Increasing evidence demonstrate that the electron transfer chain plays a critical role in controlling the effector functions of macrophages. In this work, we have generated a Ndufs4-/- murine ...macrophage cell lines. The Ndufs4 gene, which encodes a supernumerary subunit of complex I, is a mutational hotspot in Leigh syndrome patients. Ndufs4-/- macrophages showed decreased complex I activity, altered complex I assembly, and lower levels of maximal respiration and ATP production. These mitochondrial respiration alterations were associated with a shift towards a pro-inflammatory cytokine profile after lipopolysaccharide challenge and improved ability to phagocytose Gram-negative bacteria.
Combination treatment with BRAF (BRAFi) plus MEK inhibitors (MEKi) has demonstrated survival benefit in patients with advanced melanoma harboring activating BRAF mutations. Previous preclinical ...studies suggested that an intermittent dosing of these drugs could delay the emergence of resistance. Contrary to expectations, the first published phase 2 randomized study comparing continuous versus intermittent schedule of dabrafenib (BRAFi) plus trametinib (MEKi) demonstrated a detrimental effect of the "on-off" schedule. Here we report confirmatory data from the Phase II randomized open-label clinical trial comparing the antitumoral activity of the standard schedule versus an intermittent combination of vemurafenib (BRAFi) plus cobimetinib (MEKi) in advanced BRAF mutant melanoma patients (NCT02583516). The trial did not meet its primary endpoint of progression free survival (PFS) improvement. Our results show that the antitumor activity of the experimental intermittent schedule of vemurafenib plus cobimetinib is not superior to the standard continuous schedule. Detection of BRAF mutation in cell free tumor DNA has prognostic value for survival and its dynamics has an excellent correlation with clinical response, but not with progression. NGS analysis demonstrated de novo mutations in resistant cases.
The structural and electronic properties of the alizarin dye supported on TiO2 nanoclusters have been examined by means of time-dependent density-functional (TD-DFT) calculations performed in the ...time-domain framework. The calculated electronic absorption spectrum of free alizarin shows a first band centered at 2.67 eV that upon adsorption features a red shift by 0.31 eV, in agreement with both experimental and previous theoretical work. This red shift arises from a relative stabilization of the dye LUMO when adsorbed. To analyze the dependence of the electronic properties of the dye-support couple on the size of metal-oxide nanoparticles, different models of (TiO2) n nanoclusters have been used (with n = 1, 2, 3, 6, 9, 15, and 38). As a conclusion, the minimal model is good enough to theoretically reproduce the main feature in the spectrum (i.e., the energy shift of the main band upon binding to TiO2). However, it fails in creating intermediate states which could play a significant role under real experimental conditions (dynamics of the electronic transfer). Indeed, as the size of the nanocluster grows, the dye LUMO moves from the edge to well inside the conduction band (Ti 3d band). On the other hand, to assess the consistency of the time-domain approach in the case of such systems, conventional (frequency-domain) TD-DFT calculations have been carried out. It is found that, as far as the functional and basis set are equivalent, both approaches lead to similar results. While for small systems the standard TD-DFT is better suited, for medium to large sized systems, the real-time TD-DFT becomes competitive and more efficient.
Herein we show that Pt(111) and Pt(100) can produce the ketone through the oxidation of the secondary carbon of the polyols. After the Bi modification, the selectivity for the ketone formation ...increases. On the other hand, we observe that pure and Bi‐modified Pt(110) only produced the C3 molecules oxidized in the primary carbon, and it is the only facet that shows an enhancement in the activity due to the modification. In line with these findings, small Pt nanoparticles are not selective for ketone formation. Finally, based on data obtained through DFT calculations, we suggest that positively charged Bi adatoms interact with the OH‐ groups of the enediol‐like intermediate (believed to be the precursor for the ketone/aldehyde production), facilitating the oxidation of the secondary carbon to produce DHA.
The electro‐oxidation of glycerol on different Pt surfaces with/without Bi‐modification was studied through electrochemical, in situ FTIR and DFT experiments to understand the effect of the surface on the activity and selectivity. We show that the oxidation of the secondary carbon is more likely to occur on more coordinated Pt atoms and how the selectivity is enhanced in the presence of Bi species.
