The electrochemical reduction of atmospheric CO2 by renewable electricity opens new routes to synthesize fuels and chemicals, but more selective and efficient catalysts are needed. Herein, by ...combining experimental and first-principles studies, we explain why chalcogen modified copper catalysts are selective toward formate as the only carbon product. On the unmodified copper, adsorbed CO2 is the key intermediate, yielding carbon monoxide and formate as carbon products. On sulfur, selenium, or tellurium modified copper, chalcogen adatoms are present on the surface and actively participate in the reaction, either by transferring a hydride or by tethering CO2 thus suppressing the formation of CO. These results highlight the active role of chalcogen centers via chemical steps and point toward basicity as the key descriptor for the stability and selectivity of these catalysts.
The massive assessment of immune evasion due to viral mutations that increase COVID-19 susceptibility can be computationally facilitated. The adaptive cytotoxic T response is critical during primary ...infection and the generation of long-term protection. Here, potential HLA class I epitopes in the SARS-CoV-2 proteome were predicted for 2,915 human alleles of 71 families using the netMHCIpan EL algorithm. Allele families showed extreme epitopic differences, underscoring genetic variability of protective capacity between humans. Up to 1,222 epitopes were associated with any of the twelve supertypes, that is, allele clusters covering 90% population. Next, from all mutations identified in ~118,000 viral NCBI isolates, those causing significant epitope score reduction were considered epitope escape mutations. These mutations mainly involved non-conservative substitutions at the second and C-terminal position of the ligand core, or total ligand removal by large recurrent deletions. Escape mutations affected 47% of supertype epitopes, which in 21% of cases concerned isolates from two or more sub-continental areas. Some of these changes were coupled, but never surpassed 15% of evaded epitopes for the same supertype in the same isolate, except for B27. In contrast to most supertypes, eight allele families mostly contained alleles with few SARS-CoV-2 ligands. Isolates harboring cytotoxic escape mutations for these families co-existed geographically within sub-Saharan and Asian populations enriched in these alleles according to the Allele Frequency Net Database. Collectively, our findings indicate that escape mutation events have already occurred for half of HLA class I supertype epitopes. However, it is presently unlikely that, overall, it poses a threat to the global population. In contrast, single and double mutations for susceptible alleles may be associated with viral selective pressure and alarming local outbreaks. The integration of genomic, geographical and immunoinformatic information eases the surveillance of variants potentially affecting the global population, as well as minority subpopulations.
To demonstrate the efficacy of the anti-interleukin-6 receptor monoclonal antibody tocilizumab in patients with moderate-to-severe corticosteroid-resistant Graves orbitopathy (GO).
Double-masked ...randomized clinical trial.
Setting and Participants: Thirty-two adults with moderate-to-severe corticosteroid-resistant GO from 10 medical centers in Spain were randomized (1:1). Intervention: Randomization to either 8 mg/kg body weight tocilizumab or placebo administered intravenously at weeks 0, 4, 8, and 12, and follow-up for an additional 28 weeks. Main Outcomes and Measures: The primary outcome was the proportion of patients with a change from baseline to week 16 of at least 2 in the clinical activity score (CAS).
The primary outcome was met by 93.3% (95% confidence interval CI 70.1%-98.8%) of the patients receiving tocilizumab and 58.8% (36%-78.3%) receiving placebo (P = .04; odds ratio, 9.8 CI 1.3-73.2). A significant difference was also observed in the proportion of patients achieving a CAS < 3 (86.7% CI 62.1%-96.2% vs 35.2% CI 17.3%-58.7%, P = .005; OR 11.9 CI 2.1-63.1) at week 16. Additionally, a larger proportion of patients with improvement in the European Group on GO–proposed composite ophthalmic score at week 16 (73.3% CI 48%-89.1% vs 29.4% CI 13.2%-53.1%; P = .03), and exophthalmos size change from baseline to week 16 (-1.5 -2.0 to 0.5 mm vs 0.0 -1.0 to 0.5 mm; P = .01) were seen with tocilizumab. One patient experienced a moderate increase in transaminases at week 8; another had an acute pyelonephritis at week 32 in the tocilizumab-treated group.
Tocilizumab offers a meaningful improvement in activity and severity in corticosteroid-resistant GO. This trial justifies further studies to characterize the role of tocilizumab in GO.
A frequency downscaling technique for enhancing the accuracy of analog lock-in amplifier (LIA) architectures in giant magneto-impedance (GMI) sensor applications is presented in this paper. As a ...proof of concept, the proposed method is applied to two different LIA topologies using, respectively, analog and switching-based multiplication for phase-sensitive detection. Specifically, the operation frequency of both the input and the reference signals of the phase-sensitive detector (PSD) block of the LIA is reduced through a subsampling process using sample-and-hold (SH) circuits. A frequency downscaling from 200 kHz, which is the optimal operating frequency of the employed GMI sensor, to 1 kHz has been performed. In this way, the proposed technique exploits the inherent advantages of analog signal multiplication at low frequencies, while the principle of operation of the PSD remains unaltered. The circuits were assembled using discrete components, and the frequency downscaling proposal was experimentally validated by comparing the measurement accuracy with the equivalent conventional circuits. The experimental results revealed that the error in the signal magnitude measurements was reduced by a factor of 8 in the case of the analog multipliers and by a factor of 21 when a PSD based on switched multipliers was used. The error in-phase detection using a two-phase LIA was also reduced by more than 25%.
