Protein phosphorylation is a major post‐translational modification involved in cell signalling that regulates many physiological and pathological processes. Despite their biological importance, ...protein phosphatases are less studied than protein kinases. Importantly, the activity of Cys‐based protein tyrosine phosphatases (PTPs) can be regulated by reversible oxidation. The initial two‐electron oxidation product of the active site Cys is a sulfenic acid (Cys‐SOH) that can then undergo distinct outcomes, such as the disulfide bond or a sulfenyl amide formation. Here, we review the biochemical and structural features of PTPs to find patterns that might specify their oxidation products, aiming to get insights into redox regulatory mechanisms. Initially, the structure and biochemistry of PTP1B is presented. Then, we describe structural aspects that are relevant for substrate recognition and catalysis. Notably, all PTPs contain critical Cys residues for the catalysis of dephosphorylation that is prone to oxidative inactivation, which are frequently found oxidized in cells under physiological conditions, such as upon growth factor stimuli. However, direct oxidations of Cys residues in PTPs by H2O2 are rather slow. Therefore, we discuss possible mechanisms that may account for this apparent contradiction between biological and chemical redox aspects of PTPs. Furthermore, we performed a systematic analysis of the distance between active site cysteine and its backdoor cysteine with the attempt to analyse the preference between disulfide bond formation or sulfenyl amide interaction upon oxidation. In summary, PTPs have been showing many possibilities to auto‐protect from irreversible oxidation, which is important for cell signalling regulation.
Cysteine‐based protein tyrosine phosphatases (PTPs) are reversibly inactivated by oxidants, generating diverse thiol products, such as disulfides or sulfenyl amides, and showing distinct biochemical and structural features. Although direct oxidation of PTPs by H2O2 is rather slow, these phosphatases are somehow regulated by oxidants during cell signalling. Here, we review the diverse redox regulation mechanisms of PTPs and different pathways to autoprotect these signalling proteins from irreversible oxidation.
Obstructive sleep apnoea syndrome (OSAS) often coexists in patients with chronic obstructive pulmonary disease (COPD). The present prospective cohort study tested the effect of OSAS treatment with ...continuous positive airway pressure (CPAP) on the survival of hypoxaemic COPD patients. It was hypothesised that CPAP treatment would be associated with higher survival in patients with moderate-to-severe OSAS and hypoxaemic COPD receiving long-term oxygen therapy (LTOT). Prospective study participants attended two outpatient advanced lung disease LTOT clinics in São Paulo, Brazil, between January 1996 and July 2006. Of 603 hypoxaemic COPD patients receiving LTOT, 95 were diagnosed with moderate-to-severe OSAS. Of this OSAS group, 61 (64%) patients accepted and were adherent to CPAP treatment, and 34 did not accept or were not adherent and were considered not treated. The 5-yr survival estimate was 71% (95% confidence interval 53-83%) and 26% (12-43%) in the CPAP-treated and nontreated groups, respectively (p<0.01). After adjusting for several confounders, patients treated with CPAP showed a significantly lower risk of death (hazard ratio of death versus nontreated 0.19 (0.08-0.48)). The present study found that CPAP treatment was associated with higher survival in patients with moderate-to-severe OSAS and hypoxaemic COPD receiving LTOT.
Infectious bovine keratoconjunctivitis (IBK) is an ocular disease affecting bovine herds worldwide, and it causes significant economic loss. The etiologic agent of IBK is considered to be
Moraxella ...bovis
, but
M. ovis
and
M. bovoculi
are frequently recovered of animals presenting clinical signs of IBK. The therapeutic measures available for its control have limited efficacy. Antimicrobial photodynamic therapy (aPDT) using porphyrins as photosensitizing molecules is an alternative method that can be used to reduce microbial growth. We evaluated the antibacterial activity of aPDT using two water-soluble tetra-cationic porphyrins (
H
2
TMeP
and
ZnTMeP
) against 22 clinical isolates and standard strains of
Moraxella
spp. in vitro and in an ex vivo model. For the in vitro assay, 4.0 µM of porphyrin was incubated with approximately 1.0 × 10
4
CFU/mL of each
Moraxella
sp. isolate and exposed to artificial light for 0, 2.5, 5, and 7.5 min. Next, 50 µL of this solution was plated and incubated for 24 h until CFU measurement. For the ex vivo assay, corneas excised from the eyeballs of slaughtered cattle were irrigated with
Moraxella
spp. culture, followed by the addition of zinc(II) porphyrin
ZnTMeP
(4.0 μM). The corneal samples were irradiated for 0, 7.5, and 30 min, followed by swab collection, plating, and CFU count. The results demonstrated the in vitro inactivation of the strains and clinical isolates of
Moraxella
spp. after 2.5 min of irradiation using
ZnTMeP
, reaching complete inactivation until 7.5 min. In the ex vivo experiment, the use of
ZnTMeP
resulted in the most significant reduction in bacterial concentration after 30 min of irradiation. These results encourage future in vivo experiments to investigate the role of metalloporphyrin
ZnTMeP
in the inactivation of
Moraxella
spp. isolates causing IBK.
