capacity.

Inherited human ezrin deficiency impairs adaptive immunity.

BACKGROUND: Inborn errors of immunity (IEI) are a group of monogenic diseases that confer susceptibility to infection, autoimmunity, and cancer. Despite the life-threatening consequences of some IEI, their genetic cause remains unknown in many patients. OBJECTIVE: We investigated a patient with an IEI of unknown genetic etiology. METHODS: Whole-exome sequencing identified a homozygous missense mutation of the gene encoding ezrin (EZR), substituting a threonine for an alanine at position 129. RESULTS: Ezrin is one of the subunits of the ezrin, radixin, and moesin (ERM) complex. The ERM complex links the plasma membrane to the cytoskeleton and is crucial for the assembly of an efficient immune response. The A129T mutation abolishes basal phosphorylation and decreases calcium signaling, leading to complete loss of function. Consistent with the pleiotropic function of ezrin in myriad immune cells, multidimensional immunophenotyping by mass and flow cytometry revealed that in addition to hypogammaglobulinemia, the patient had low frequencies of switched memory B cells, CD4+ and CD8+ T cells, MAIT, γδ T cells, and centralnaive CD4+ cells. CONCLUSIONS: Autosomal-recessive human ezrin deficiency is a newly recognized genetic cause of B-cell deficiency affecting cellular and humoral immunity.

Abscisic Acid-Triggered Persulfidation of the Cys Protease ATG4 Mediates Regulation of Autophagy by Sulfide.

Hydrogen sulfide is a signaling molecule that regulates essential processes in plants, such as autophagy. In Arabidopsis (Arabidopsis thaliana), hydrogen sulfide negatively regulates autophagy independently of reactive oxygen species via an unknown mechanism. Comparative and quantitative proteomic analysis was used to detect abscisic acid-triggered persulfidation that reveals a main role in the control of autophagy mediated by the autophagy-related (ATG) Cys protease AtATG4a. This protease undergoes specific persulfidation of Cys170 that is a part of the characteristic catalytic Cys-His-Asp triad of Cys proteases. Regulation of the ATG4 activity by persulfidation was tested in a heterologous assay using the Chlamydomonas reinhardtii CrATG8 protein as a substrate. Sulfide significantly and reversibly inactivates AtATG4a. The biological significance of the reversible inhibition of the ATG4 by sulfide is supported by the results obtained in Arabidopsis leaves under basal and autophagy-activating conditions. A significant increase in the overall ATG4 proteolytic activity in Arabidopsis was detected under nitrogen starvation and osmotic stress and can be inhibited by sulfide. Therefore, the data strongly suggest that the negative regulation of autophagy by sulfide is mediated by specific persulfidation of the ATG4 protease.

Influence of social, demographic, and clinical factors in live births with spinal dysraphism in Brazil: an ecological study of 21 years.

OBJECTIVES: This study aimed to verify possible associations between sociodemographic and clinical factors in live births with spinal dysraphism. METHODS: An analytical (descriptive and inferential) and ecological study was carried out based on secondary data of 11,308 live births with spinal dysraphism registered in the Live Birth Information System (SINASC) in Brazil from 1999 to 2019. Demographic factors analyzed were age, education, mothers' marital status and geographic region. The clinical factors analyzed were duration, gestation period, birthweight, and number of prenatal visits performed by women who underwent medical follow-up. RESULTS: There was an increase in the number of cases of spinal dysraphism in recent years in Brazil with an annual percentage variation of 3.52%. However, the period from 2005 to 2009 showed a reduction in live births with spinal dysraphism. The regions with the highest incidence were the South and Southeast. The risk increased in mothers born after 1980, older than 30 years and with a high level of education. The risk was increased in live births of whites and blacks, born from double pregnancy and with body weight less than 3000 g. The absence of prenatal care was associated with a higher incidence. CONCLUSION: Sociodemographic and clinical factors have specific characteristics that can predict spinal dysraphism in newborns in Brazil.

Pulsed Photothermal Radiometric Depth Profiling of Bruises by 532 nm and 1064 nm Lasers.

