The ubiquitin system is important for drug discovery, and the discovery of selective small-molecule inhibitors of deubiquitinating enzymes (DUBs) remains an active yet extremely challenging task. ...With a few exceptions, previously developed inhibitors have been found to bind the evolutionarily conserved catalytic centers of DUBs, resulting in poor selectivity. The small molecule IU1 was the first-ever specific inhibitor identified and exhibited surprisingly excellent selectivity for USP14 over other DUBs. However, the molecular mechanism for this selectivity was elusive. Herein, we report the high-resolution co-crystal structures of the catalytic domain of USP14 bound to IU1 and three IU1 derivatives. All the structures of these complexes indicate that IU1 and its analogs bind to a previously unknown steric binding site in USP14, thus blocking the access of the C-terminus of ubiquitin to the active site of USP14 and abrogating USP14 activity. Importantly, this steric site in USP14 is very unique, as suggested by structural alignments of USP14 with several known DUB X-ray structures. These results, in conjunction with biochemical characterization, indicate a coherent steric blockade mechanism for USP14 inhibition by compounds of the IU series. In light of the recent report of steric blockade of USP7 by FT671, this work suggests a potential generally applicable allosteric mechanism for the regulation of DUBs via steric blockade, as showcased by our discovery of IU1-248 which is 10-fold more potent than IU1.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
An efficient and practical route to various 3-alkoxylquinoxalin-2(1H)-ones through visible-light photocatalytic C(sp2)−H/O−H cross-dehydrogenation coupling of quinoxalin-2(1H)-ones and alcohols, ...employing ambient air as an oxidant at room temperature under metal-free conditions, was developed.
An efficient and practical procedure for the synthesis of 3-alkoxylquinoxalin-2(1H)-ones through the visible-light photocatalytic cross-dehydrogenation coupling of quinoxalin-2(1H)-ones and alcohols, with ambient air as the sole oxidant at room temperature, was developed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Excessive emission of carbon dioxide (CO2) has posed an imminent threat to human's environment and global prosperity. To achieve a sustainable future, solid oxide electrolysis cell (SOEC), which can ...efficiently combine CO2 reduction reaction (CO2RR) and renewable energy storage, has become increasingly attractive owing to its unique functionalities. Additionally, symmetrical SOEC (SSOEC) has been considered as one of the most versatile cell configurations due to its simplified process, high compatibility, and low cost. However, the electrode material requirements become very demanding since efficient catalytic-activities are required for both CO2RR and oxygen evolution reaction (OER). Herein, we demonstrate a novel high-entropy perovskite type symmetrical electrode Pr0.5Ba0.5Mn0.2Fe0.2Co0.2Ni0.2Cu0.2O3-δ (HE-PBM) for SSOEC. B-site doping of transition metals such as Mn, Fe, Co, Ni, and Cu in HE-PBM anode has been found to strongly accelerate the OER in the anode. Moreover, the presence of in-situ formed Fe–Co–Ni–Cu quaternary alloy nanocatalysts from HE-PBM cathode under reducing atmosphere has resulted in superior catalytic-activity towards CO2RR. The faster kinetics are also reflected by the significantly low polarization resistance of 0.289 Ω⋅cm2 and high electrolysis current density of 1.21 A⋅cm−2 for CO2RR at 2.0 V and 800 °C. The excellent electrochemical performance and stability demonstrate that the high-entropy perovskite material is a promising electrode material in SSOEC for efficient and durable CO2RR.
