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Background and Aims: Molecular processes driving immune‐active chronic hepatitis B (CHB) with and without hepatitis B e antigen (HBeAg) remain incompletely understood. This study aimed to investigate expression profiles of serum and intrahepatic HBV markers and replicative activity of HBV in CHB patients with or without HBeAg. Methods: This study recruited 111 untreated immune‐active CHB (60 HBeAg‐positive and 51 HBeAg‐negative) patients and quantified intrahepatic covalently closed circular DNA (cccDNA), pre‐genomic RNA (pgRNA), total HBV DNA (tDNA), and replicative intermediates as well as serum HBV markers (HBV DNA, hepatitis B surface antigen, hepatitis B core‐related antigen). Correlations between HBV markers and clinico‐virological factors influencing expression levels of HBV markers were analysed. Results: Levels of all serum markers and intrahepatic cccDNA/tDNA as well as cccDNA transcriptional activity and virion productivity were significantly reduced in HBeAg‐negative patients compared to those in HBeAg‐positive patients. Additionally, correlations between intrahepatic cccDNA/pgRNA and serum markers were impaired in HBeAg‐negative individuals. Aminotransferase levels were positively correlated with cccDNA transcriptional activity in HBeAg‐positive patients, but not in HBeAg‐negative patients. Notably, among HBeAg‐positive patients, there was a progressive decline in pgRNA level, transcriptional activity, and serum HBV markers as liver fibrosis advanced, which was not observed in HBeAg‐negative patients. Conclusions: HBeAg loss is correlated with diminished intrahepatic HBV reservoirs and cccDNA transcription, leading to decreased serum HBV marker levels. Circulating HBV markers are not reliable indicators of intrahepatic HBV replicative activity for HBeAg‐negative patients. Our findings reveal distinct disease phenotypes between immune‐active CHB with and without HBeAg, highlighting the need to establish optimal surrogate biomarkers that can accurately mirror intrahepatic viral activity to aid in decision‐making for antiviral therapy for immune‐active CHB. [ABSTRACT FROM AUTHOR]

Frustrated Lewis pairs (FLPs), composed of spatially hindered Lewis acids and bases, are promising catalysts for the catalytic hydrogenation of unsaturated organic substrates, but the lack of reusability limits their development. The functionalization of solid materials with molecular FLP is a promising method for preparing heterogeneous FLP catalysts. In this work, a magnetically recyclable FLP catalyst was successfully prepared for the reductive carbonyl compounds to the corresponding alcohols. FLP of 2‐Ph2PPhCHO/B(C6F5)3 was grafted into NH2‐MIL‐101@Fe3O4 composite material through an aldehyde‐amine condensation reaction. The as‐prepared FLP‐NH‐MIL‐101@Fe3O4 exhibited remarkable catalytic activity for aldehyde/ketone carbonyl compounds. In addition, FLP‐NH‐MIL‐101@Fe3O4 displays outstanding magnetic recyclability and can be reused 8 times without loss of activity. [ABSTRACT FROM AUTHOR]

Objectives: The exclusive endoscopic transcanal transpromontorial approach (EETTA) has recently been developed for the removal of small‐sized acoustic neuromas in the labyrinth (intralabyrinthine schwannoma [ILS]) or internal auditory canal (IAC). Although small tumors that meet the indications for EETTA are also good candidates for cochlear implantation (CI), there are few reports on CI after schwannoma removal using EETTA. Here we present an outcome of patients who underwent simultaneous EETTA and CI. Methods: Five patients (two with IAC fundus tumors and three with ILS) who underwent simultaneous EETTA and CI between 2020 and 2022 were retrospectively enrolled. Their medical charts and test results were reviewed. Results: After at least 12 months of follow‐up, there were no severe surgical complications such as meningitis, infection, or skin necrosis. Four of the five patients responded to auditory stimulation. Three out of four auditory‐responsive patients scored >80% on sentence recognition. Conclusion: Simultaneous EETTA and CI are feasible for the treatment of ILS and IAC fundus tumors. Preservation of the cochlear nerve and modiolus is important for favorable CI outcomes. Therefore, ILS and IAC fundus tumors in patients with nonserviceable hearing should be surgically removed as early as possible to enable proper hearing rehabilitation with CI. Level of Evidence: Level 4. [ABSTRACT FROM AUTHOR]

The finite periodic arrangement of functional nanomaterials on the two‐dimensional scale enables the integration and enhancement of individual properties, making them an important research topic in the field of tuneable nanodevices. Although layer‐controllable lattices such as graphene have been successfully synthesized, achieving similar control over colloidal nanoparticles remains a challenge. DNA origami technology has achieved remarkable breakthroughs in programmed nanoparticle assembly. Based on this technology, we proposed a hierarchical assembly strategy to construct a universal DNA origami platform with customized layer properties, which we called 2.5‐dimensional (2.5D) DNA origami crystals. Methodologically, this strategy divides the assembly procedure into two steps: 1) array synthesis, and 2) lattice synthesis, which means that the layer properties, including layer number, interlayer distance, and surface morphology, can be flexibly customized based on the independent designs in each step. In practice, these synthesized 2.5D crystals not only pioneer the expansion of the DNA origami crystal library to a wider range of dimensions, but also highlight the technological potential for templating 2.5D colloidal nanomaterial lattices. [ABSTRACT FROM AUTHOR]