Cell division protein FtsZ can form single-stranded filaments with a cooperative behavior by self-switching assembly. Subsequent condensation and bending of FtsZ filaments are important for the ...formation and constriction of the cytokinetic ring. PC190723 is an effective bactericidal cell division inhibitor that targets FtsZ in the pathogen Staphylococcus aureus and Bacillus subtilis and does not affect Escherichia coli cells, which apparently binds to a zone equivalent to the binding site of the antitumor drug taxol in tubulin (Haydon, D. J., Stokes, N. R., Ure, R., Galbraith, G., Bennett, J. M., Brown, D. R., Baker, P. J., Barynin, V. V., Rice, D. W., Sedelnikova, S. E., Heal, J. R., Sheridan, J. M., Aiwale, S. T., Chauhan, P. K., Srivastava, A., Taneja, A., Collins, I., Errington, J., and Czaplewski, L. G. (2008) Science 312, 1673–1675). We have found that the benzamide derivative PC190723 is an FtsZ polymer-stabilizing agent. PC190723 induced nucleated assembly of Bs-FtsZ into single-stranded coiled protofilaments and polymorphic condensates, including bundles, coils, and toroids, whose formation could be modulated with different solution conditions. Under conditions for reversible assembly of Bs-FtsZ, PC190723 binding reduced the GTPase activity and induced the formation of straight bundles and ribbons, which was also observed with Sa-FtsZ but not with nonsusceptible Ec-FtsZ. The fragment 2,6-difluoro-3-methoxybenzamide also induced Bs-FtsZ bundling. We propose that polymer stabilization by PC190723 suppresses in vivo FtsZ polymer dynamics and bacterial division. The biochemical action of PC190723 on FtsZ parallels that of the microtubule-stabilizing agent taxol on the eukaryotic structural homologue tubulin. Both taxol and PC190723 stabilize polymers against disassembly by preferential binding to each assembled protein. It is yet to be investigated whether both ligands target structurally related assembly switches.
The electroreduction of carbon dioxide using renewable electricity is an appealing strategy for the sustainable synthesis of chemicals and fuels. Extensive research has focused on the production of ...ethylene, ethanol and n‐propanol, but more complex C4 molecules have been scarcely reported. Herein, we report the first direct electroreduction of CO2 to 1‐butanol in alkaline electrolyte on Cu gas diffusion electrodes (Faradaic efficiency=0.056 %, j1‐Butanol=−0.080 mA cm−2 at −0.48 V vs. RHE) and elucidate its formation mechanism. Electrolysis of possible molecular intermediates, coupled with density functional theory, led us to propose that CO2 first electroreduces to acetaldehyde‐a key C2 intermediate to 1‐butanol. Acetaldehyde then undergoes a base‐catalyzed aldol condensation to give crotonaldehyde via electrochemical promotion by the catalyst surface. Crotonaldehyde is subsequently electroreduced to butanal, and then to 1‐butanol. In a broad context, our results point to the relevance of coupling chemical and electrochemical processes for the synthesis of higher molecular weight products from CO2.
Carbon dioxide was electroreduced to 1‐butanol on oxide‐derived copper. The reaction mechanism was determined to proceed through a combination of electrochemical and chemical steps, some of which require contrasting conditions. This example highlights limitations in one‐pot synthesis and provides a case for utilizing independently optimized sequential reactors in a tandem system to build complex molecules from low molecular‐weight feedstocks.
Heterologous vaccines, which induce immunity against several related pathogens, can be a very useful and rapid way to deal with new pandemics. In this study, the potential impact of licensed COVID-19 ...vaccines on cytotoxic and helper cell immune responses against Khosta-2, a novel sarbecovirus that productively infects human cells, was analyzed for the 567 and 41 most common HLA class I and II alleles, respectively. Computational predictions indicated that most of these 608 alleles, covering more than 90% of the human population, contain sufficient fully conserved T-cell epitopes between the Khosta-2 and SARS-CoV-2 spike-in proteins. Ninety percent of these fully conserved peptides for class I and 93% for class II HLA molecules were verified as epitopes recognized by CD8+ or CD4+ T lymphocytes, respectively. These results show a very high correlation between bioinformatic prediction and experimental assays, which strongly validates this study. This immunoinformatics analysis allowed a broader assessment of the alleles that recognize these peptides, a global approach at the population level that is not possible with experimental assays. In summary, these findings suggest that both cytotoxic and helper cell immune protection elicited by currently licensed COVID-19 vaccines should be effective against Khosta-2 virus infection. Finally, by being rapidly adaptable to future coronavirus pandemics, this study has potential public health implications.