Significance
The detection of ethanolamine (
N
H
2
C
H
2
C
H
2
OH) in a molecular cloud in the interstellar medium confirms that a precursor of phospholipids is efficiently formed by interstellar ...chemistry. Hence, ethanolamine could have been transferred from the proto-Solar nebula to planetesimals and minor bodies of the Solar System and thereafter to our planet. The prebiotic availability of ethanolamine on early Earth could have triggered the formation of efficient and permeable amphiphilic molecules such as phospholipids, thus playing a relevant role in the evolution of the first cellular membranes needed for the emergence of life.
Cell membranes are a key element of life because they keep the genetic material and metabolic machinery together. All present cell membranes are made of phospholipids, yet the nature of the first membranes and the origin of phospholipids are still under debate. We report here the presence of ethanolamine in space,
N
H
2
C
H
2
C
H
2
OH, which forms the hydrophilic head of the simplest and second-most-abundant phospholipid in membranes. The molecular column density of ethanolamine in interstellar space is
N
= (1.51
±
0.07)
×
10
13
c
m
−
2
, implying a molecular abundance with respect to
H
2
of
(
0.9
−
1.4
)
×
10
−
10
. Previous studies reported its presence in meteoritic material, but they suggested that it is synthesized in the meteorite itself by decomposition of amino acids. However, we find that the proportion of the molecule with respect to water in the interstellar medium is similar to the one found in the meteorite (
10
−
6
). These results indicate that ethanolamine forms efficiently in space and, if delivered onto early Earth, could have contributed to the assembling and early evolution of primitive membranes.
Background and purpose
Alcohol abuse has been associated with erectile dysfunction (ED), but the implicated molecular mechanisms are unresolved. This study analyses the role of alterations in soluble ...guanylyl cyclase (sGC) in ED.
Experimental approach
ED was analysed in adult male C57BL/6J mice subjected to the Chronic Intermittent Ethanol (CIE) paradigm. Erectile function was assessed in anaesthetised mice in vivo by evaluating intracavernosal pressure (ICP) and in vitro in isolated mice corpora cavernosa (CC) mounted in a myograph. Protein expression and reactive oxygen species were analysed by western blot and dihydroethidium staining, respectively.
Key results
In CIE mice, we observed a significant decrease in the relaxant response of the CC to stimulation of NO release from nitrergic nerves by electrical field stimulation, to NO release from endothelial cells by acetylcholine, to the PDE5 inhibitor sildenafil, and to the sGC stimulator riociguat. Conversely, the response to the sGC activator cinaciguat, whose action is independent of the oxidation state of sGC, was significantly enhanced in these CC. The responses to adenylyl cyclase stimulation with forskolin were unchanged. We found an increase in reactive oxygen species in the CC from CIE mice as well as an increase in CYP2E1 and NOX2 protein expression. In vivo pre‐treatment with tempol prevented alcohol‐induced erectile dysfunction.
Conclusions and implications
Our results demonstrate that alcoholic mice show ED in vitro and in vivo due to an alteration in the redox state of sGC and suggest that sGC activators may be effective in ED associated with alcoholism.
When responding to infectious disease outbreaks, rapid and accurate estimation of the epidemic trajectory is critical. However, two common data collection problems affect the reliability of the ...epidemiological data in real time: missing information on the time of first symptoms, and retrospective revision of historical information, including right censoring. Here, we propose an approach to construct epidemic curves in near real time that addresses these two challenges by 1) imputation of dates of symptom onset for reported cases using a dynamically-estimated "backward" reporting delay conditional distribution, and 2) adjustment for right censoring using the NobBS software package to nowcast cases by date of symptom onset. This process allows us to obtain an approximation of the time-varying reproduction number (Rt) in real time. We apply this approach to characterize the early SARS-CoV-2 outbreak in two Spanish regions between March and April 2020. We evaluate how these real-time estimates compare with more complete epidemiological data that became available later. We explore the impact of the different assumptions on the estimates, and compare our estimates with those obtained from commonly used surveillance approaches. Our framework can help improve accuracy, quantify uncertainty, and evaluate frequently unstated assumptions when recovering the epidemic curves from limited data obtained from public health systems in other locations.