Background: Sigmoid sinus diverticulum/dehiscence (SSD) is one of the treatable causes of venous pulsatile tinnitus. It can be diagnosed using temporal bone computed tomography (CT) or magnetic resonance angiography/venography (MRA). In cases where patients find their symptoms intolerable, surgical treatment is typically preferred. Here, we have presented a novel surgical technique involving sigmoid sinus re-roofing and have analyzed its feasibility. Methods: Between January 2020 and July 2023, approximately 150 patients with pulsatile tinnitus were evaluated at two different tertiary hospitals. Of these, 12 patients were diagnosed with SSD, and seven underwent surgical treatment. Five patients were treated with tailored reroofing (TRR) of the sigmoid sinus and two with transmastoid resurfacing (MRS) of the sigmoid sinus. We compared the Korean tinnitus handicap inventory (K-THI) score, pure tone audiogram (PTA) threshold, and CT findings before and a month after surgeries for these two techniques. The operation time was also analyzed. Results: In TRR cases, the K-THI score reduced from 55.0 ± 31.4 preoperatively to 4.0 ± 3.0 postoperatively, and the SSD was well-repositioned and covered by a bone chip postoperatively. In MRS cases, the K-THI score reduced from 41.0 ± 9.9 preoperatively to 15.0 ± 21.2 postoperatively, and the SSD was well-covered with bone cement postoperatively. The average surgical time of five TRR and two MRS cases were 77.5 ± 32.5 and 174.0 ± 75.0 min, respectively. No complications were noted. Conclusions: Despite the insufficient number of cases, we noted that TRR requires a reasonable amount of time, involves a smaller incision, and may provide favorable outcomes compared to conventional MRS in cases of pulsatile tinnitus associated with SSD. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to perform a nationwide analysis of medication errors (MEs) from hospitals using national reporting system data and to compare the ME patterns among different age groups. Methods: We analyzed medication‐related incidents in acute care hospitals reported to the Korean Patient Safety Reporting and Learning System (KOPS), which is a patient safety reporting system, from July 2016 to December 2020. The stages of the medication use process, type of errors, medication class involved in MEs, and degree of harm were analyzed. Results: Among a total of 5071 medication‐related incidents, 37.7% (1911 cases) were incidents that caused patient harm and 1.2% caused long‐term, permanent, and fatal harm. The proportion of medication‐related incidents that resulted in harm was the highest among the <1‐year‐old age group (67 cases, 51.5%), followed by the elderly (≥ 65 years) (828 cases, 40.9%). The cases leading to patient death were most frequently reported in patients aged ≥65 years. Medication‐related incidents occurred mainly in the administration stage (2954 cases, 58.3%), and wrong dose was the most frequently reported ME type. The most prevalent medication class occurring in the 20–64‐year age group (256 cases, 11.7%) was 'antibacterials for systemic use', whereas 'contrast media' (236 cases, 11.6%) and 'blood substitutes and perfusion solutions' (98 cases, 19.3%) were the most prevalent drug classes in the ≥65‐ and <20‐year‐old age groups, respectively. Conclusions: It is necessary to establish guidelines for the prevention of medication‐related incidents according to the medication use process and patient age group. [ABSTRACT FROM AUTHOR]

While there is much research on coordinating the dual‐channel supply chain using the revenue‐sharing contract, it is unclear if there is a better mechanism design in the buy‐online‐and‐pickup‐in‐store (BOPS) mode. In this channel integration environment, the customer service provided by the bricks‐and‐mortar store is critical to the chain's success. Based on a stackable game model, we analyze the contract methods for the cases of revenue sharing and no revenue sharing, where the latter is classified into two types: All the credit goes to the offline or online channel. Focusing on improving consumer service and supply chain performance in the BOPS mode, we observe that revenue sharing is not necessarily the best contract type, while the non‐revenue‐sharing contract of a lump‐sum subsidy plus quantity discount can coordinate the supply chain. We also analyze the impacts of some endogenous parameters and derive the conditions for the equilibrium outcomes. We find that revenue sharing cannot effectively stimulate the offline channel to improve its service effort as the offline channel is more concerned about service cost sharing than revenue sharing. The results are similar to those of revenue allocation to the online or offline channel in the BOPS mode, but the conditions are slightly different. Conducting numerical studies to gain insights from the analytical findings, we find that the subsidy contract is better than the revenue‐sharing approach under various market conditions. [ABSTRACT FROM AUTHOR]

Background: No tick‐borne pathogens (TBPs) causing haemolytic anaemia in cattle have been reported, except Theileria orientalis and complete blood count (CBC) profile is the only haematological parameter to determine the severity of regenerative haemolytic anaemia. Objectives: To identify the causative agents of TBP‐induced haemolytic anaemia and determine haematological parameters that indicate haemolytic anaemia in grazing cattle. Methods: Eighty‐two Korean indigenous cattle (Hanwoo) were divided into two groups: grazing (n = 67) and indoor (n = 15) groups. CBC and serum biochemistry were performed. PCR was conducted using whole blood‐extracted DNA to investigate the prevalence of TBPs. Results: TBP‐induced haemolytic anaemia was observed in the grazing group. In grazing cattle, co‐infection (43.3%, 29/67) was most frequently detected, followed by T. orientalis (37.6%, 25/67) and Anaplasma phagocytophilum infections (1.5%, 1/67). In indoor cattle, only co‐infection (20%, 3/15) was identified. Grazing cattle exhibited regenerative haemolytic anaemia with marked monocytosis, mild neutropenia, and thrombocytopenia. According to grazing frequency, the 1st‐time grazing group had more severe anaemia than the 2nd‐time grazing group. Elevations in indirect bilirubin and L‐lactate due to haemolytic anaemia were identified, and correlations with the respective markers were determined in co‐infected grazing cattle. Conclusions: Quantitative evaluation of haematocrit, mean corpuscular volume, and reticulocytes (markers of regenerative haemolytic anaemia in cattle) was performed for the first time. Our results show that, in addition to T. orientalis, A. phagocytophilum is strongly associated with anaemia. The correlation between haemolytic anaemia severity and haematological parameters (indirect bilirubin, reticulocytes, and L‐lactate) was confirmed. [ABSTRACT FROM AUTHOR]

The concept of "Frustrated Lewis pairs" (FLPs), which emerged from the discovery that H2 can be reversibly activated by combinations of sterically encumbered Lewis acids and bases. Since then, the field of FLP chemistry has expanded enormously. One of the most remarkable achievements is the development of FLP catalysts for hydrogenation, which are environmentally friendly and have potential industrial application prospects. In recent years, this unique catalysis concept has pushed the study of FLP chemistry to a new direction: heterogeneous FLP catalysts. This review outlines the recent research progress of new strategies to design and synthesize heterogeneous FLPs for hydrogenation reaction, and prospects the development of novel heterogeneous FLP catalysts. [ABSTRACT FROM AUTHOR]

Chemotherapy combined with debulking surgery is the standard treatment protocol for high‐grade serous ovarian carcinoma (HGSOC). Nonetheless, a significant number of patients encounter relapse due to the development of chemotherapy resistance. To better understand and address this resistance, we conducted a comprehensive study investigating the transcriptional alterations at the single‐cell resolution in tissue samples from patients with HGSOC, using single‐cell RNA sequencing and T‐cell receptor sequencing techniques. Our analyses unveiled notable changes in the tumor signatures after chemotherapy, including those associated with epithelial–mesenchymal transition and cell cycle arrest. Within the immune compartment, we observed alterations in the T‐cell profiles, characterized by naïve or pre‐exhausted populations following chemotherapy. This phenotypic change was further supported by the examination of adjoining T‐cell receptor clonotypes in paired longitudinal samples. These findings underscore the profound impact of chemotherapy on reshaping the tumor landscape and the immune microenvironment. This knowledge may provide clues for the development of future therapeutic strategies to combat treatment resistance in HGSOC. [ABSTRACT FROM AUTHOR]

