The outbreak of coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), has become a significant and urgent threat to global health. This review ...provided strong support for central nervous system (CNS) infection with SARS‐CoV‐2 and shed light on the neurological mechanism underlying the lethality of SARS‐CoV‐2 infection. Among the published data, only 1.28% COVID‐19 patients who underwent cerebrospinal fluid (CSF) tests were positive for SARS‐CoV‐2 in CSF. However, this does not mean the absence of CNS infection in most COVID‐19 patients because postmortem studies revealed that some patients with CNS infection showed negative results in CSF tests for SARS‐CoV‐2. Among 20 neuropathological studies reported so far, SARS‐CoV‐2 was detected in the brain of 58 cases in nine studies, and three studies have provided sufficient details on the CNS infection in COVID‐19 patients. Almost all in vitro and in vivo experiments support the neuroinvasive potential of SARS‐CoV‐2. In infected animals, SARS‐CoV‐2 was found within neurons in different brain areas with a wide spectrum of neuropathology, consistent with the reported clinical symptoms in COVID‐19 patients. Several lines of evidence indicate that SARS‐CoV‐2 used the hematopoietic route to enter the CNS. But more evidence supports the trans‐neuronal hypothesis. SARS‐CoV‐2 has been found to invade the brain via the olfactory, gustatory, and trigeminal pathways, especially at the early stage of infection. Severe COVID‐19 patients with neurological deficits are at a higher risk of mortality, and only the infected animals showing neurological symptoms became dead, suggesting that neurological involvement may be one cause of death.
A novel and unusual palladium‐catalyzed 4+2 annulation of cyclopropenes with benzosilacyclobutanes is reported. This reaction occurred through chemoselective Si−C(sp2) bond activation in synergy with ...ring expansion/insertion of cyclopropenes to form new C(sp2)−C(sp3) and Si−C(sp3) bonds. An array of previously elusive bicyclic skeleton with high strain, silabicyclo4.1.0heptanes, were formed in good yields with excellent diastereoselectivity under mild conditions. An asymmetric version of the reaction with a chiral phosphoramidite ligand furnished a variety of chiral bicyclic silaheterocycle derivatives with good enantioselectivity (up to 95.5:4.5 er). Owing to the mild reaction conditions, the good stereoselectivity profile, and the ready availability of the functionalized precursors, this process constitutes a useful and straightforward strategy for the synthesis of densely functionalized silacycles.
When Si−C meets C=C bond activation: Cyclopropenes were functionalized stereoselectively with benzosilacyclobutanes by palladium‐catalyzed Si−C(sp2) bond activation and a ring‐expansion/4+2 annulation sequence to form new C(sp2)−C(sp3) and Si−C(sp3) bonds of silabicyclo4.1.0heptanes. The transformation provided an array of these previously elusive highly strained bicyclic skeletons in good yields with high selectivity (see scheme).
Hydrosilylation of unsaturated carbon-carbon bonds with hydrosilanes is a very important process to access organosilicon compounds and ranks as one of the most fundamental reactions in organic ...chemistry. However, catalytic asymmetric hydrosilylation of activated alkenes and internal alkenes has proven elusive, due to competing reduction of carbon-carbon double bond or isomerization processes. Herein, we report a highly enantioselective Si-C coupling by hydrosilylation of carbonyl-activated alkenes using a palladium catalyst with a chiral TADDOL-derived phosphoramidite ligand, which inhibits O-hydrosilylation/olefin reduction. The stereospecific Si-C coupling/hydrosilylation of maleimides affords a series of silyl succinimides with up to 99% yield, >99:1 diastereoselectivity and >99:1 enantioselectivity. The high degree of stereoselectivity exerts remote control of axial chirality, leading to functionalized, axially chiral succinimides which are versatile building blocks. The product utility is highlighted by the enantioselective construction of N-heterocycles bearing up to three stereocenters.
The rational design of the directional charge transfer channel represents an important strategy to finely tune the charge migration and separation in photocatalytic CO2‐to‐fuel conversion. Despite ...the progress made in crafting high‐performance photocatalysts, developing elegant photosystems with precisely modulated interfacial charge transfer feature remains a grand challenge. Here, a facile one‐pot method is developed to achieve in situ self‐assembly of Pd nanocrystals (NYs) on the transition metal chalcogenide (TMC) substrate with the aid of a non‐conjugated insulating polymer, i.e., branched polyethylenimine (bPEI), for photoreduction of CO2 to syngas (CO/H2). The generic reducing capability of the abundant amine groups grafted on the molecular backbone of bPEI fosters the homogeneous growth of Pd NYs on the TMC framework. Intriguingly, the self‐assembled TMCs@bPEI@Pd heterostructure with bi‐directional spatial charge transport pathways exhibit significantly boosted photoactivity toward CO2‐to‐syngas conversion under visible light irradiation, wherein bPEI serves as an efficient hole transfer mediator, and simultaneously Pd NYs act as an electron‐withdrawing modulator for accelerating spatially vectorial charge separation. Furthermore, in‐depth understanding of the in situ formed intermediates during the CO2 photoreduction process are exquisitely probed. This work provides a quintessential paradigm for in situ construction of multi‐component heterojunction photosystem for solar‐to‐fuel energy conversion.