A solid oxide electrolysis cell driven by renewable energy sources such as solar and wind is efficient in converting greenhouse gas CO2 to high-value-added chemicals. The high-entropy strategy can simultaneously enhance the CO2 reduction reaction and oxygen evolution reaction by the in-situ formed Fe–Co–Ni–Cu quaternary alloy nanocatalysts in the cathode and Fe–Co–Ni–Cu–Mn active transition metal elements in the anode, respectively. Display omitted
•A novel high-entropy symmetrical electrode is successfully constructed for simultaneously efficient CO2RR and OER.•In-situ exsolved Co–Fe–Ni–Cu quaternary alloy nanocatalysts could significantly benefit CO2RR in the cathode.•High-entropy metal element doping could greatly accelerate OER in the anode.•Electrolysis current density at 2.0 V is greatly improved from 0.55 to 1.21 A cm−2 via high-entropy strategy.•HE-PEM is a promising symmetrical electrode candidate due to its good performance and durability.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A reliable and sensitive ultra‐performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) method was developed for the determination of zanubrutinib in the plasma of beagle dogs. The ...column used was an Acquity BEH C18 column (2.1 mm × 50 mm, 1.7 μm), maintained at 40°C with an injection volume of 2 μl. The gradient elution program was as follows: 0–1 min, 10–10% A; 1–1.1 min, 10–90% A; 1.1–2.1 min, 90–90% A; 2.1–2.2 min, 90–10% A; 2.2–3.0 min, 10–10% A. Mobile phase A was 0.1% formic acid, B was acetonitrile, and the total analysis time was 3 min. The mass spectrometry was performed in positive ion mode, and the scanning mode was multi‐reaction monitoring mode with electrospray ionization as the ion source; m/z 472.2 → 455.01 for zanubrutinib and m/z 441.03 → 137.99 for ibrutinib (internal standard). The plasma samples were processed by protein precipitation. The standard curve showed good linearity (r2 = 0.999 8) in the range of 1.0–1,000 ng/ml (zanubrutinib) with a low limit of quantification of 1 ng/ml. Also, the intra‐day and inter‐day precision (RSD) was <5.88% and the accuracy (RE) ranged from −1.56 to 1.08%; the recoveries of zanubrutinib in beagle plasma ranged from 90.12 to 93.53% (RSD 1.67–6.42%) and the ME values of zanubrutinib were 98.70–101.06% (RSD 5.37–8.49%, n = 6). All values meet US Food and Drug Administration requirements. A rapid, highly selective and sensitive method for the determination of zanubrutinib concentration in plasma by UPLC–MS/MS was successfully developed. This method is suitable for pharmacokinetic studies in beagle dogs by following oral administration of zanubrutinib.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The human genome encodes over 14,000 pseudogenes that are evolutionary relics of protein-coding genes and commonly considered as nonfunctional. Emerging evidence suggests that some pseudogenes may ...exert important functions. However, to what extent human pseudogenes are functionally relevant remains unclear. There has been no large-scale characterization of pseudogene function because of technical challenges, including high sequence similarity between pseudogene and parent genes, and poor annotation of transcription start sites.
To overcome these technical obstacles, we develop an integrated computational pipeline to design the first genome-wide library of CRISPR interference (CRISPRi) single-guide RNAs (sgRNAs) that target human pseudogene promoter-proximal regions. We perform the first pseudogene-focused CRISPRi screen in luminal A breast cancer cells and reveal approximately 70 pseudogenes that affect breast cancer cell fitness. Among the top hits, we identify a cancer-testis unitary pseudogene, MGAT4EP, that is predominantly localized in the nucleus and interacts with FOXA1, a key regulator in luminal A breast cancer. By enhancing the promoter binding of FOXA1, MGAT4EP upregulates the expression of oncogenic transcription factor FOXM1. Integrative analyses of multi-omic data from the Cancer Genome Atlas (TCGA) reveal many unitary pseudogenes whose expressions are significantly dysregulated and/or associated with overall/relapse-free survival of patients in diverse cancer types.
Our study represents the first large-scale study characterizing pseudogene function. Our findings suggest the importance of nuclear function of unitary pseudogenes and underscore their underappreciated roles in human diseases. The functional genomic resources developed here will greatly facilitate the study of human pseudogene function.
Inflammatory bowel disease (IBD) is a serious digestive system disease, for which the clinical therapeutic choices remain limited. Dried fruits of
L. (CAL) are a traditional medicine used for ...regulation of the digestive system. The aim of this study was to identify the regulatory effects of CAL on IBD and to clarify the mechanism of the active compounds. In trinitrobenzene sulfonic acid-induced IBD rats, 125 to 500 mg/kg of oral CAL significantly alleviated weight loss and diarrhea, decreased colitis inflammatory cell infiltration, and inhibited pro-inflammatory cytokine production. The mechanisms of characteristic flavonoids in CAL were evaluated involving inflammation and intestine contraction aspects. Naringenin, nobiletin, and hesperetin showed anti-inflammatory effects on lipopolysaccharide-induced RAW cells. The mechanism may be related to the inhibition of the tumor necrosis factor-α (TNF-α)-induced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway to suppress cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expressions. Naringenin and nobiletin showed inhibitory effects on isolated jejunum contraction. The mechanism of naringenin is partly related to COX, NOS, inositol triphosphate (IP₃), and finally, to decreased jejunum motility. This study demonstrated that CAL, and its flavonoids' regulatory effects on IBD through anti-inflammation and inhibition of intestine muscle contraction, can provide basic information on developing new drugs or supplements against IBD based on CAL.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Transcranial direct current stimulation (tDCS) is a non-invasive brain modulation technique that has been proved to exert beneficial effects in the acute phase of stroke. To explore the underlying ...mechanism, we investigated the neuroprotective effects of cathodal tDCS on brain injury caused by middle cerebral artery occlusion (MCAO).