Optical techniques are often inadequate in estimating bruise age since they are not sensitive to the depth of chromophores at the location of the bruise. To address this shortcoming, we used pulsed photothermal radiometry (PPTR) for depth profiling of bruises with two wavelengths, 532 nm (KTP laser) and 1064 nm (Nd:YAG laser). Six volunteers with eight bruises of exactly known and documented times of injury were enrolled in the study. A homogeneous part of the bruise was irradiated first with a 5 ms pulse at 532 nm and then with a 5 ms pulse at 1064 nm. The resulting transient surface temperature change was collected with a fast IR camera. The initial temperature-depth profiles were reconstructed by solving the ill-posed inverse problem using a custom reconstruction algorithm. The PPTR signals and reconstructed initial temperature profiles showed that the 532 nm wavelength probed the shallow skin layers revealing moderate changes during bruise development, while the 1064 nm wavelength provided additional information for severe bruises, in which swelling was present. Our two-wavelength approach has the potential for an improved estimation of the bruise age, especially if combined with modeling of bruise dynamics.

Non-tumoral metastatic lesions as a debut of primary biliary cholangitis and concomitant sarcoidosis.

Sarcoidosis is included within the multisystemic granulomatous diseases with autoimmune character. The case of a 51-year-old man with hemoptysis, cholestasis and bone lesions is presented. After ruling out infectious, inflammatory and neoplastic entities, a diagnosis of sarcoidosis and autoimmune hepatitis with primary biliary cholangitis was established.

On Identifying and Mitigating Bias in Inferred Measurements for Solar Vector Magnetic-Field Data.

The problem of bias, meaning over- or under-estimation, of the component perpendicular to the line-of-sight [ B ⊥ ] in vector magnetic-field maps is discussed. Previous works on this topic have illustrated that the problem exists; here we perform novel investigations to quantify the bias, fully understand its source(s), and provide mitigation strategies. First, we develop quantitative metrics to measure the B ⊥ bias and quantify the effect in both local (physical) and native image-plane components. Second, we test and evaluate different options available to inversions and different data sources, to systematically characterize the impacts of these choices, including explicitly accounting for the magnetic fill fraction [ f f ]. Third, we deploy a simple model to test how noise and different models of the bias may manifest. From these three investigations we find that while the bias is dominantly present in under-resolved structures, it is also present in strong-field, pixel-filling structures. Noise in the spectropolarimetric data can exacerbate the problem, but it is not the primary cause of the bias. We show that fitting f f explicitly provides significant mitigation, but that other considerations such as the choice of χ 2 -weights and optimization algorithms can impact the results as well. Finally, we demonstrate a straightforward "quick fix" that can be applied post facto but prior to solving the 180 ∘ ambiguity in B ⊥ , and which may be useful when global-scale structures are, e.g., used for model boundary input. The conclusions of this work support the deployment of inversion codes that explicitly fit f f or, as with the new SyntHIA neural-net, that are trained on data that did so.

Results from two-year rodent oral carcinogenicity studies of cizolirtine, a substance-P and calcitonin gene-related peptide release modulator.

Cizolirtine is a substance-P and calcitonin gene-related peptide release modulator developed for the treatment of pain and urinary incontinence. To assess its carcinogenic potential, cizolirtine was administered by oral route once daily for up to 104 weeks to CD-1 mice at doses of 40, 90, or 200 mg/kg/day, and to Han Wistar rats at doses of 40, 90 or 200 mg/kg/day to males and 40, 110 or 160 mg/kg/day to females. There were treatment-related neoplastic findings both in mice and rats. In mice, administration of cizolirtine was associated to an increase in skin fibrosarcomas and sarcomas among high-dose males, considered secondary to increased aggression and specific to the animal model. In rats, there was an increased incidence of liver adenomas in males and females, and carcinomas in males, in association with an increased incidence of hepatocyte hypertrophy, vacuolation and clear cell foci, and considered related to sustained long-term enzyme induction resulting in increased liver metabolism and associated hypertrophic changes. The observed neoplastic findings in mouse skin and rat liver after life-time oral administration of cizolirtine are considered related to rodent-specific non-genotoxic mechanisms of questionable relevance to man.

Robotic chemotherapy compounding: A multicenter productivity approach.

INTRODUCTION: The aim of this study is to compare productivity of the KIRO Oncology compounding robot in three hospital pharmacy departments and identify the key factors to predict and optimize automatic compounding time. METHODS: The study was conducted in three hospitals. Each hospital compounding workload and workflow were analyzed. Data from the robotic compounding cycles from August 2017 to July 2018 were retrospectively obtained. Nine cycle specific parameters and five productivity indicators were analysed in each site. One-to-one differences between hospitals were evaluated. Next, a correlation analysis between cycle specific factors and productivity indicators was conducted; the factors presenting a highest correlation to automatic compounding time were used to develop a multiple regression model (afterwards validated) to predict the automatic compounding time. RESULTS: A total of 2795 cycles (16367 preparations) were analysed. Automatic compounding time showed a relevant positive correlation (ǀrs|>0.40) with the number of preparations, number of vials and total volume per cycle. Therefore, these cycle specific parameters were chosen as independent variables for the mathematical model. Considering cycles lasting 40 minutes or less, predictability of the model was high for all three hospitals (R2:0.81; 0.79; 0.72). CONCLUSION: Workflow differences have a remarkable incidence in the global productivity of the automated process. Total volume dosed for all preparations in a cycle is one of the variables with greater influence in automatic compounding time. Algorithms to predict automatic compounding time can be useful to help users in order to plan the cycles launched in KIRO Oncology.

