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The development of readily accessible and interpretable descriptors is pivotal yet challenging in the rational design of metal-organic framework (MOF) catalysts. This study presents a straightforward and physically interpretable activity descriptor for the oxygen evolution reaction (OER), derived from a dataset of bimetallic Ni-based MOFs. Through an artificial-intelligence (AI) data-mining subgroup discovery (SGD) approach, a combination of the d-band center and number of missing electrons in eg states of Ni, as well as the first ionization energy and number of electrons in eg states of the substituents, is revealed as a gene of a superior OER catalyst. The found descriptor, obtained from the AI analysis of a dataset of MOFs containing 3-5d transition metals and 13 organic linkers, has been demonstrated to facilitate in-depth understanding of structure-activity relationship at the molecular orbital level. The descriptor is validated experimentally for 11 Ni-based MOFs. Combining SGD with physical insights and experimental verification, our work offers a highly efficient approach for screening MOF-based OER catalysts, simultaneously providing comprehensive understanding of the catalytic mechanism.
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The ability to synthesize compositionally complex nanostructures rapidly is a key to high-throughput functional materials discovery. In addition to being time-consuming, a majority of conventional materials synthesis processes closely follow thermodynamics equilibria, which limit the discovery of new classes of metastable phases such as high entropy oxides (HEO). Herein, a photonic flash synthesis of HEO nanoparticles at timescales of milliseconds is demonstrated. By leveraging the abrupt heating and cooling cycles induced by a high-power-density xenon pulsed light, mixed transition metal salt precursors undergo rapid chemical transformations. Hence, nanoparticles form within milliseconds with a strong affinity to bind to the carbon substrate. Oxygen evolution reaction (OER) activity measurements of the synthesized nanoparticles demonstrate two orders of magnitude prolonged stability at high current densities, without noticeable decay in performance, compared to commercial IrO2 catalyst. This superior catalytic activity originates from the synergistic effect of different alloying elements mixed at a high entropic state. It is found that Cr addition influences surface activity the most by promoting higher oxidation states, favoring optimal interaction with OER intermediates. The proposed high-throughput method opens new pathways toward developing next-generation functional materials for various electronics, sensing, and environmental applications, in addition to renewable energy conversion.
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Aleaciones , Carbono , Entropía , Termodinámica , Óxidos , OxígenoRESUMEN
BACKGROUND: Neurite dystrophy is a pathologic hallmark of Alzheimer's disease (AD). However, drug discovery targeting neurite protection in AD remains largely unexplored. METHODS: Aß-induced neurite and mitochondrial damage assays were used to evaluate Aß toxicity and the neuroprotective efficacy of a natural compound salidroside (SAL). The 5×FAD transgenic mouse model of AD was used to study the neuroprotective function of SAL. To verify the direct target of SAL, we used surface plasmon resonance and cellular thermal shift assays to analyze the drug-protein interaction. RESULTS: SAL ameliorates Aß-mediated neurite damage in cell culture. We further reveal that SAL represses mitochondrial damage in neurites by promoting mitophagy and maintaining mitochondrial homeostasis, dependent on an NAD-dependent deacetylase SIRT3. In AD mice, SAL protects neurite morphology, mitigates Aß pathology, and improves cognitive function, which are all SIRT3-dependent. Notably, SAL directly binds to transcription factor NRF2, inhibits its degradation by blocking its interaction with KEAP1 ubiquitin ligase, and then advances NRF2-mediated SIRT3 transcription. CONCLUSIONS: Overall, we demonstrate that SAL, a potential anti-aging drug candidate, attenuates AD pathology by targeting NRF2/SIRT3 pathway for mitochondrial and neurite protection. Drug discovery strategies focusing on SAL may thus provide promising therapeutics for AD.
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The effectiveness of piperacillin/tazobactam for managing nosocomial pneumonia caused by extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae is unknown. To answer this question, we conducted a retrospective cohort study in two tertiary teaching hospitals of patients admitted between January 2018 and July 2021 with a diagnosis of nosocomial pneumonia caused by ESBL-producing K. pneumoniae receiving either piperacillin/tazobactam or carbapenems within 24 h from the onset of pneumonia for at least 72 h. Clinical outcomes, including 28-day mortality and 14-day clinical and microbiological cure, were analyzed. Of the 136 total patients, 64 received piperacillin/tazobactam and 72 received carbapenems. The overall 28-day mortality was 19.1% (26/136). In the inverse probability of treatment weighted cohort, piperacillin/tazobactam therapy was not associated with worse clinical outcomes, as the 28-day mortality (OR, 0.82, 95% CI, 0.23-2.87, p = 0.748), clinical cure (OR, 0.94, 95% CI, 0.38-2.35, p = 0.894), and microbiological cure (OR, 1.10, 95% CI, 0.53-2.30, p = 0.798) were comparable to those of carbapenems. Subgroup analyses also did not demonstrate any statistical differences. In conclusion, piperacillin/tazobactam could be an effective alternative to carbapenems for treating nosocomial pneumonia due to ESBL-producing K. pneumoniae when the MICs are ≤8 mg/L.
