Notes

Psychiatric entry being a danger issue pertaining to posttraumatic anxiety problem.
Short hydrogen bonds, with heavy-atom distances less than 2.7 Å, are believed to exhibit proton delocalization, and their possible role in catalysis has been widely debated. While spectroscopic and/or structural methods are usually employed to study the degree of proton delocalization, ambiguities still arise, and no direct information on the corresponding potential energy surface is obtained. Here, we apply an external electric field to perturb the short hydrogen bond(s) within a collection of green fluorescent protein S65T/H148D variants and photoactive yellow protein mutants, where the chromophore participates in the short hydrogen bond(s) and serves as an optical probe of the proton position. As the proton is charged, its position may shift in response to the external electric field, and the chromophore's electronic absorption can thus reflect the ease of proton transfer. The results suggest that low-barrier hydrogen bonds (LBHBs) are not present within these proteins even when proton affinities between donor and acceptor are closely matched. Exploiting the chromophores as precalibrated electrostatic probes, the covalency of short hydrogen bonds as a nonelectrostatic component is also revealed. A theoretical framework is developed to address a possible contribution of unusually large polarizabilities of short hydrogen bonds due to proton delocalization, but no clear evidence for this phenomenon is found in accordance with the absence of LBHBs.Defect chemistry in SnO2 is well established for resistive sensors but remains to be elusive for photoluminescence (PL) sensors. It demands a comprehensive understanding of the role of cationic and oxygen defects as well as the creation of abundant such defects to provide a selective PL signal. To accomplish it, SnO2 quantum dots (QDs ∼ 2.4 nm) are prepared without a capping agent along with other dimensions. Then, the relationship of defects with the blue-emission PL is unfolded by electron energy loss spectroscopy, lifetime measurements, X-ray absorption, and Raman spectroscopic measurements. The defects acting as Lewis acid sites are utilized for selective ammonia detection. Huge enhancements of the obscured blue luminescence at 2.77 and 2.96 eV from the SnO2 QDs are observed because of interaction with ammonia. The linear variation of PL intensities with analyte concentrations and the recovery of the sensor are elaborated with detection up to 5 ppm. The interplay of defects in SnO2 is further established theoretically for site-specific interactions with ammonia by density functional theory (DFT) calculations. Thus, the unique mechanism revealed for the superlative performance of the PL sensor with uncapped SnO2 QDs provides a novel platform for defect-engineering-based optoelectronic applications.Immune checkpoint blockade (ICB) therapy elicits antitumor response by inhibiting immune suppressor components, including programmed cell death protein 1 and its ligand (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Despite improved therapeutic efficacy, the clinical response rate is still unsatisfactory as revealed by the fact that only a minority of patients experience durable benefits. Additionally, "off-target" effects after systemic administration remain challenging for ICB treatment. To this end, the local and targeted delivery of ICB agents instead could be a potential solution to maximize the therapeutic outcomes while minimizing the side effects.In this Account, our recent studies directed at the development of different strategies for the local and targeted delivery of ICB agents are discussed. For example, transdermal microneedle patches loaded with anti-programmed death-1 antibody (aPD1) and anti-CTLA4 were developed to facilitate sustained release of ICB agents at the diseon conjugates of platelets and hematopoietic stem cells (HSCs) for leukemia treatment. With the homing ability of HSCs to the bone marrow, the HSC-platelet-aPD1 assembly could effectively deliver aPD1 in an acute myeloid leukemia mouse model. Besides living cells, we also leveraged HEK293T-derived vesicles with PD1 receptors on their surfaces to disrupt the PD-1/PD-L1 immune inhibitory pathway. Moreover, the inner space of the vesicles allowed the packaging of an indoleamine 2,3-dioxygenase inhibitor, further reinforcing the therapeutic efficacy. A similar approach has also been demonstrated by genetically engineering platelets overexpressing PD1 receptor for postsurgical treatment. We hope the local and targeted ICB agent delivery methods introduced in this collection would further inspire the development of advanced drug delivery strategies to improve the efficiency of cancer treatment while alleviating side effects.Several studies in hepatocyte cell lines reported that medium-chain fatty acids (MCFAs) with 6-12 carbons showed different metabolic properties from long-chain fatty acids (LCFAs). However, these studies reported unclear effects of different fatty acid molecules on hepatocyte metabolism. This study is aimed to capture the metabolic kinetics of MCFA assimilation in AML12 cells treated with octanoic acid (FA 80), decanoic acid (FA 100), or lauric acid (FA120) [LCFA; oleic acid (FA 181)] via metabolic profiling and dynamic metabolome analysis with 13C-labeling. The concentrations of total ketone bodies in the media of cells treated with FA 80 or FA 100 were 3.22- or 3.69-fold higher than those obtained with FA 181 treatment, respectively. FA 120 treatment did not significantly increase ketone body levels compared to DMSO treatment (control), whereas FA 120 treatment increased intracellular triacylglycerol (TG) levels 15.4 times compared to the control. Metabolic profiles of FA 120-treated samples differed from those of the FA 80-treated and FA 100-treated samples, suggesting that metabolic assimilation of MCFAs differed significantly depending on the MCFA type. Furthermore, the dynamic