Lymphocyte integration of complement cues.

We address current data, views and puzzles on the emerging topic of regulation of lymphocytes by complement proteins or fragments. Such regulation is believed to take place through complement receptors (CR) and membrane complement regulators (CReg) involved in cell function or protection, respectively, including intracellular signalling. Original observations in B cells clearly support that complement cues through CR improve their performance. Other lymphocytes likely integrate complement-derived signals, as most lymphoid cells constitutively express or regulate CR and CReg upon activation. CR-induced signals, particularly by anaphylatoxins, clearly regulate lymphoid cell function. In contrast, data obtained by CReg crosslinking using antibodies are not always confirmed in human congenital deficiencies or knock-out mice, casting doubts on their physiological relevance. Unsurprisingly, human and mouse complement systems are not completely homologous, adding further complexity to our still fragmentary understanding of complement-lymphocyte interactions.

Twenty six-week repeat dose oral rat toxicity study of cizolirtine, a substance-P and calcitonin gene-related peptide release modulator.

Cizolirtine, a substance-P and calcitonin gene-related peptide release modulator developed for the treatment of pain and urinary incontinence, was orally administered for 26-weeks to rats at dosages of 20, 60 and 200 mg/kg/day. Clinical signs were limited to post-dosing salivation and brown staining on head and muzzle. There were slight decreases in bodyweight gain and slight increases in water consumption among cizolirtine-treated animals. Slight increases in plasma alkaline phosphatase activity, and cholesterol and phospholipid concentrations were observed in mid- and/or high-dose animals. Low urinary volume, pH and sodium and potassium outputs were observed after 12-weeks, and low urinary pH, low sodium and high potassium outputs at end of treatment. Increased relative (to bodyweight) liver weight was observed in high-dose animals. Treated males and high-dose females showed a dose-related increase in the incidence and severity of periacinar hepatocytic hypertrophy and midzonal/periacinar hepatocytic fat vacuolization. Increased incidences of hepatic clear cell foci were observed in all cizolirtine-treated male groups and, to a lesser extent, in treated females. Ovaries of treated females showed a dose-dependent increased incidence of absent corpora lutea and, occasionally, follicular cysts. The dosages of 20 and 60 mg/kg/day were considered as the No-Observed-Adverse-Effect Levels for males and females, respectively.

Noninvasive Monitoring of Dynamical Processes in Bruised Human Skin Using Diffuse Reflectance Spectroscopy and Pulsed Photothermal Radiometry.

We have augmented a recently introduced method for noninvasive analysis of skin structure and composition and applied it to monitoring of dynamical processes in traumatic bruises. The approach combines diffuse reflectance spectroscopy in visible spectral range and pulsed photothermal radiometry. Data from both techniques are analyzed simultaneously using a numerical model of light and heat transport in a four-layer model of human skin. Compared to the earlier presented approach, the newly introduced elements include two additional chromophores (ß-carotene and bilirubin), individually adjusted thickness of the papillary dermal layer, and analysis of the bruised site using baseline values assessed from intact skin in its vicinity. Analyses of traumatic bruises in three volunteers over a period of 16 days clearly indicate a gradual, yet substantial increase of the dermal blood content and reduction of its oxygenation level in the first days after injury. This is followed by the emergence of bilirubin and relaxation of all model parameters towards the values characteristic for healthy skin approximately two weeks after the injury. The assessed parameter values and time dependences are consistent with existing literature. Thus, the presented methodology offers a viable approach for objective characterization of the bruise healing process.

Survey of palliative care providers' needs, perceived roles, and ethical concerns about addressing cancer family history at the end of life.