Sustained cardiac hypertrophy damages the heart and weakens cardiac function, often leading to heart failure and even death. Pathological cardiac hypertrophy has become a central therapeutic target for many heart diseases including heart failure. However, the underlying mechanisms of cardiac hypertrophy, especially the involvement of autophagy program, are still ill‐understood. Synaptotagmin‐7 (Syt7), a multifunctional and high‐affinity calcium sensor, plays a pivotal role in asynchronous neurotransmitter release, synaptic facilitation, and vesicle pool regulation during synaptic transmission. However, little is known about whether Syt7 is expressed in the myocardium and involved in the pathogenesis of heart diseases. Here we showed that Syt7 was significantly upregulated in Ang II‐treated hearts and cardiomyocytes. Homozygous syt7 knockout (syt7−/−) mice exhibited significantly attenuated cardiac hypertrophy and fibrosis and improved cardiac function. We further found that Syt7 exerted a pro‐hypertrophic effect by suppressing the autophagy process. In exploring the upstream mechanisms, microRNA (miR)‐93 was identified to participate in the regulation of Syt7 expression. miR‐93 protected hearts against Ang II‐induced hypertrophy through targeting Syt7‐autophagy pathway. In summary, our data reveal a new cardiac hypertrophy regulator and a novel hypertrophy regulating model composed of miR‐93, Syt7 and autophagy program. These molecules may serve as potential therapeutic targets in the treatment of cardiac hypertrophy and heart failure. [ABSTRACT FROM AUTHOR]

The primary objective of this study was to investigate the factors contributing to hyperglycemic adverse events (AEs) associated with the administration of remdesivir in hospitalized patients diagnosed with coronavirus disease 2019 (COVID‐19). Furthermore, the study aimed to develop a risk score model employing various machine learning approaches. A total of 1262 patients were enrolled in this investigation. The relationship between covariates and hyperglycemic AEs was assessed through logistic regression analysis. Diverse machine learning algorithms were employed for the purpose of forecasting hyperglycemia‐related complications. After adjusting for covariates, individuals with a body mass index ≥23 kg/m2, those using proton pump inhibitors, cholinergic medications, or individuals with cardiovascular diseases exhibited approximately 2.41‐, 2.73‐, 2.65‐, and 1.97‐fold higher risks of experiencing hyperglycemic AEs (95% CI 1.271–4.577, 1.223–6.081, 1.168–5.989, and 1.119–3.472, respectively). Multivariate logistic regression, elastic net, and random forest models displayed area under the receiver operating characteristic curve values of 0.65, 0.66, and 0.60, respectively (95% CI 0.572–0.719, 0.640–0.671, and 0.583–0.611, respectively). This study comprehensively explored factors associated with hyperglycemic complications arising from remdesivir administration and, concurrently, leveraged a range of machine learning methodologies to construct a risk scoring model, thereby facilitating the tailoring of individualized remdesivir treatment regimens for patients with COVID‐19. [ABSTRACT FROM AUTHOR]

The catalytic alkoxycarbonylation of alkenes is an attractive, atom‐efficient method for producing value‐added carboxylic esters. However, the conventional catalyst system for this reaction needs coordination with a noble metal, sensitive ligands and proton acid additives. Therefore, the design of a simple and efficient catalyst system without any acid additives under mild conditions is still a major challenge. In this work, a simple ruthenium/deep eutectic solvent catalytic system was developed to effectively catalyse the alkoxycarbonylation reaction without any sensitive ligands or acid additives under mild conditions. The conversion of 1‐hexene reached 99.0 %, and the ester selectivity was 99.1 %, much higher than that of Ruthenium carbonyl without deep eutectic solvent. The excellent performance of the catalytic system could be ascribed to the form of the ruthenium active species [Ru(CO)2Br3]− in the deep eutectic solvent. This innovative catalyst system presents a significant advancement in the alkoxycarbonylation reaction, eliminating the use of acid additives and delicate ligands. [ABSTRACT FROM AUTHOR]

Background: Dysfunction of the primary motor cortex, participating in regulation of posture and gait, is implicated in freezing of gait (FOG) in Parkinson's disease (PD). Objective: The aim was to reveal the mechanisms of "OFF‐period" FOG (OFF‐FOG) and "levodopa‐unresponsive" FOG (ONOFF‐FOG) in PD. Methods: We measured the transcranial magnetic stimulation (TMS) indicators and gait parameters in 21 healthy controls (HCs), 15 PD patients with ONOFF‐FOG, 15 PD patients with OFF‐FOG, and 15 PD patients without FOG (Non‐FOG) in "ON" and "OFF" medication conditions. Difference of TMS indicators in the four groups and two conditions and its correlations with gait parameters were explored. Additionally, we explored the effect of 10 Hz repetitive TMS on gait and TMS indicators in ONOFF‐FOG patients. Results: In "OFF" condition, short interval intracortical inhibition (SICI) exhibited remarkable attenuation in FOG patients (both ONOFF‐FOG and OFF‐FOG) compared to Non‐FOG patients and HCs. The weakening of SICI correlated with impaired gait characteristics in FOG. However, in "ON" condition, SICI in ONOFF‐FOG patients reduced compared to OFF‐FOG patients. Pharmacological treatment significantly improved SICI and gait in OFF‐FOG patients, and high‐frequency repetitive TMS distinctly improved gait in ONOFF‐FOG patients, accompanied by enhanced SICI. Conclusions: Motor cortex disinhibition, represented by decreased SICI, is related to FOG in PD. Refractory freezing in ONOFF‐FOG patients correlated with the their reduced SICI insensitive to dopaminergic medication. SICI can serve as an indicator of the severity of impaired gait characteristics in FOG and reflect treatments efficacy for FOG in PD patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Oxidative damage‐triggered apoptosis in lens epithelial cells is considered as a main risk factor in the pathogenesis of age‐related cataracts. Ku70 is a key factor in the DNA repair process of double‐strand breaks. In the present study, we aimed to investigate the role of Ku70 and its related E3 ubiquitin ligase in lens epithelial cell apoptosis. The levels of Ku70 in the anterior lens capsules of human cataracts and Emory mice were lower compared to controls. H2O2 treatment resulted in decreased expression of Ku70 through accelerating Ku70 ubiquitination. Parkin, an E3 ubiquitin ligase, could interact with Ku70 and promote the ubiquitination and degradation of this protein. In addition, ubiquitinated Ku70 was regulated by ubiquitin‐proteasome, autophagy‐lysosome and mitophagy pathways. Ectopic expression of Ku70 protected SRA01/04 cells from H2O2‐induced apoptosis, whereas silencing Ku70 exhibited the opposite trend. Co‐transfected with Parkin non‐ubiquitinatable Ku70 mutant could maintain its anti‐apoptosis ability, whereas wild‐type Ku70 failed. Moreover, Ku70 might facilitate mitochondrial fusion by increasing the expression of Mitofusin 1/2. The present study revealed that Parkin‐mediated Ku70 ubiquitination facilitated H2O2‐induced lens epithelial cell apoptosis through alleviating mitochondrial fusion, which could provide potential targets for age‐related cataract treatment. [ABSTRACT FROM AUTHOR]