We established the MCAO model and sham MCAO model with an epicranial electrode implanted adult male Sprague-Dawley rats, and then they were randomly divided into four groups (MCAO + tDCS, MCAO + sham tDCS (Sham), Control + tDCS and Control + Sham group). In this study, the severity degree of neurological deficit, the morphology of brain damage, the apoptosis, the level of neuron-specific enolase and inflammatory factors, the activation of glial cells was detected. The results showed that cathodal tDCS significantly improved the level of neurological deficit and the brain morphology, reduced the brain damage area and apoptotic index, and increased the number of Nissl body in MCAO rats, compared with MCAO + Sham group. Meanwhile, the high level of NSE, inflammatory factors, Caspase 3 and Bax/Bcl2 ratio in MCAO rats was reduced by cathodal tDCS. Additionally, cathodal tDCS inhibited the activation of astrocyte and microglia induced by MCAO. No difference was found in two Control groups.
Our results suggested that cathodal tDCS could accelerate the recovery of neurologic deficit and brain damage caused by MCAO. The inhibition of neuroinflammation and apoptosis resulted from cathodal tDCS may be involved in the neuroprotective process.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Conditioned pain modulation (CPM) is impaired in people with chronic pain such as knee osteoarthritis (KOA). The purpose of this randomized, controlled clinical trial was to investigate whether ...strong electroacupuncture (EA) was more effective on chronic pain by strengthening the CPM function than weak EA or sham EA in patients with KOA.
In this multicenter, three-arm parallel, single-blind randomized controlled trial, 301 patients with KOA were randomly assigned. Patients were randomized into three groups based on EA current intensity: strong EA (> 2 mA), weak EA (< 0.5 mA), and sham EA (non-acupoint). Treatments consisted of five sessions per week, for 2 weeks. Primary outcome measures were visual analog scale (VAS), CPM function, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC).
Three hundred one patients with KOA were randomly assigned, among which 271 (90.0%) completed the study (mean age 63.93 years old). One week of EA had a clinically important improvement in VAS and WOMAC but not in CPM function. After 2 weeks treatment, EA improved VAS, CPM, and WOMAC compared with baseline. Compared with sham EA, weak EA (3.8; 95% CI 3.45, 4.15; P < .01) and strong EA (13.54; 95% CI 13.23, 13.85; P < .01) were better in improving CPM function. Compared with weak EA, strong EA was better in enhancing CPM function (9.73; 95% CI 9.44, 10.02; P < .01), as well as in reducing VAS and total WOMAC score.
EA should be administered for at least 2 weeks to exert a clinically important effect on improving CPM function of KOA patients. Strong EA is better than weak or sham EA in alleviating pain intensity and inhibiting chronic pain.
This study was registered with the Chinese Clinical Trial Registry ( ChiCTR-ICR-14005411 ), registered on 31 October 2014.
α-Terpineol (1), the main volatile constituent in some traditional Chinese medicines, has been reported to be metabolized to 4
-oleuropeic acid by the larvae of common cutworms. The present study ...verified that α-terpineol could be converted to 4
-oleuropeic acid (2) and (1
,2
,4
)-
-menthane-1,2,8-triol (3) by
fermentation. Using shortened fermentation times, 7-hydroxy-α-terpineol (2a) was identified as an oxidative intermediate, which was consistent with the hypothesis put forward by previous studies. Cytochrome P450 enzymes were also confirmed to catalyze this biotransformation. This is the first study on the biotransformation of α-terpineol by microbial fermentation.
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IJS, KILJ, NUK, UL, UM, UPUK
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