OBJECTIVE: Palliative care providers may face questions from patients and relatives regarding the heritability of cancers. Implications of such discussions for providers have been little explored. This study aimed to gather palliative care providers' views on their main needs, roles, and ethical concerns regarding cancer family history discussions. METHOD: The palliative care providers who participated in the 2015 and 2017 annual meetings of the Quebec Palliative Care Association were approached to complete a web-based questionnaire. Study participants answered the questionnaire between November 2016 and July 2017. They were asked to identify the most facilitating factor for cancer family history discussions, as well as their most important knowledge needs, potential role, and ethical concerns. Descriptive analyses were conducted. RESULTS: Ninety-four palliative care providers answered the questionnaire. Access to specialized resources to obtain information and protocols or guidelines were considered the most facilitating factors for cancer family history discussions by 32% and 20% of providers, respectively. Knowledge of hereditary cancers was the most relevant educational need for 53%. Thirty-eight per cent considered essential to be informed about their rights and duties regarding cancer family history discussions. Being attentive to patients' concerns and referring families to appropriate resources were identified as the most relevant roles for palliative care providers by 47% and 34% of respondents, respectively. Fifty-eight per cent agreed that cancer family history discussions should be initiated only if beneficial to family members. SIGNIFICANCE OF RESULTS: Education on hereditary cancers made consensus among palliative care providers as the most important knowledge need regarding discussing cancer family history at the end of life. Nonetheless, other less commonly expressed needs, including access to genetics specialists, protocols, or guidelines, and awareness of provider rights and duties concerning such discussions, deserve attention. Answering providers' needs might help optimize cancer predisposition management in palliative care.

Driving Risk Assessment Using Near-Miss Events Based on Panel Poisson Regression and Panel Negative Binomial Regression.

This study proposes a method for identifying and evaluating driving risk as a first step towards calculating premiums in the newly emerging context of usage-based insurance. Telematics data gathered by the Internet of Vehicles (IoV) contain a large number of near-miss events which can be regarded as an alternative for modeling claims or accidents for estimating a driving risk score for a particular vehicle and its driver. Poisson regression and negative binomial regression are applied to a summary data set of 182 vehicles with one record per vehicle and to a panel data set of daily vehicle data containing four near-miss events, i.e., counts of excess speed, high speed brake, harsh acceleration or deceleration and additional driving behavior parameters that do not result in accidents. Negative binomial regression (AICoverspeed = 997.0, BICoverspeed = 1022.7) is seen to perform better than Poisson regression (AICoverspeed = 7051.8, BICoverspeed = 7074.3). Vehicles are separately classified to five driving risk levels with a driving risk score computed from individual effects of the corresponding panel model. This study provides a research basis for actuarial insurance premium calculations, even if no accident information is available, and enables a precise supervision of dangerous driving behaviors based on driving risk scores.

Structure effects on electrocatalysts. Oxygen reduction on Te-modified Pt(111) surfaces: Site-blocking vs electronic effects.

In this work, the oxygen reduction reaction (ORR) on tellurium-modified Pt(111) surfaces has been studied. Adsorption of Te adatoms on Pt(111) progressively shifts toward less positive values of both the ORR reaction onset and the half-wave potential in 0.1M HClO4 for 0 < θTe < 0.25. However, at θTe > 0.25, the ORR activity increases relative to the one at θTe < 0.25, but remains lower than that on clean Pt(111). Results were analyzed in light of simulations of kinetic currents as a function of θTe, calculated by employing a simple mean field model including both site blocking and electronic effects. Inside this framework, experimental data are best explained by considering that oxygenated Te species inhibit the ORR by either negatively modifying adsorption energies of reaction intermediates or combined site-blocking and electronic effects. A redox ORR catalysis due to redox properties of Te adatoms is discarded. Contrarily, in 0.05M H2SO4, a positive catalytic effect has been found, interpreted in terms of a competitive adsorption-desorption mechanism involving the replacement of adsorbed sulfate by Te adatoms. On the other hand, despite the strong site-blocking effect on Hads and OHads adsorption by Te adatoms, it appears that the reduced Te-Pt(111) adlayer does not inhibit the reaction, suggesting different active sites for Hads and OHads adsorption and for the rate-determining step of the ORR mechanism.

Assessing Driving Risk Using Internet of Vehicles Data: An Analysis Based on Generalized Linear Models.

With the major advances made in internet of vehicles (IoV) technology in recent years, usage-based insurance (UBI) products have emerged to meet market needs. Such products, however, critically depend on driving risk identification and driver classification. Here, ordinary least square and binary logistic regressions are used to calculate a driving risk score on short-term IoV data without accidents and claims. Specifically, the regression results reveal a positive relationship between driving speed, braking times, revolutions per minute and the position of the accelerator pedal. Different classes of risk drivers can thus be identified. This study stresses both the importance and feasibility of using sensor data for driving risk analysis and discusses the implications for traffic safety and motor insurance.