T‐cell acute lymphoblastic leukemia (T‐ALL) is an aggressive malignant blood disorder with a high rate of relapse. Patients relapse as a result of minimal residual disease (MRD), which originates from residual T‐ALL cells in the bone marrow microenvironment (BMM). In the present study, it is observed that adipocytes increase dramatically in the BMM of T‐ALL patients after exposure to chemotherapeutic drugs. Then, it is proved that adipocytes attract T‐ALL cells by releasing CXCL13 and support leukemia cell survival by activating the Notch1 signaling pathway via DLL1 and Notch1 binding. Furthermore, it is verified that dexamethasone (DEX) induces adipogenic differentiation by enhancing the expression of SREBF1 in bone marrow mesenchymal stromal cells (BMSCs), and an SREBF1 inhibitor significantly decreases the adipogenic potential of BMSCs and the subsequent ability of adipocytes to support T‐ALL cells in vitro and in vivo. These findings confirm that the differentiation of BMSCs to adipocytes induced by DEX contributes to MRD in T‐ALL and provides an auxiliary clinical treatment to reduce the recurrence rate. [ABSTRACT FROM AUTHOR]

Background: Minimal residual disease (MRD) is an important prognostic factor for survival in adults with acute leukemia. The role of pretransplantation MRD status in myelodysplastic syndrome with excess blasts (MDS‐EB) is unknown. This study retrospectively analyzed the relationship between pretransplantation MRD status and long‐term survival. Materials and Methods: Patients with MDS‐EB who underwent allogeneic hematopoietic stem cell transplantation (allo‐HSCT) from March 5, 2005, to November 8, 2020, were included. The relationship between pretransplantation MRD status and long‐term survival was analyzed using univariate and multivariate logistic regression models. Results: Of 220 patients with MDS‐EB who underwent allo‐HSCT, 198 were eligible for inclusion in this multicenter, retrospective cohort study. Complete remission was attained in 121 (61.1%) patients, and 103 patients underwent detection of MRD pretransplantation, with 67 patients being MRD‐positive and 36 patients being MRD‐negative. The median follow‐up time was 16 months, the median age was 41 years (6–65 years), and 58% of the patients were men. The 3‐year disease‐free survival (DFS) and overall survival (OS) probabilities for all patients were 70.1% and 72.9%, respectively. For patients in complete remission, the 3‐year DFS and OS probabilities were 72.2% and 74.8%, respectively. Further analysis found that the 3‐year DFS rates of MRD‐negative and MRD‐positive patients were 85.6% and 66.5% (p =.045), respectively, whereas the 3‐year OS rates were 91.3% and 66.4% (p =.035), respectively. Univariate and multivariate analyses showed that poor pretransplantation MRD clearance was an independent prognostic risk factor for DFS and OS. Conclusion: Poor pretransplantation MRD clearance is an independent prognostic risk factor for long‐term survival after allo‐HSCT for patients with MDS‐EB. Plain language summary: Poor minimal residual disease clearance pretransplanation is an independent prognostic risk factor for long‐term survival after allogeneic hematopoietic stem cell transplantation for patients with myelodysplastic syndrome with excess blasts. The role of minimal residual disease (MRD) status pretransplantation in the survival of patients with myelodysplastic syndrome with excess blasts after allogeneic hematopoietic stem cell transplantation in present multicenter, retrospective, cohort study was evaluated. The primary outcome showed that MRD status was the only independent prognostic factor that affects long‐term survival. [ABSTRACT FROM AUTHOR]

The strong explosiveness, toxicity and environmental pollution of picric acid make its sensitive detection important. Recently, LMOF materials are showing great potential toward efficient detection of PA. However, hindered by the weak connections between LMOFs and analytes, a feasible fluorescence selectivity and sensitivity to desired compounds by constructed LMOFs remain challenging. Herein, we propose a new strategy by using the innate adsorption ability of MOFs. We choose NDC−Zn, a highly stable LMOF with unique pore structures. The topology of ligands can capture PAs specifically inside the pores and the selectivities are further elevated. PET effects are boosted due to longer and closer contact between ligands and trapped PAs, thus higher sensitivity is also achieved. Besides, a fluorescence enhancement at a visible wavelength was found as the concentration of PA increased, suggesting a potential application of naked‐eye recognition for PA. NDC−Zn exhibited an outstanding detection sensitivity for PA with a quenching constant of 49657 M−1, as well as distinctive fluorescence quenching among 9 nitro explosives. From DFT calculations, the fluorescence quenching mechanisms such as PET and the complexation between H2NDC and PA were supported. [ABSTRACT FROM AUTHOR]

Objectives: As a critical component of the autophagic machinery, autophagy‐related gene 5 (ATG5) is essential for autophagosome formation. Autophagy participates in the transformation and progression of various malignant tumors, but the role of ATG5 in hepatocellular carcinoma (HCC) remains to be illustrated. In this study we aimed to investigate the prognostic significance of ATG5 in HCC. Methods: ATG5 expression was evaluated in 89 pairs of HCC tissues and adjacent non‐tumor tissues. The relationship between ATG5 expression and patients' clinicopathological characteristics and prognosis were evaluated. Moreover, subgroup analyses were performed regarding patients' age and number of tumors. Nomograms estimating overall survival (OS) and disease‐free survival (DFS) were conducted. Results: ATG5 expression was increased in HCC specimens rather than adjacent non‐tumor tissues. The upregulated ATG5 expression was positively associated with serum α‐fetoprotein (AFP) level. Moreover, cases with a strong ATG5 expression had a poorer disease‐free survival (DFS) and overall survival (OS) than those with a weak ATG5 expression. Multivariate analysis showed that a strong expression of ATG5 was related to a poor OS and DFS in patients with HCC. Further analysis indicated that cases with a higher ATG5 expression had a poorer OS and DFS in the young patients (≤55 years) and those with solitary tumor. The nomogram suggested that there was a coherence between nomogram prediction and the actual situation of patient survival related to ATG5. Conclusion: ATG5 promotes tumor progression in HCC, making it a potential biomarker in the diagnosis and a therapeutic target of HCC. [ABSTRACT FROM AUTHOR]

