Electrochemical oxidative C–H/N–H activations have been accomplished with a versatile cobalt catalyst in terms of 4 + 2 annulations of internal alkynes. The electro-oxidative C–H activation manifold ...proved viable with an undivided cell setup under exceedingly mild reaction conditions at room temperature using earth-abundant cobalt catalysts. The electrochemical cobalt catalysis prevents the use of transition metal oxidants in C–H activation catalysis, generating H2 as the sole byproduct. Detailed mechanistic studies provided strong support for a facile C–H cobaltation by an initially formed cobalt(III) catalyst. The subsequent alkyne migratory insertion was interrogated by mass spectrometry and DFT calculations, providing strong support for a facile C–H activation and the formation of a key seven-membered cobalta(III) cycle in a regioselective fashion. Key to success for the unprecedented use of internal alkynes in electrochemical C–H/N–H activations was represented by the use of N-2-pyridylhydrazides, for which we developed a traceless electrocleavage strategy by electroreductive samarium catalysis at room temperature.
A flow-metallaelectro-catalyzed C–H activation was realized in terms of robust rhodaelectro-catalyzed alkyne annulations. To this end, a modular electro-flow cell with a porous graphite felt anode ...was designed to ensure efficient turnover. Thereby, a variety of C–H/N–H functionalizations proved amenable for alkyne annulations with high levels of regioselectivity and functional group tolerance, viable in both an inter- or intramolecular manner. The electro-flow C–H activation allowed easy scale up, while in-operando kinetic analysis was accomplished by online flow-NMR spectroscopy. Mechanistic studies suggest an oxidatively induced reductive elimination pathway on rhodium(III) in an electrocatalytic regime.
Introduction
The ACCM/PALS guidelines address early correction of paediatric septic shock using conventional measures. In the evolution of these recommendations, indirect measures of the balance ...between systemic oxygen delivery and demands using central venous or superior vena cava oxygen saturation (ScvO
2
≥ 70%) in a goal-directed approach have been added. However, while these additional goal-directed endpoints are based on evidence-based adult studies, the extrapolation to the paediatric patient remains unvalidated.
Objective
The purpose of this study was to compare treatment according to ACCM/PALS guidelines, performed with and without ScvO
2
goal-directed therapy, on the morbidity and mortality rate of children with severe sepsis and septic shock.
Design, participants and interventions
Children and adolescents with severe sepsis or fluid-refractory septic shock were randomly assigned to ACCM/PALS with or without ScvO
2
goal-directed resuscitation.
Measurements
Twenty-eight-day mortality was the primary endpoint.
Results
Of the 102 enrolled patients, 51 received ACCM/PALS with ScvO
2
goal-directed therapy and 51 received ACCM/PALS without ScvO
2
goal-directed therapy. ScvO
2
goal-directed therapy resulted in less mortality (28-day mortality 11.8% vs. 39.2%,
p
= 0.002), and fewer new organ dysfunctions (
p
= 0.03). ScvO
2
goal-directed therapy resulted in more crystalloid (28 (20–40) vs. 5 (0–20) ml/kg,
p
< 0.0001), blood transfusion (45.1% vs. 15.7%,
p
= 0.002) and inotropic (29.4% vs. 7.8%,
p
= 0.01) support in the first 6 h.
Conclusions
This study supports the current ACCM/PALS guidelines. Goal-directed therapy using the endpoint of a ScvO
2
≥ 70% has a significant and additive impact on the outcome of children and adolescents with septic shock.
We report an alternative random laser (RL) architecture based on a flexible and ZnO-enriched cellulose acetate (CA) fiber matrix prepared by electrospinning. The electrospun fibers, mechanically ...reinforced by polyethylene oxide and impregnated with zinc oxide powder, were applied as an adsorbent surface to incorporate plasmonic centers (silver nanoprisms). The resulting structures - prepared in the absence (CA-ZnO) and in the presence of silver nanoparticles (CA-ZnO-Ag) - were developed to support light excitation, guiding and scattering prototypes of a RL. Both materials were excited by a pulsed (5 Hz, 5 ns) source at 355 nm and their fluorescence emission monitored at 387 nm. The results suggest that the addition of silver nanoprisms to the ZnO- enriched fiber matrix allows large improvement of the RL performance due to the plasmon resonance of the silver nanoprisms, with ~80% reduction in threshold energy. Besides the intensity and spectral analysis, the RL characterization included its spectral and intensity angular dependences. Bending the flexible RL did not affect the spectral characteristics of the device. No degradation was observed in the random laser emission for more than 10,000 shots of the pump laser.
Asymmetric pallada‐electrocatalyzed C−H olefinations were achieved through the synergistic cooperation with transient directing groups. The electrochemical, atroposelective C−H activations were ...realized with high position‐, diastereo‐, and enantio‐control under mild reaction conditions to obtain highly enantiomerically‐enriched biaryls and fluorinated N−C axially chiral scaffolds. Our strategy provided expedient access to, among others, novel chiral BINOLs, dicarboxylic acids and helicenes of value to asymmetric catalysis. Mechanistic studies by experiments and computation provided key insights into the catalyst's mode of action.
EE: Enantioselective Electrocatalysis was realized in terms of asymmetric C−H activation through transient directing group (TDG)‐enabled pallada‐electrocatalysis. Experiments and calculations rationalize the key transition states, while asymmetric electrocatalysis provided step‐economical access to axially chiral bi(hetero)aryl diols, diacids and helicenes.