Effects of the COVID-19 pandemic on the use and perceptions of urban green space: An international exploratory study.

Urban green space (UGS) is an essential element in the urban environment, providing multiple ecosystem services as well as beneficial effects on physical and mental health. In a time of societal crisis these effects may be amplified, but ensuring that they are maintained requires effective planning and management - which is a complex challenge given the rapid changes in modern society and the need for continual adaptation. This study aims to identify the drivers that normally attract visitors to UGS, and to assess the effects of social isolation on the usage and perception of UGS during the COVID-19 pandemic. We conducted an online survey during the period in which restrictive measures were imposed in response to the pandemic (March-May 2020), in Croatia, Israel, Italy, Lithuania, Slovenia and Spain. Results showed that urban residents normally have a need for accessible UGS, mainly for physical exercise, relaxing and observing nature. The reduction in UGS visitation during the containment period was related to distinct changes in the motivations of those who did visit, with a relative increase in "necessary activities" such as taking the dog out, and a reduction in activities that could be considered non-essential or high-risk such as meeting people or observing nature. Behavioral changes related to proximity were also observed, with an increase in people walking to small urban gardens nearby (e.g. in Italy) or tree-lined streets (e.g. in Spain, Israel), and people traveling by car to green areas outside the city (e.g. in Lithuania). What the respondents missed the most about UGS during the pandemic was "spending time outdoors" and "meeting other people" - highlighting that during the COVID-19 isolation, UGS was important for providing places of solace and respite, and for allowing exercise and relaxation. Respondents expressed the need for urban greenery even when legally mandated access was limited - and many proposed concrete suggestions for improved urban planning that integrates green spaces of different sizes within the fabric of cities and neighborhoods, so that all residents have access to UGS.

Cadmium induces reactive oxygen species-dependent pexophagy in Arabidopsis leaves.

Cadmium treatment induces transient peroxisome proliferation in Arabidopsis leaves. To determine whether this process is regulated by pexophagy and to identify the mechanisms involved, we analysed time course-dependent changes in ATG8, an autophagy marker, and the accumulation of peroxisomal marker PEX14a. After 3 hr of Cd exposure, the transcript levels of ATG8h, ATG8c, a, and i were slightly up-regulated and then returned to normal. ATG8 protein levels also increased after 3 hr of Cd treatment, although an opposite pattern was observed in PEX14. Arabidopsis lines expressing GFP-ATG8a and CFP-SKL enabled us to demonstrate the presence of pexophagic processes in leaves. The Cd-dependent induction of pexophagy was demonstrated by the accumulation of peroxisomes in autophagy gene (ATG)-related Arabidopsis knockout mutants atg5 and atg7. We show that ATG8a colocalizes with catalase and NBR1 in the electron-dense peroxisomal core, thus suggesting that NBR1 may be an autophagic receptor for peroxisomes, with catalase being possibly involved in targeting pexophagy. Protein carbonylation and peroxisomal redox state suggest that protein oxidation may trigger pexophagy. Cathepsine B, legumain, and caspase 6 may also be involved in the regulation of pexophagy. Our results suggest that pexophagy could be an important step in rapid cell responses to cadmium.

Signaling by hydrogen sulfide and cyanide through post-translational modification.

Two cysteine metabolism-related molecules, hydrogen sulfide and hydrogen cyanide, which are considered toxic, have now been considered as signaling molecules. Hydrogen sulfide is produced in chloroplasts through the activity of sulfite reductase and in the cytosol and mitochondria by the action of sulfide-generating enzymes, and regulates/affects essential plant processes such as plant adaptation, development, photosynthesis, autophagy, and stomatal movement, where interplay with other signaling molecules occurs. The mechanism of action of sulfide, which modifies protein cysteine thiols to form persulfides, is related to its chemical features. This post-translational modification, called persulfidation, could play a protective role for thiols against oxidative damage. Hydrogen cyanide is produced during the biosynthesis of ethylene and camalexin in non-cyanogenic plants, and is detoxified by the action of sulfur-related enzymes. Cyanide functions include the breaking of seed dormancy, modifying the plant responses to biotic stress, and inhibition of root hair elongation. The mode of action of cyanide is under investigation, although it has recently been demonstrated to perform post-translational modification of protein cysteine thiols to form thiocyanate, a process called S-cyanylation. Therefore, the signaling roles of sulfide and most probably of cyanide are performed through the modification of specific cysteine residues, altering protein functions.