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Enterobacteriaceae Resistentes a los Carbapenémicos , Infecciones por Klebsiella , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Carbapenémicos/farmacología , Carbapenémicos/uso terapéutico , China/epidemiología , Enfermedad Crítica , Humanos , Infecciones por Klebsiella/tratamiento farmacológico , Infecciones por Klebsiella/epidemiología , Klebsiella pneumoniae , Pruebas de Sensibilidad Microbiana , Centros de Atención TerciariaRESUMEN
Background: Neuronal death is a major hallmark of Alzheimer's disease (AD). Necroptosis, as a programmed necrotic process, is activated in AD. However, what signals and factors initiate necroptosis in AD is largely unknown. Methods: We examined the expression levels of critical molecules in necroptotic signaling pathway by immunohistochemistry (IHC) staining and immunoblotting using brain tissues from AD patients and AD mouse models of APP/PS1 and 5×FAD. We performed brain stereotaxic injection with recombinant TNF-α, anti-TNFR1 neutralizing antibody or AAV-mediated gene expression and knockdown in APP/PS1 mice. For in vitro studies, we used TNF-α combined with zVAD-fmk and Smac mimetic to establish neuronal necroptosis models and utilized pharmacological or molecular biological approaches to study the signaling pathways. Results: We find that activated neuronal necroptosis is dependent on upstream TNF-α/TNFR1 signaling in both neuronal cell cultures and AD mouse models. Upon TNF-α stimulation, accumulated p62 recruits RIPK1 and induces its self-oligomerization, and activates downstream RIPK1/RIPK3/MLKL cascade, leading to neuronal necroptosis. Ectopic accumulation of p62 is caused by impaired autophagy flux, which is mediated by UVRAG downregulation during the TNF-α-promoted necroptosis. Notably, UVRAG overexpression inhibits neuronal necroptosis in cell and mouse models of AD. Conclusions: We identify a finely controlled regulation of neuronal necroptosis in AD by coordinated TNF-α signaling, RIPK1/3 activity and autophagy machinery. Strategies that could fine-tune necroptosis and autophagy may bring in promising therapeutics for AD.
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Enfermedad de Alzheimer/fisiopatología , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas Supresoras de Tumor/fisiología , Enfermedad de Alzheimer/metabolismo , Animales , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/metabolismo , Autofagia/efectos de los fármacos , Encéfalo/patología , Muerte Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Expresión Génica , Humanos , Ratones , Necroptosis/fisiología , Necrosis/metabolismo , Neuronas/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Transducción de Señal/efectos de los fármacos , Transcriptoma/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
INTRODUCTION: Tigecycline is a potential alternative to trimethoprim-sulfamethoxazole in treating Stenotrophomonas maltophilia infections due to its potent in vitro antimicrobial activity. Clinical evidence regarding the use of tigecycline in the treatment of S. maltophilia infections is scarce. In this study, we assessed the efficacy of tigecycline treating ventilator-associated pneumonia (VAP) due to S. maltophilia in comparison with fluoroquinolones. METHODS: This is a multicenter retrospective cohort study of patients admitted between January 2017 and December 2020 with the diagnosis of VAP caused by S. maltophilia receiving either tigecycline or fluoroquinolones as the definitive therapy ≥ 48 h. Clinical outcomes including 28-day mortality, clinical cure and microbiological cure were analyzed. RESULTS: Of 82 patients with S. maltophilia VAP included, 46 received tigecycline, and 36 received fluoroquinolones; 70.7% of patients had polymicrobial pneumonia, and the appropriate empiric therapy was applied to only 14.6% of patients. The overall 28-day mortality was 39%. Compared with patients receiving fluoroquinolones, tigecycline therapy resulted in worse clinical cure (32.6% vs. 63.9%, p = 0.009) and microbiological cure (28.6% vs. 59.1%, p = 0.045), while there was no statistical difference between 28-day mortality (47.8% vs. 27.8%, p = 0.105) in the two groups. Similar results were also shown in the inverse probability of treatment weighted univariable regression model and multivariable regression model. CONCLUSIONS: The standard dose of tigecycline therapy was associated with a lower clinical and microbiological cure rate but not associated with an increased 28-day mortality in patients with S. maltophilia VAP compared with fluoroquinolones. Considering the unfavorable clinical outcomes, we therefore recommend against using the standard dose of tigecycline in treating S. maltophilia VAP unless new clinical evidence emerges.
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Free-standing macroporous air electrodes with enhanced interfacial contact, rapid mass transport, and tailored deposition space for large amounts of Li2 O2 are essential for improving the rate performance of Li-O2 batteries. An ordered mesoporous carbon membrane with continuous macroporous channels was prepared by inversely topological transformation from ZnO nanorod array. Utilized as a free-standing air cathode for Li-O2 battery, the hierarchically porous carbon membrane shows superior rate performance. However, the increased cross-sectional area of the continuous macropores on the cathode surface leads to a kinetic overpotential with large voltage hysteresis and linear voltage variation against Butler-Volmer behavior. The kinetics were investigated based on the rate-determining step of second electron transfer accompanied by migration of Li+ in solid or quasi-solid intermediates. These discoveries shed light on the design of the air cathode for Li-O2 batteries with high-rate performance.