metabolome analysis clearly revealed that FA 80 was rapidly and quantitatively oxidized to acetyl-CoA and assimilated into ketone bodies, citrate cycle intermediates, and glucogenic amino acids but not readily into TGs.Acute respiratory distress syndrome (ARDS) is an inflammatory lung disease with a high morbidity and mortality rate, for which no pharmacologic treatment is currently available. Our previous studies discovered that a pivotal step in the disease process is the activation of the nuclear factor of activated T cells (NFAT) c3 in lung macrophages, suggesting that inhibitors against the upstream protein phosphatase calcineurin should be effective for prevention/treatment of ARDS. Herein, we report the development of a highly potent, cell-permeable, and metabolically stable peptidyl inhibitor, CNI103, which selectively blocks the interaction between calcineurin and NFATc3, through computational and medicinal chemistry. CNI103 specifically inhibited calcineurin signaling in vitro and in vivo and exhibited a favorable pharmacokinetic profile, broad tissue distribution following different routes of administration, and minimal toxicity. Our data indicate that CNI103 is a promising novel treatment for ARDS and other inflammatory diseases.Three YTH-domain family proteins (YTHDF1, YTHDF2, and YTHDF3) recognize the N6-methyladenosine (m6A) modification of mRNA in cells. BBI608 molecular weight However, the redundancy of their cellular functions has been disputed. We investigate their interactions with m6A-containing RNA using X-ray crystallography and molecular dynamics (MD). The new X-ray structures and MD simulations show that the three proteins share identical interactions with the m6A-containing RNA and have similar intrinsic plasticity, thus evidencing the redundant roles of the three proteins in cellular functions.The ring-closing reactions based on chemical bond metathesis enable the efficient construction of a wide variety of cyclic systems which receive broad interest from medicinal and organic communities. However, the analogous reaction with C-N bond metathesis as a strategic fundamental step remains an unanswered challenge. Herein, we report the design of a new fundamental metallic C-N bond metathesis reaction that enables the palladium-catalyzed ring-closing reaction of aminodienes with aminals. The reactions proceed efficiently under mild conditions and exhibit broad substrate generality and functional group compatibility, leading to a wide variety of 5- to 16-membered N-heterocycles bearing diverse frameworks and functional groups.Concentrations of 137Cs in seawater, seabed sediment, and pore water collected from the area around Fukushima were investigated from 2015 to 2018, and the potential of coastal sediments to supply radiocesium to the bottom environment was evaluated. The 137Cs concentration in the pore water ranged from 33 to 1934 mBq L-1 and was 10-40 times higher than that in the overlying water (seawater overlying within 30 cm on the seabed). At most stations, the 137Cs concentrations in the overlying water and the pore water were approximately proportional to those in the sediment. The conditional partition coefficient between pore water and sediment was [0.9-14] × 102 L kg-1, independent of the year of sampling. These results indicated that an equilibrium of 137Cs between pore water and sediment has been established in a relatively short period, and 137Cs in the pore water is gradually exported to seawater near the seabed. A simple box model estimation based on these results showed that 137Cs in the sediment decreased by about 6% per year by desorption/diffusion of 137Cs from the seabed.With the global outbreak of the coronavirus disease 2019 (COVID-19), the highly infective, highly pathogenic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has attracted great attention. Currently, a method to simultaneously diagnose the seven known types human coronaviruses remains lacking and is urgently needed. In this work, we successfully developed a portable microfluidic system for the rapid, accurate, and simultaneous detection of SARS-CoV, middle east respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2, and four other human coronaviruses (HCoVs) including HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1. The disk-like microfluidic platform integrated with loop-mediated isothermal amplification provides highly accurate, sensitive, and specific results with a wide linear range within 40 min. The diagnostic tool achieved 100% consistency with the "gold standard" polymerase chain reaction in detecting 54 real clinical samples. The integrated system, with its simplicity, is urgently needed for the diagnosis of SARS-CoV-2 during the COVID-19 pandemic.Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common form of dementia in the world. Studies report the presence of extracellular amyloid plaques consisting of β-amyloid peptide and intracellular tangles consisting of hyperphosphorylated tau proteins as the histopathological indicators of AD. The process of β-amyloid peptide generation by sequential cleavage of amyloid precursor protein by β-secretase (BACE1) and γ-secretase, followed by its aggregation to form amyloid plaques, is the mechanistic basis of the amyloid hypothesis. Other popular hypotheses related to the pathogenesis of AD include the tau hypothesis and the oxidative stress hypothesis. Various targets of the amyloid cascade are now in prime focus to develop drugs for AD. Many BACE1 inhibitors, β-amyloid aggregation inhibitors, and Aβ clearance strategies using monoclonal antibodies are in various stages of clinical trials. This review provides an in-depth evaluation of the role of BACE1 in disease pathogenesis and also highlights the therapeutic approaches developed to find more potent but less toxic inhibitors for BACE1, particularly emphasizing the natural scaffold as a nontoxic lead for BACE1 inhibition.
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