Non‐conjugated insulating polymer encapsulation and in‐situ growth of metal nanocrystal synergistically contribute to the spatially separated bi‐directional charge transfer pathways toward boosted solar CO2‐to‐syngas conversion.
TP53 is the most frequently mutated gene in cancer, yet these mutations remain therapeutically non-actionable. Major challenges in drugging p53 mutations include heterogeneous mechanisms of ...inactivation and the absence of broadly applicable allosteric sites. Here we report the identification of small molecules, including arsenic trioxide (ATO), an established agent in treating acute promyelocytic leukemia, as cysteine-reactive compounds that rescue structural p53 mutations. Crystal structures of arsenic-bound p53 mutants reveal a cryptic allosteric site involving three arsenic-coordinating cysteines within the DNA-binding domain, distal to the zinc-binding site. Arsenic binding stabilizes the DNA-binding loop-sheet-helix motif alongside the overall β-sandwich fold, endowing p53 mutants with thermostability and transcriptional activity. In cellular and mouse xenograft models, ATO reactivates mutant p53 for tumor suppression. Investigation of the 25 most frequent p53 mutations informs patient stratification for clinical exploration. Our results provide a mechanistic basis for repurposing ATO to target p53 mutations for widely applicable yet personalized cancer therapies.
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•ATO rescues multiple p53 mutants effectively in various assays•The structural mechanism of how mutant p53 function is restored by ATO is described•Most p53 mutants are stabilized structurally but only some are transcriptionally rescued•Widely applicable, yet has individual p53 mutation-based therapeutic potential
Chen et al. show that ATO, an FDA-approved drug, robustly rescues mutant p53, uncover the underlying molecular mechanism, and report the rescue pattern among frequent p53 mutants.
CO2 reduction to carbon feedstocks using heterogeneous photocatalysis technique has been deemed as an attractive means of addressing both deteriorating greenhouse effect and depletion of fossil ...fuels. Nevertheless, deficiency of accessible active sites on the catalyst surface, low CO2 adsorption rate, and short carrier lifetime retard the photocatalytic CO2 conversion into hydrocarbon fuels. In this study, the controllable construction of spatially separated directional charge transport pathways over multilayered heterostructured transition metal chalcogenides (TMCs) based photosystems for high‐performance photocatalytic CO2‐to‐syngas conversion are shown. In this scenario, ultrathin non‐conjugated insulating poly(diallyl‐dimethyl‐ammonium chloride) (PDDA) layer are intercalated in‐between TMCs and layered double hydroxide (LDH) and serve as an efficient electron transfer mediator, whilst LDH functions as a hole‐withdrawing regulator, both of which synergistically foster the spatial vectorial charge migration/separation over TMCs, thus endowing the TMCs/PDDA/LDH heterostructures with significantly boosted visible‐light‐driven photoactivity toward CO2 conversion into syngas. This study can inspire sparkling new ideas to realize fine tuning of charge motion for stimulating solar‐to‐fuel conversion.
Ultrathin non‐conjugated insulating poly(diallyl‐dimethyl‐ammonium chloride) (PDDA) serves as an efficient electron transfer mediator, and simultaneously layered double hydroxide (LDH) functions as a hole‐withdrawing regulator, both of which synergistically contributes to the spatially separated bi‐directional charge transfer pathways over transition metal chalcogenides toward significantly boosted CO2 photoreduction catalysis under visible light irradiation.
The sirtuin family in health and disease Wu, Qi-Jun; Zhang, Tie-Ning; Chen, Huan-Huan ...