IMPORTANCE: Acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) is associated with substantial mortality and use of health care resources. Dexamethasone use might ...attenuate lung injury in these patients. OBJECTIVE: To determine whether intravenous dexamethasone increases the number of ventilator-free days among patients with COVID-19–associated ARDS. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized, open-label, clinical trial conducted in 41 intensive care units (ICUs) in Brazil. Patients with COVID-19 and moderate to severe ARDS, according to the Berlin definition, were enrolled from April 17 to June 23, 2020. Final follow-up was completed on July 21, 2020. The trial was stopped early following publication of a related study before reaching the planned sample size of 350 patients. INTERVENTIONS: Twenty mg of dexamethasone intravenously daily for 5 days, 10 mg of dexamethasone daily for 5 days or until ICU discharge, plus standard care (n =151) or standard care alone (n = 148). MAIN OUTCOMES AND MEASURES: The primary outcome was ventilator-free days during the first 28 days, defined as being alive and free from mechanical ventilation. Secondary outcomes were all-cause mortality at 28 days, clinical status of patients at day 15 using a 6-point ordinal scale (ranging from 1, not hospitalized to 6, death), ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, and Sequential Organ Failure Assessment (SOFA) scores (range, 0-24, with higher scores indicating greater organ dysfunction) at 48 hours, 72 hours, and 7 days. RESULTS: A total of 299 patients (mean SD age, 61 14 years; 37% women) were enrolled and all completed follow-up. Patients randomized to the dexamethasone group had a mean 6.6 ventilator-free days (95% CI, 5.0-8.2) during the first 28 days vs 4.0 ventilator-free days (95% CI, 2.9-5.4) in the standard care group (difference, 2.26; 95% CI, 0.2-4.38; P = .04). At 7 days, patients in the dexamethasone group had a mean SOFA score of 6.1 (95% CI, 5.5-6.7) vs 7.5 (95% CI, 6.9-8.1) in the standard care group (difference, −1.16; 95% CI, −1.94 to −0.38; P = .004). There was no significant difference in the prespecified secondary outcomes of all-cause mortality at 28 days, ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, or the 6-point ordinal scale at 15 days. Thirty-three patients (21.9%) in the dexamethasone group vs 43 (29.1%) in the standard care group experienced secondary infections, 47 (31.1%) vs 42 (28.3%) needed insulin for glucose control, and 5 (3.3%) vs 9 (6.1%) experienced other serious adverse events. CONCLUSIONS AND RELEVANCE: Among patients with COVID-19 and moderate or severe ARDS, use of intravenous dexamethasone plus standard care compared with standard care alone resulted in a statistically significant increase in the number of ventilator-free days (days alive and free of mechanical ventilation) over 28 days. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04327401
Fractional calculus generalizes integer order derivatives and integrals. During the last half century a considerable progress took place in this scientific area. This paper addresses the evolution ...and establishes an assertive measure of the research development.
Protein function originates from a cooperation of structural rigidity, dynamics at different timescales, and allostery. However, how these three pillars of protein function are integrated is still ...only poorly understood. Here we show how these pillars are connected in Protein Tyrosine Phosphatase 1B (PTP1B), a drug target for diabetes and cancer that catalyzes the dephosphorylation of numerous substrates in essential signaling pathways. By combining new experimental and computational data on WT-PTP1B and ≥10 PTP1B variants in multiple states, we discovered a fundamental and evolutionarily conserved CH/π switch that is critical for positioning the catalytically important WPD loop. Furthermore, our data show that PTP1B uses conformational and dynamic allostery to regulate its activity. This shows that both conformational rigidity and dynamics are essential for controlling protein activity. This connection between rigidity and dynamics at different timescales is likely a hallmark of all enzyme function.
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•Distinct dynamic timescales underlie catalysis versus allosteric control in PTP1B•Fast and slow timescale motions are uncoupled in PTP1B•The rigid CH/π switch is critical for the opening and closing of the WPD loop•Fast timescale motions, via helix α7, allow for PTP1B allosteric control
By integrating NMR, crystallography, and enzymatic studies of PTP1B and its variants in multiple states, Choy et al. reveal that in PTP1B, rigidity and slow timescale motions are required for catalysis, while fast timescale motions allow for its allosteric control
Wound healing can be delayed following colonization and infection with the common bacterium
. While multiple therapies are used for their treatment, these are ineffective, expensive, and ...labour-intensive. Thus, there is an enormous unmet need for the treatment of infected wounds. Cinnamaldehyde, the major component of cinnamon oil, is well known for its antimicrobial properties. Herein, we investigated the effects of sub-inhibitory concentrations of cinnamaldehyde in the virulence of
. We also assessed its healing potential in
-infected mouse skin wounds and the mechanisms involved in this response. Sub-inhibitory concentrations of cinnamaldehyde reduced
metabolic rate and its ability to form biofilm and to cause haemolysis. Daily topical application of cinnamaldehyde on
-infected skin wounds reduced tissue bacterial load and promoted faster healing. Lower interleukin-17 (IL-17), vascular endothelial growth factor (VEGF) and nitric oxide levels were detected in cinnamaldehyde-treated wound samples. Blockage of transient receptor potential ankyrin 1, the pharmacological target of cinnamaldehyde, abrogated its healing activity and partially reversed the inhibitory actions of this compound on VEGF and IL-17 generation. We suggest that topical application of sub-inhibitory concentrations of cinnamaldehyde may represent an interesting approach to improve the healing of
-infected skin wounds.