Background: Mounting research support that cholinergic dysfunction plays a prominent role in freezing of gait (FOG), which commonly occurs in Parkinson's disease (PD). Basal forebrain (BF), especially the cholinergic nuclei 4 (Ch4), provides the primary source of the brain cholinergic input. However, whether the degeneration of BF and its innervated cortex contribute to the pathogenesis of FOG is unknown. Objective: To explore the role of structural alterations of BF and its innervated cortical brain regions in the pathogenesis of PD patients with freezing. Methods: Magnetic resonance imaging assessments and neurological assessments were performed on 20 PD patients with FOG (PD‐FOG), 20 without FOG (PD‐NFOG), and 21 healthy participants. Subregion volumes of the BF were compared among groups. Local gyrification index (LGI) was computed to reveal the cortical alternations. Relationships among subregional BF volumes, LGI, and the severity of FOG were evaluated by multiple linear regression. Results: Our study discovered that, compared to PD‐NFOG, PD‐FOG exhibited significant Ch4 atrophy (p = 4.6 × 10−5), accompanied by decreased LGI values in the left entorhinal cortex (p = 3.00 × 10−5) and parahippocampal gyrus (p = 2.90 × 10−5). Based on the regression analysis, Ch4 volume was negatively associated with FOG severity in PD‐FOG group (β = −12.224, T = −2.556, p = 0.031). Interpretation: Our results imply that Ch4 degeneration and microstructural disorganization of its innervated cortical brain regions may play important roles in PD‐FOG. [ABSTRACT FROM AUTHOR]

Objectives: Drug‐induced liver injury (DILI) is an increasing etiology of liver dysfunction, with various incidence worldwide. To better understand the disease burden and establish appropriate preventive and treatment strategies, a systematic review and meta‐analysis was conducted. Methods: PubMed, EMBASE, Web of Science, and Cochrane Library were searched for studies on the incidence of DILI published up to June 1, 2022. According to the predefined criteria, only population‐based studies were included. Incidence was presented as cases per 100 000 person‐years with 95% confidence interval (CI) using a random‐effects model. Results: A total of 14 studies were included. The overall incidence of DILI was 4.94 per 100 000 person‐years (95% CI 4.05–5.83). Time‐based cumulative meta‐analysis suggested that the incidence of DILI increased over time since 2010. The incidence varied by regions, with Asia having the highest incidence of 17.82 per 100 000 person‐years (95% CI 6.26–29.38), while North America having the lowest incidence of 1.72 per 100 000 person‐years (95% CI 0.48–2.95). All studies reported a higher incidence of DILI in the elderly but comparable incidences between male and female (3.42 per 100 000 person‐years vs 4.64 per 100 000 person‐years). Conclusions: The global incidence of DILI has been increasing since 2010, with the highest incidence in Asia. Understanding the epidemiological characteristics of DILI helps establish specific strategies to deal with this emerging health problems. [ABSTRACT FROM AUTHOR]

Isobutene dimerization is an important route to properly utilize mixed C4 and further produce isooctane with a high‐octane number to replace MTBE in gasoline. A highly selective catalyst, which is effective for isobutene dimerization but ineffective for other olefins in the C4 mixture, is necessary for industrial implementation. In this work, a series of supported metal sulfate catalysts FexZny/SiO2 were prepared and characterized by XRD, SEM, N2 physical adsorption‐desorption, NH3‐TPD, Py‐FTIR, and XPS. Fe0.2Zn1.8/SiO2 can achieve isobutene conversion up to 89 % with 0 % conversion of n‐butene, and the selectivity of isooctenes (C8=) product is 57 % (10 h on stream). Furthermore, isobutene conversion can sustain above 80 % after 50 h. It is found that these supported catalysts contain Zn2+, Zn+, Fe3+, and Fe2+ species, and there is a synergetic effect between Zn2+ and Fe2+. Zn2+ is beneficial to improve the conversion of isobutene, and Fe2+ facilitates the formation of C8=, resulting in a high C8= yield. [ABSTRACT FROM AUTHOR]

Summary: In a prospective, explorative study, the donor‐source difference of haploidentical family (HF), matched sibling (MS), and unrelated donors (UD) was evaluated for the outcome of haematopoietic cell transplantations (HCT) in 101 patients with acute myeloid leukaemia (AML) in complete remission (CR). To eliminate compounding effects, a uniform conditioning regimen containing antithymocyte globulin (ATG) was used. After transplantation, there was a significantly higher cumulative incidence of acute graft‐versus‐host disease (GVHD) in HF‐HCT patients (49%, 7%, and 16% for HF‐, MS‐ and UD‐HCT respectively; p < 0.001). A quarter of acute GVHD cases observed in HF‐HCT patients occurred within three days of engraftment and were characterized by diffuse skin rash, fever, weight gain, and hypoalbuminaemia. This peri‐engraftment acute GVHD was not observed in MS‐HCT or UD‐HCT patients. Additionally, a significantly higher proportion of HF‐HCT patients achieved complete donor chimaerism in the peripheral mononuclear cells at one month (88%, 46%, and 69% for HF‐, MS‐ and UD‐HCT respectively; p = 0.001). There was no significant difference in engraftment, chronic GVHD, leukaemia recurrence, non‐relapse mortality, and patient survival. In patients with AML in CR who received HCT using ATG‐containing conditioning, stronger donor–patient alloreactivity was observed in HF‐HCT, in terms of increased acute GVHD and higher likelihood of complete donor chimaerism. [ABSTRACT FROM AUTHOR]

Methylthioadenosine phosphorylase (MTAP) deficiency occurs in various malignancies and is associated with poor survival in cancer patients. However, the mechanisms underlying tumour progression due to MTAP loss are yet to be elucidated. Utilizing integrated analyses of the transcriptome, proteome and secretome, we demonstrated that MTAP deficiency alters tumour‐intrinsic, immune‐related pathways and reprograms cytokine profiles towards a tumour‐favourable environment. Additionally, MTAP‐knockout cells exhibited a marked increase in the immune checkpoint protein PD‐L1. Upon co‐culturing primary T cells with cancer cells, MTAP loss‐mediated PD‐L1 upregulation inhibited T cell‐mediated killing activity and induced several T cell exhaustion markers. In two xenograft tumour models, we showed a modest increase in average volume of tumours derived from MTAP‐deficient cells than that of MTAP‐proficient tumours. Surprisingly, a remarkable increase in tumour size was observed in humanized mice bearing MTAP‐deficient tumours, as compared to their MTAP‐expressing counterparts. Following immunophenotypic characterization of tumour‐infiltrating leukocytes by mass cytometry analysis, MTAP‐deficient tumours were found to display decreased immune infiltrates with lower proportions of both T lymphocytes and natural killer cells and higher proportions of immunosuppressive cells as compared to MTAP‐expressing tumour xenografts. Taken together, our results suggest that MTAP deficiency restructures the tumour immune microenvironment, promoting tumour progression and immune evasion. [ABSTRACT FROM AUTHOR]