Atropoisomeric (hetero)biaryls are scaffolds with increasing importance in the pharmaceutical and agrochemical industries. Although it is the most obvious disconnection to construct such compounds, ...the direct enantioselective C–H arylation through the concomitant induction of the chiral information remains extremely challenging and uncommon. Herein, the unprecedented earth-abundant 3d-metal-catalyzed atroposelective direct arylation is reported, furnishing rare atropoisomeric C2-arylated indoles. Kinetic studies and DFT computation revealed an uncommon mechanism for this asymmetric transformation, with the oxidative addition being the rate- and enantio-determining step. Excellent stereoselectivities were reached (up to 96% ee), while using an unusual N-heterocyclic carbene ligand bearing an essential remote substituent. Attractive dispersion interactions along with positive C–H---π interactions exerted by the ligand were identified as key factors to guarantee the excellent enantioselection.
Digestion of blood in the midgut of Aedes aegypti results in the release of pro-oxidant molecules that can be toxic to the mosquito. We hypothesized that after a blood meal, the antioxidant capacity ...of the midgut is increased to protect cells against oxidative stress. Concomitantly, pathogens present in the blood ingested by mosquitoes, such as the arboviruses Dengue and Zika, also have to overcome the same oxidative challenge, and the antioxidant program induced by the insect is likely to influence infection status of the mosquito and its vectorial competence.
We found that blood-induced catalase mRNA and activity in the midgut peaked 24 h after feeding and returned to basal levels after the completion of digestion. RNAi-mediated silencing of catalase (AAEL013407-RB) reduced enzyme activity in the midgut epithelia, increased H2O2 leakage and decreased fecundity and lifespan when mosquitoes were fed H2O2. When infected with Dengue 4 and Zika virus, catalase-silenced mosquitoes showed no alteration in infection intensity (number of plaque forming units/midgut) 7 days after the infectious meal. However, catalase knockdown reduced Dengue 4, but not Zika, infection prevalence (percent of infected midguts).
Here, we showed that blood ingestion triggers an antioxidant response in the midgut through the induction of catalase. This protection facilitates the establishment of Dengue virus in the midgut. Importantly, this mechanism appears to be specific for Dengue because catalase silencing did not change Zika virus prevalence. In summary, our data suggest that redox balance in the midgut modulates mosquito vectorial competence to arboviral infections.
Aedes aegypti is the vector of some of the most important vector-borne diseases like dengue, chikungunya, zika and yellow fever, affecting millions of people worldwide. The cellular processes that ...follow a blood meal in the mosquito midgut are directly associated with pathogen transmission. We studied the homeostatic response of the midgut against oxidative stress, as well as bacterial and dengue virus (DENV) infections, focusing on the proliferative ability of the intestinal stem cells (ISC). Inhibition of the peritrophic matrix (PM) formation led to an increase in reactive oxygen species (ROS) production by the epithelial cells in response to contact with the resident microbiota, suggesting that maintenance of low levels of ROS in the intestinal lumen is key to keep ISCs division in balance. We show that dengue virus infection induces midgut cell division in both DENV susceptible (Rockefeller) and refractory (Orlando) mosquito strains. However, the susceptible strain delays the activation of the regeneration process compared with the refractory strain. Impairment of the Delta/Notch signaling, by silencing the Notch ligand Delta using RNAi, significantly increased the susceptibility of the refractory strains to DENV infection of the midgut. We propose that this cell replenishment is essential to control viral infection in the mosquito. Our study demonstrates that the intestinal epithelium of the blood fed mosquito is able to respond and defend against different challenges, including virus infection. In addition, we provide unprecedented evidence that the activation of a cellular regenerative program in the midgut is important for the determination of the mosquito vectorial competence.
Aims
Brazil ranks high in the number of coronavirus disease 19 (COVID‐19) cases and the COVID‐19 mortality rate. In this context, autopsies are important to confirm the disease, determine associated ...conditions, and study the pathophysiology of this novel disease. The aim of this study was to assess the systemic involvement of COVID‐19. In order to follow biosafety recommendations, we used ultrasound‐guided minimally invasive autopsy (MIA‐US), and we present the results of 10 initial autopsies.
Methods and results
We used MIA‐US for tissue sampling of the lungs, liver, heart, kidneys, spleen, brain, skin, skeletal muscle and testis for histology, and reverse transcription polymerase chain reaction to detect severe acute respiratory syndrome coronavirus 2 RNA. All patients showed exudative/proliferative diffuse alveolar damage. There were intense pleomorphic cytopathic effects on the respiratory epithelium, including airway and alveolar cells. Fibrinous thrombi in alveolar arterioles were present in eight patients, and all patients showed a high density of alveolar megakaryocytes. Small thrombi were less frequently observed in the glomeruli, spleen, heart, dermis, testis, and liver sinusoids. The main systemic findings were associated with comorbidities, age, and sepsis, in addition to possible tissue damage due to the viral infection, such as myositis, dermatitis, myocarditis, and orchitis.
Conclusions
MIA‐US is safe and effective for the study of severe COVID‐19. Our findings show that COVID‐19 is a systemic disease causing major events in the lungs and with involvement of various organs and tissues. Pulmonary changes result from severe epithelial injury and microthrombotic vascular phenomena. These findings indicate that both epithelial and vascular injury should be addressed in therapeutic approaches.
The enantioselective cobalt(III)‐catalyzed C−H alkylation was achieved through the design of a novel chiral acid. The cobalt(III)‐catalyzed enantioselective C−H activation was characterized by high ...position‐, regio‐ and enantio‐control under exceedingly mild reaction conditions. Thereby, the robust cooperative cobalt(III) catalysis proved tolerant of valuable electrophilic functional groups, including hydroxyl, bromo, and iodo substituents. Mechanistic studies revealed a considerable additive effect on kinetics and on a negative non‐linear‐effect.
CoIII goes chiral: Enantioselective Cp*CoIII‐catalyzed C−H functionalization was realized by synergistic cooperation with a newly developed chiral carboxylic acid for robust and versatile C−H activation.
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