An aggregation-induced emission enhancement (AIEE) effect in fluorescent lipophilic 2,1,3-benzothiadiazole (BTD) derivatives and their organic nanoaggregates were studied. A set of techniques such as ...single-crystal X-ray, dynamic light scattering (DLS), electron paramagnetic resonance (EPR), UV–vis, fluorescence, and density functional theory (DFT) calculations have been used to decipher the formation/break (kinetics), properties, and dynamics of the organic nanoaggregates of three BTD small organic molecules. An in-depth study of the excited-state also revealed the preferential relaxation emissive pathways for the BTD derivatives and the dynamics associated with it. The results described herein, for the first time, explain the formation of fluorescent BTD nanoaggregate derivatives and allow for the understanding of their dynamics in solution as well as the ruling forces of both aggregation and break processes along with the involved equilibrium. One of the developed dyes could be used at a nanomolar concentration to selectively stain lipid droplets emitting an intense and bright fluorescence at the red channel. The other two BTDs could also stain lipid droplets at very low concentrations and were visualized preferentially at the blue channel.
Socioeconomic factors have been consistently associated with suicide, and economic recessions are linked to rising suicide rates. However, evidence on the impact of socioeconomic interventions to ...reduce suicide rates is limited. This study investigates the association of the world's largest conditional cash transfer programme with suicide rates in a cohort of half of the Brazilian population.
We used data from the 100 Million Brazilian Cohort, covering a 12-year period (2004 to 2015). It comprises socioeconomic and demographic information on 114,008,317 individuals, linked to the "Bolsa Família" programme (BFP) payroll database, and nationwide death registration data. BFP was implemented by the Brazilian government in 2004. We estimated the association of BFP using inverse probability of treatment weighting, estimating the weights for BFP beneficiaries (weight = 1) and nonbeneficiaries by the inverse probability of receiving treatment (weight = E(ps)/(1-E(ps))). We used an average treatment effect on the treated (ATT) estimator and fitted Poisson models to estimate the incidence rate ratios (IRRs) for suicide associated with BFP experience. At the cohort baseline, BFP beneficiaries were younger (median age 27.4 versus 35.4), had higher unemployment rates (56% versus 32%), a lower level of education, resided in rural areas, and experienced worse household conditions. There were 36,742 suicide cases among the 76,532,158 individuals aged 10 years, or older, followed for 489,500,000 person-years at risk. Suicide rates among beneficiaries and nonbeneficiaries were 5.4 (95% CI = 5.32, 5.47, p < 0.001) and 10.7 (95% CI = 10.51, 10.87, p < 0.001) per 100,000 individuals, respectively. BFP beneficiaries had a lower suicide rate than nonbeneficiaries (IRR = 0.44, 95% CI = 0.42, 0.45, p < 0.001). This association was stronger among women (IRR = 0.36, 95% CI = 0.33, 0.38, p < 0.001), and individuals aged between 25 and 59 (IRR = 0.41, 95% CI = 0.40, 0.43, p < 0.001). Study limitations include a lack of control for previous mental disorders and access to means of suicide, and the possible under-registration of suicide cases due to stigma.
We observed that BFP was associated with lower suicide rates, with similar results in all sensitivity analyses. These findings should help to inform policymakers and health authorities to better design suicide prevention strategies. Targeting social determinants using cash transfer programmes could be important in limiting suicide, which is predicted to rise with the economic recession, consequent to the Coronavirus Disease 2019 (COVID-19) pandemic.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this paper we present a comprehensive analysis of exclusive vector-meson photoproduction in pp, pPb and PbPb collisions at Run 2 LHC energies using the color dipole formalism. The rapidity ...distributions and total cross sections for the ρ, ϕ, J/Ψ, Ψ(2S) and ϒ production are estimated considering the more recent phenomenological models for the dipole-proton scattering amplitude, which are based on the color glass condensate formalism and are able to describe the inclusive and exclusive ep HERA data. Moreover, we also discuss the impact of the modeling of the vector-meson wave functions on the predictions. The current theoretical uncertainty in the color dipole predictions is estimated and a comparison with the experimental results is performed.
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