The chemical compounds carrying the thiol group (-SH) have been considered essential in recent prebiotic studies regarding the polymerization of amino acids. We have searched for this kind of ...compound toward the Galactic Center quiescent cloud G+0.693–0.027. We report the first detection in the interstellar space of the trans-isomer of monothioformic acid (t-HC(O)SH) with an abundance of ∼1 נ10−10. Additionally, we provide a solid confirmation of the gauche isomer of ethyl mercaptan (g-C2H5SH) with an abundance of ∼3 נ10−10, and we also detect methyl mercaptan (CH3SH) with an abundance of ∼5 נ10−9. Abundance ratios were calculated for the three SH-bearing species and their OH analogs, revealing similar trends between alcohols and thiols with increasing complexity. Possible chemical routes for the interstellar synthesis of t-HC(O)SH, CH3SH, and C2H5SH are discussed, as well as the relevance of these compounds in the synthesis of prebiotic proteins in the primitive Earth.
Periodic treatments with estrogen receptor subtype‐β (ER‐β) agonist reduce post‐ischemic hippocampal injury in ovariectomized rats. However, the underlying mechanism of how ER‐β agonists protect the ...brain remains unknown. Global cerebral ischemia activates the innate immune response, and a key component of the innate immune response is the inflammasome. This study tests the hypothesis that ER‐β regulates inflammasome activation in the hippocampus, thus reducing ischemic hippocampal damage in reproductively senescent female rats that received periodic ER‐β agonist treatments. First, we determined the effect of hippocampal ER‐β silencing on the expression of the inflammasome proteins caspase 1, apoptosis‐associated speck‐like protein containing a CARD (ASC), and interleukin (IL)‐1β. Silencing of ER‐β attenuated 17β‐estradiol mediated decrease in caspase 1, ASC, and IL‐1β. Next, we tested the hypothesis that periodic ER‐β agonist treatment reduces inflammasome activation and ischemic damage in reproductively senescent female rats. Periodic ER‐β agonist treatments significantly decreased inflammasome activation and increased post‐ischemic live neuronal counts by 32% (p < 0.05) as compared to the vehicle‐treated, reproductively senescent rats. Current findings demonstrated that ER‐β activation regulates inflammasome activation and protects the brain from global ischemic damage in reproductively senescent female rats. Further investigation on the role of a periodic ER‐β agonist regimen to reduce the innate immune response in the brain could help reduce the incidence and the impact of global cerebral ischemia in post‐menopausal women.
We propose that estrogen receptor subtype‐β (ER‐β) activation regulates inflammasome activation and protects the brain from global ischemic damage in reproductively senescent female rats.
We propose that estrogen receptor subtype‐β (ER‐β) activation regulates inflammasome activation and protects the brain from global ischemic damage in reproductively senescent female rats.
Little is known about employee reactions in the form of un/ethical behavior to perceived acts of unfairness toward their peers perpetrated by the supervisor. Based on prior work suggesting that third ...parties also make fairness judgments and respond to the way employees are treated, this study first suggests that perceptions of interactional justice for peers (IJP) lead employees to two different responses to injustice at work: deviant workplace behaviors (DWBs) and organizational citizenship behaviors (OCBs). Second, based on prior literature pointing to supervisors as among the most important sources of moral guidance at work, a mediating role is proposed for ethical leadership. The article suggests that supervisors who inflict acts of injustice on staff will be perceived as unethical leaders, and that these perceptions would explain why employees react to IJP in the form of deviance (DWBs) and citizenship (OCBs). Data were collected from 204 hotel employees. Results of structural equation modeling demonstrate that DWBs and OCBs are substantive reactions to IJP, whereas ethical leadership significantly mediates reactions in the form of DWBs and OCBs. Behavioral ethics and managerial implications are discussed.
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