Signal transduction and targeted therapy,
12/2022, Volume:
7, Issue:
1
Journal Article
Peer reviewed
Open access
Sirtuins (SIRTs) are nicotine adenine dinucleotide(+)-dependent histone deacetylases regulating critical signaling pathways in prokaryotes and eukaryotes, and are involved in numerous biological ...processes. Currently, seven mammalian homologs of yeast Sir2 named SIRT1 to SIRT7 have been identified. Increasing evidence has suggested the vital roles of seven members of the SIRT family in health and disease conditions. Notably, this protein family plays a variety of important roles in cellular biology such as inflammation, metabolism, oxidative stress, and apoptosis, etc., thus, it is considered a potential therapeutic target for different kinds of pathologies including cancer, cardiovascular disease, respiratory disease, and other conditions. Moreover, identification of SIRT modulators and exploring the functions of these different modulators have prompted increased efforts to discover new small molecules, which can modify SIRT activity. Furthermore, several randomized controlled trials have indicated that different interventions might affect the expression of SIRT protein in human samples, and supplementation of SIRT modulators might have diverse impact on physiological function in different participants. In this review, we introduce the history and structure of the SIRT protein family, discuss the molecular mechanisms and biological functions of seven members of the SIRT protein family, elaborate on the regulatory roles of SIRTs in human disease, summarize SIRT inhibitors and activators, and review related clinical studies.
The C3‐alkenyl‐substituted 2‐indolylmethanols have been designed as a new class of substrates for catalytic asymmetric interrupted Nazarov‐type cyclizations. In the presence of chiral phosphoric acid ...as a mild chiral Brønsted acid, the interrupted Nazarov‐type cyclization of C3‐alkenyl‐substituted 2‐indolylmethanols with nucleophiles occurred smoothly to construct cyclopentabindole frameworks in generally excellent diastereo‐ and enantioselectivities (up to >95:5 dr, >99% ee).
The physiological effects of prone ventilation in ARDS patients have been discussed for a long time but have not been fully elucidated. Electrical impedance tomography (EIT) has emerged as a tool for ...bedside monitoring of pulmonary ventilation and perfusion, allowing the opportunity to obtain data. This study aimed to investigate the effect of prone positioning (PP) on ventilation-perfusion matching by contrast-enhanced EIT in patients with ARDS.
Monocenter prospective physiologic study.
University medical ICU.
Ten mechanically ventilated ARDS patients who underwent PP.
We performed EIT evaluation at the initiation of PP, 3 h after PP initiation and the end of PP during the first PP session.
The regional distribution of ventilation and perfusion was analyzed based on EIT images and compared to the clinical variables regarding respiratory and hemodynamic status. Prolonged prone ventilation improved oxygenation in the ARDS patients. Based on EIT measurements, the distribution of ventilation was homogenized and dorsal lung ventilation was significantly improved by PP administration, while the effect of PP on lung perfusion was relatively mild, with increased dorsal lung perfusion observed. The ventilation-perfusion matched region was found to increase and correlate with the increased PaO
/FiO
by PP, which was attributed mainly to reduced shunt in the lung.
Prolonged prone ventilation increased dorsal ventilation and perfusion, which resulted in improved ventilation-perfusion matching and oxygenation.
ClinicalTrials.gov, NCT04725227. Registered on 25 January 2021.
Ibuprofen and acetaminophen as two anti-fever agents have been widely used in human. Due to lack of full understanding, this work firstly summarized their occurrence and fate in municipal wastewater ...treatment plants (WWTPs) across 30 countries. The respective influent concentrations of ibuprofen and acetaminophen were not detected (ND)-39,830,000 and ND-66440000 ng/L, while their corresponding respective effluent concentrations were ND-58710 and ND-90500 ng/L. The removal efficiencies of ibuprofen and acetaminophen in municipal WWTPs were 6.5–100 % and 14.3–100 % with respective average removal efficiencies of 87.6 % and 94.7 %. There have been many batch studies on ibuprofen biodegradation with kbio values available, while such investigation for acetaminophen was very limited. The theoretically calculated removal efficiency of ibuprofen with kbio agreed well with that of the observed average removal efficiency of on-site investigations on full-scale WWTP, which was quite different from natural estrogens and some other emerging contaminants. One possible reason is that conjugated ibuprofen could be easily cleaved and the cleavage step gives little effect on the biodegradation of ibuprofen. Due to extremely high concentrations of ibuprofen and acetaminophen in influent of municipal WWTP, their concentration levels in effluent likely high enough to pose adverse effects on some aquatic organisms. To protect water environment, advanced treatment is necessary to further remove residue ibuprofen and acetaminophen in the effluent. To the best of our knowledge, this is the systematical summarization on the occurrence and fate of ibuprofen and acetaminophen in municipal WWTP as well as their potential effect on aquatic organisms, which addressed known knowledge and unknowns to be further investigated.
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•Occurrence and removals of ibuprofen and acetaminophen were summarized•Ibuprofen and acetaminophen could be well removed in municipal WWTP•Conjugated ibuprofen and acetaminophen might be readily cleaved•Remarkable concentrations of ibuprofen and acetaminophen were found in the effluent•Potential ecological risks of ibuprofen and acetaminophen should not be ignored
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