Metal sulfides generally show high visible light photocatalytic activity, but lower selectivity in the CO2 photoreduction due to the competitive hydrogen evolution. Here, a partial hydrolysis method is reported to promote the selective photocatalytic CO2 reduction over ZnIn2S4. The ZnIn2S4 was post‐hydrolyzed in an aqueous ammonia solution to form oxide species (ZIS‐[InOx]). Detailed experiment and DFT calculation demonstrated that the post‐hydrolysis treatment facilely prohibits the recombination of photogenerated charge carriers and benefits CO2 activation. Under visible light irradiation, the ZIS‐[InOx] photocatalyst shows enhanced CO2‐to‐CO conversion activity with a CO‐evolving rate of 1771 μmol g−1 h−1, which is about 8 times higher than that over pristine ZIS and 3.5 times higher than that over bulk ZIS/In2O3. More importantly, the post hydrolysis treatment significantly prohibits the hydrogen evolution and increases the CO/H2 ratio from 0.08 over ZIS to 1.8 over ZIS‐[InOx]. This work provides a new strategy to prepare catalysts for photocatalytic CO2 reduction. [ABSTRACT FROM AUTHOR]

T‐cell acute lymphoblastic leukemia (T‐ALL) is an aggressive hematological malignancy with a poor prognosis, urging for novel therapeutic targets and treatment strategies. N6‐methyladenosine (m6A) is a crucial methylation modification that affects the pathogenesis of leukemia by regulating the mRNA of key genes. Interferon regulatory factor 8 (IRF8) is a crucial transcription factor for hematological lineage commitment, but its role in T‐ALL is unclear. Here, IRF8 is shown to suppress T‐ALL. The expression of IRF8 is abnormally silenced in patients with T‐ALL. Knockout of Irf8 significantly hastens the progression of Notch1‐induced T‐ALL in vivo. Overexpression of IRF8 suppresses the proliferation and invasion of T‐ALL cells by inhibiting the phosphatidylinositol 3‐kinase/AKT signaling pathway. The fat mass‐ and obesity‐associated protein (FTO), an m6A demethylase, is responsible for directly binding to m6A sites in 3′ untranslated region of IRF8 messenger RNA (mRNA) and inducing mRNA degradation via m6A modification. Targeting the FTO‐IRF8 axis is used as a proof of concept therapy; inhibition of FTO's demethylase activity drastically alleviates the proliferation of leukemic cells and prolongs the survival of T‐ALL mice by restoring IRF8 expression. This study elucidates the pathogenesis of T‐ALL from the perspective of epitranscriptomics and provides new insight into the genetic mechanisms and targeted therapy of T‐ALL. [ABSTRACT FROM AUTHOR]

All‐optical responsive nanomaterials, which can rapidly switch between two stable states, have been regarded as the next‐generation memories due to their potential to realize binary information storage and implement on‐chip, integrated photonic neuromorphic systems. Rare earth oxides are preeminent candidates owing to their extraordinary luminescent stability and narrow optical transitions. However, due to the lack of simple and effective optical switches, it is difficult to realize all‐optical data storage, encoding, and retrieval by pure rare earth‐doped luminescent nanoparticles. Here, a rapid and high‐contrast of 104 luminescent switching of Y2O3:Eu3+ nanoparticle between the enhancement and quenching states is achieved by employing the strong light confinement and ultrafast thermal response of localized surface plasmon resonance. A self‐encrypted all‐optical memory is presented with optical information writing, encryption, reading, and re‐writing, and a high‐sensitivity synaptic response of emitters to frequency and light intensity flux, which can be harnessed to encrypt information flows and promote convenient and high‐security information encryption. Such a convenient and secure plasmonic thermally assisted self‐encrypting luminescent switch paves the way for constructing high‐performance stimuli‐responsive rare earth oxide crystals on demand and expanding their applications in various data encryption, anti‐counterfeiting, and rewritable colouration devices. [ABSTRACT FROM AUTHOR]

Retinoic acid receptor–related orphan receptor α (RORα) is a transcription factor involved in nuclear gene expression and a known tumor suppressor. RORα was the first identified substrate of lysine methylation–dependent degradation. However, the mechanisms of other post‐translational modifications (PTMs) that occur in RORα remain largely unknown, especially in liver cancer. Arginine methylation is a common PTM in arginine residues of nonhistone and histone proteins and affects substrate protein function and fate. We found an analogous amino acid disposition containing R37 at the ROR N‐terminus compared to histone H3 residue, which is arginine methylated. Here, we provide evidence that R37 methylation–dependent degradation is carried out by protein arginine methyltransferase 5 (PRMT5). Further, we discovered that PRMT5 regulated the interaction between the E3 ubiquitin ligase ITCH and RORα through RORα arginine methylation. Arginine methylation–dependent ubiquitination‐mediated RORα degradation reduced downstream target gene activation. H2O2‐induced reactive oxygen species (ROS) decreased PRMT5 protein levels, consequently increasing RORα protein levels in HepG2 liver cancer cells. In addition, ROS inhibited liver cancer progression by inducing apoptosis via PRMT5‐mediated RORα methylation and the ITCH axis. Our results potentiate PRMT5 as an elimination target in cancer therapy, and this additional regulatory level within ROS signaling may help identify new targets for therapeutic intervention in liver cancer. [ABSTRACT FROM AUTHOR]