In this paper, a highly power-efficient class-AB-AB Miller op-amp is discussed. The structure uses <inline-formula> <tex-math notation="LaTeX">g_{m} </tex-math></inline-formula> enhancement based on ...local common-mode feedback to provide class-AB operation with enhanced effective <inline-formula> <tex-math notation="LaTeX">g_{m} </tex-math></inline-formula>, open-loop gain, unity-gain frequency, and slew rate (<inline-formula> <tex-math notation="LaTeX">SR </tex-math></inline-formula>) without significant increase in quiescent power consumption. Utilization of a nonlinear load leads to large symmetric positive and negative <inline-formula> <tex-math notation="LaTeX">SR\text{s} </tex-math></inline-formula>. Stability over an extremely wide range of capacitive loads is achieved through a combination of Miller and phase-lead compensations. The unity-gain frequency does not show sensitivity to capacitive load values. A test chip prototype fabricated in 0.18-<inline-formula> <tex-math notation="LaTeX">\mu \text{m} </tex-math></inline-formula> CMOS technology shows 90.8-dB open-loop gain, 12.5-MHz bandwidth for a 25-pF load capacitance, and a factor <inline-formula> <tex-math notation="LaTeX">60~SR </tex-math></inline-formula> enhancement with maximum output current close to 1-mA and 43-<inline-formula> <tex-math notation="LaTeX">\mu \text{A} </tex-math></inline-formula> total static current.
during the COVID-19 pandemic, the number of Acute Care Surgery procedures performed in Spanish hospitals decreased significantly. The aim of this study was to compare Acute Care Surgery activity ...during the COVID-19 pandemic and during a control period.
a multicenter retrospective cohort study was performed including patients who underwent Acute Care Surgery in three tertiary care hospitals in Spain during a control (11th March 2019 to 21st April 2019) and a pandemic (16th March 2020 to 26th April 2020) period. Type of surgical procedures, patients' features and postoperative complications were compared.
two hundred and eighty-five and 117 patients were included in each group. Mean number of patients who underwent Acute Care Surgery during the control and pandemic periods was 2.3 and 0.9 patients per day and hospital (p < 0.001), representing a 58.9% decrease in Acute Care Surgery activity. Time from symptoms onset to patient arrival at the Emergency Department was longer during the pandemic (44.6 vs. 71.0 h, p < 0.001). Surgeries due to acute cholecystitis and complications from previous elective procedures decreased (26.7% vs. 9.4%) during the pandemic, while bowel obstructions and abdominal wall hernia surgeries increased (12.3% vs. 22.2%) (p = 0.001). Morbidity was higher during pandemic period (34.7% vs. 47.1%, p = 0.022), although this difference was not statistically significant in the multivariate analysis. Reoperation rate (17.9% vs. 12.8%, p = 0.212) and mortality (6.7% vs. 4.3%, p = 0.358) were similar in both groups.
during the COVID-19 pandemic, a significant reduction in the performance of Acute Care Surgery procedures was observed. Moreso, a longer time from symptoms onset to patient arrival at the Emergency Department was noted. Higher morbidity was observed in patients undergoing Acute Care Surgery during the pandemic period, although there was not any difference in mortality or reoperation rate.
•Acute Care Surgery Activity was decreased during the COVID-19 pandemic.•A higher delay of the patients presenting in the Emergency Department was observed during the pandemic period.•During the COVID-19 pandemic, a higher morbidity rate was found in patients undergoing Acute Care Surgery.
The molecular basis of the pathogenesis of the opportunistic invasive infections caused by isolates of the
genus remains largely unknown. Moreover, inconsistencies in the current species assignation ...were detected after genome-level comparison of 16 public
isolates. A literature search detected that, between the two most pathogenic species,
causes about twice the number of cases compared to
. These two species shared their mean diseases - sepsis and endocarditis - but differed in causing other syndromes. A number of well-known virulence factors were harbored by all species, such as a manganese transport/adhesin sharing 83% identity from oral endocarditis-causing streptococci. Likewise, all Gemellae carried the genes required for incorporating phosphorylcholine into their cell walls and encoded some choline-binding proteins. In contrast, other proteins were species-specific, which may justify the known epidemiological differences.
, but not
, harbor a gene cluster potentially encoding a polysaccharidic capsule. Species-specific surface determinants also included Rib and MucBP repeats, hemoglobin-binding NEAT domains, peptidases of C5a complement factor and domains that recognize extracellular matrix molecules exposed in damaged heart valves, such as collagen and fibronectin. Surface virulence determinants were associated with several taxonomically dispersed opportunistic genera of the oral microbiota, such as
,
, and
, suggesting the existence of a horizontally transferrable gene reservoir in the oral environment, likely facilitated by close proximity in biofilms and ultimately linked to endocarditis. The identification of the
virulence pool should be implemented in whole genome-based protocols to rationally predict the pathogenic potential in ongoing clinical infections caused by these poorly known bacterial pathogens.
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