Background: Acute myeloid leukemia (AML) is a hematopoietic malignancy with a prognosis that varies with genetic heterogeneity of hematopoietic stem/progenitor cells (HSPCs). Induction chemotherapy with cytarabine and anthracycline has been the standard care for newly diagnosed AML, but about 30% of patients have no response to this regimen. The resistance mechanisms require deeper understanding. Methods: In our study, using single‐cell RNA sequencing, we analyzed the heterogeneity of bone marrow CD34+ cells from newly diagnosed patients with AML who were then divided into sensitive and resistant groups according to their responses to induction chemotherapy with cytarabine and anthracycline. We verified our findings by TCGA database, GEO datasets, and multiparameter flow cytometry. Results: We established a landscape for AML CD34+ cells and identified HSPC types based on the lineage signature genes. Interestingly, we found a cell population with CRIP1highLGALS1highS100Ashigh showing features of granulocyte‐monocyte progenitors was associated with poor prognosis of AML. And two cell populations marked by CD34+CD52+ or CD34+CD74+DAP12+ were related to good response to induction therapy, showing characteristics of hematopoietic stem cells. Conclusion: Our study indicates the subclones of CD34+ cells confers for outcomes of AML and provides biomarkers to predict the response of patients with AML to induction chemotherapy. This study indicates the subclones of CD34+ cells confer for outcomes of acute myeloid leukemia (AML) and provides biomarkers to predict the response of patients with AML to induction chemotherapy. [ABSTRACT FROM AUTHOR]

Objectives: Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) entry into the host cells depends on the expression of angiotensin‐converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). We investigated the distribution of ACE2‐ and TMPRSS2‐expressing cells in various oral tissues to identify the underlying mechanism of oral manifestations in patients with coronavirus disease 2019. Subjects: We analyzed the expression patterns of ACE2 and TMPRSS2 in the oral mucosa (tongue, palate, and buccal mucosa), trigeminal ganglion, vessels, and salivary glands of 9 Sprague‐Dawley rats using immunohistochemistry and immunofluorescence. Results: ACE2 and TMPRSS2 were strongly expressed in the intermediate layer of the squamous epithelia of tongue papillae and buccal mucosa. ACE2‐ and TMPRSS2‐positive cells were observed in the taste buds of the tongue. Additionally, ACE2 and TMPRSS2 were co‐expressed in the ductal epithelium and acinar cells of salivary glands. Furthermore, both ACE2 and TMPRSS2 were stained in the neuronal cell body of trigeminal ganglia, but not in Schwann cells. Moreover, ACE2 and TMPRSS2 were expressed in capillaries, but not in venules/arterioles. Conclusions: SARS‐CoV‐2 can spread the suprabasal area of squamous epithelia of the oral mucosa, invades taste bud, trigeminal nerve, parotid gland, and microvessel, resulting in oral manifestations. [ABSTRACT FROM AUTHOR]

The tumour suppressor p53 has been implicated in the host defence system against hepatitis C virus (HCV) infection, although the detailed mechanism remains unknown. Here, we found that p53 inhibits HCV replication by downregulating HCV Core protein levels in human hepatoma cells. For this effect, p53 potentiated the role of E6‐associated protein (E6AP) as an E3 ligase to induce ubiquitination and proteasomal degradation of HCV Core. Specifically, p53 facilitated the binding of E6AP to HCV Core through direct interactions with the two proteins. In addition, E6AP failed to induce ubiquitination of HCV Core in the absence of p53, suggesting that p53 increases the E3 ligase activity of E6AP in a triple complex consisting of p53, E6AP and HCV Core. [ABSTRACT FROM AUTHOR]

Opioid abuse and addiction have become a global pandemic, posing tremendous health and social burdens. The rewarding effects and the occurrence of withdrawal symptoms are the two mainstays of opioid addiction. Mu‐opioid receptors (MORs), a member of opioid receptors, play important roles in opioid addiction, mediating both the rewarding effects of opioids and opioid withdrawal syndrome (OWS). The underlying mechanism of MOR‐mediated opioid rewarding effects and withdrawal syndrome is of vital importance to understand the nature of opioid addiction and also provides theoretical basis for targeting MORs to treat drug addiction. In this review, we first briefly introduce the basic concepts of MORs, including their structure, distribution in the nervous system, endogenous ligands, and functional characteristics. We focused on the brain circuitry and molecular mechanism of MORs‐mediated opioid reward and withdrawal. The neuroanatomical and functional elements of the neural circuitry of the reward system underlying opioid addiction were thoroughly discussed, and the roles of MOR within the reward circuitry were also elaborated. Furthermore, we interrogated the roles of MORs in OWS, along with the structural basis and molecular adaptions of MORs‐mediated withdrawal syndrome. Finally, current treatment strategies for opioid addiction targeting MORs were also presented. [ABSTRACT FROM AUTHOR]

Aims: This systematic literature review and meta‐analysis aimed to evaluate the risk factors for vancomycin‐associated acute kidney injury (AKI) incidence. Methods: This study assessed risk factors for vancomycin‐associated AKI in adult patients by searching studies from PubMed, the Cochrane Library and Embase. Random effect models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Results: Fifty‐three studies were included in our meta‐analysis. For patient factors, black race (OR 1.47, 95% CI: 1.16–1.87), Caucasian (OR 0.72, 95% CI: 0.58–0.90) and obesity (OR 1.46, 95% CI: 1.12–1.90) were associated with an increase in vancomycin‐associated AKIs. In terms of vancomycin‐related factors, longer treatment duration (>14 d; OR 1.73, 95% CI: 1.06–2.83), serum vancomycin trough level >15 μg/mL (OR 2.10, 95% CI: 1.43–3.07) and vancomycin trough level >20 μg/mL (OR 2.84, 95% CI: 1.48–5.44) increased the risks of vancomycin‐associated AKI. For comorbidities and clinical factors, renal disease (OR 2.19, 95% CI: 1.51–3.17) showed the highest odds of vancomycin‐associated AKI, followed by hepatic disease, intensive care unit admission, heart failure, sepsis, coronary heart disease and diabetes mellitus. For concomitant nephrotoxic drugs, amphotericin B (OR 5.21, 95% CI: 3.44–7.87) showed the highest odds of vancomycin‐associated AKI, followed by acyclovir (OR 3.22, 95% CI: 1.39–7.46), vasopressors, loop diuretics, piperacillin–tazobactam and aminoglycoside. The use of any concomitant nephrotoxic agent (OR 1.74, 95% CI: 1.17–2.58) increased the odds of vancomycin‐associated AKI. Conclusion: Our results may help predict the risk of vancomycin‐associated AKI in the clinical setting. [ABSTRACT FROM AUTHOR]

Aims: To compare the efficacy and safety of adding low‐dose lobeglitazone (0.25 mg/day) or standard‐dose lobeglitazone (0.5 mg/day) to patients with type 2 diabetes mellitus (T2DM) with inadequate glucose control on metformin and dipeptidyl peptidase (DPP4) inhibitor therapy. Materials and Methods: In this phase 4, multicentre, double‐blind, randomized controlled, non‐inferiority trial, patients with T2DM insufficiently controlled by metformin and DPP4 inhibitor combination therapy were randomized to receive either low‐dose or standard‐dose lobeglitazone. The primary endpoint was non‐inferiority of low‐dose lobeglitazone in terms of glycaemic control, expressed as the difference in mean glycated haemoglobin levels at week 24 relative to baseline values and compared with standard‐dose lobeglitazone, using 0.5% non‐inferiority margin. Results: At week 24, the mean glycated haemoglobin levels were 6.87 ± 0.54% and 6.68 ± 0.46% in low‐dose and standard‐dose lobeglitazone groups, respectively (p =.031). The between‐group difference was 0.18% (95% confidence interval 0.017‐0.345), showing non‐inferiority of the low‐dose lobeglitazone. Mean body weight changes were significantly greater in the standard‐dose group (1.36 ± 2.23 kg) than in the low‐dose group (0.50 ± 1.85 kg) at week 24. The changes in HOMA‐IR, lipid profile and liver enzyme levels showed no significant difference between the groups. Overall treatment‐emergent adverse events (including weight gain, oedema and hypoglycaemia) occurred more frequently in the standard‐dose group. Conclusions: Adding low‐dose lobeglitazone to metformin and DPP4 inhibitor combination resulted in a non‐inferior glucose‐lowering outcome and fewer adverse events compared with standard‐dose lobeglitazone. Therefore, low‐dose lobeglitazone might be one option for individualized strategy in patients with T2DM. [ABSTRACT FROM AUTHOR]

Background: Atherosclerosis‐related adverse events are commonly observed even in conditions with low cardiovascular (CV) risk. Longitudinal data regarding the association of normal systolic blood pressure maintenance (SBPmaintain) with coronary plaque volume changes (PVC) has been limited in adults without traditional CV disease. Hypothesis: Normal SBPmaintain is important to attenuate coronary atherosclerosis progression in adults without baseline CV disease. Methods: We analyzed 95 adults (56.7 ± 8.5 years; 40.0% men) without baseline CV disease who underwent serial coronary computed tomographic angiography with mean 3.5 years of follow‐up. All participants were divided into two groups of normal SBPmaintain (follow‐up SBP < 120 mm Hg) and ≥elevated SBPmaintain (follow‐up SBP ≥ 120 mm Hg). Annualized PVC was defined as PVC divided by the interscan period. Results: Compared to participants with normal SBPmaintain, those with ≥elevated SBPmaintain had higher annualized total PVC (mm3/year) (0.0 [0.0–2.2] vs. 4.1 [0.0–13.0]; p <.001). Baseline total plaque volume (β =.10) and the levels of SBPmaintain (β =.23) and follow‐up high‐density lipoprotein cholesterol (β = −0.28) were associated with annualized total PVC (all p <.05). The optimal cutoff of SBPmaintain for predicting plaque progression was 118.5 mm Hg (sensitivity: 78.2%, specificity: 62.5%; area under curve: 0.700; 95% confidence interval [CI]: 0.59–0.81; p <.05). SBPmaintain ≥ 118.5 mm Hg (odds ratio [OR]: 4.03; 95% CI: 1.51–10.75) and baseline total plaque volume (OR: 1.03; 95% CI: 1.01–1.06) independently influenced coronary plaque progression (all p <.05). Conclusion: Normal SBPmaintain is substantial to attenuate coronary atherosclerosis progression in conditions without established CV disease. [ABSTRACT FROM AUTHOR]

Systemic inflammatory response syndrome (SIRS) is characterized by dysregulated cytokine release, immune responses and is associated with organ dysfunction. IL‐6R blockade indicates promising therapeutic effects in cytokine release storm but still remains unknown in SIRS. To address the issue, we generated the human il‐6r knock‐in mice and a defined epitope murine anti‐human membrane‐bound IL‐6R (mIL‐6R) mAb named h‐mIL‐6R mAb. We found that the h‐mIL‐6R and the commercial IL‐6R mAb Tocilizumab significantly improved the survival rate, reduced the levels of TNF‐α, IL‐6, IL‐1β, IFN‐γ, transaminases and blood urea nitrogen of LPS‐induced SIRS mice. Besides, the h‐mIL‐6R mAb could also dramatically reduce the levels of inflammatory cytokines in LPS‐treated THP‐1 cells in vitro. RNA‐seq analysis indicated that the h‐mIL‐6R mAb could regulate LPS‐induced activation of NF‐κB/Ccl2 and NOD‐like receptor signaling pathways. Furthermore, we found that the h‐mIL‐6R mAb could forwardly inhibit Ccl2 expression and NLRP3‐mediated pyroptosis by suppressing NF‐κB in combination with the NF‐κB inhibitor. Collectively, mIL‐6R mAbs suppressed NF‐κB/Ccl2 signaling and inflammasome activation. IL‐6R mAbs are potential alternative therapeutics for suppressing excessive cytokine release, over‐activated inflammatory responses and alleviating organ injuries in SIRS. [ABSTRACT FROM AUTHOR]

Sarcoidosis is a systemic granulomatous disease that affects a variety of organs. Although the etiology has not been fully understood, it is thought that diverse genetic and environmental factors interact with the immune system to develop granulomas. The incidence and death rate of sarcoidosis vary according to race. This study was conducted to identify the epidemiology of sarcoidosis in Korea and reveal its association with comorbid diseases such as diabetes mellitus, hypertension, and dyslipidemia in a population‐based database. We retrospectively analyzed Korean National Health Insurance claims data between 2006 and 2017. The average annual incidence from 2006 to 2017 was 0.82/100 000 person‐years and the all‐cause death rate in sarcoidosis patients was 9.25/1000 cases. The incidence of sarcoidosis was higher in patients with diabetes mellitus, hypertension, and dyslipidemia than patients without those underlying diseases. Sarcoidosis patients with diabetes mellitus and hypertension showed an increased death rate after adjusting the confounding factors (hazard ratio [95% confidence interval], 1.66 [1.23–2.23] and 1.73 [1.29–2.31] respectively), however, patients with dyslipidemia showed a low death rate (HR = 0.64 [0.46–0.88]). In conclusion, we found that sarcoidosis is associated with diabetes mellitus, hypertension, and dyslipidemia and that diabetes mellitus and hypertension increase the risk of death in sarcoidosis patients. Extra caution is needed in sarcoidosis patients who already have these metabolic diseases. [ABSTRACT FROM AUTHOR]

Copper‐based catalysts have attracted enormous attention due to their high selectivity for C2+ products during the electrochemical reduction of CO2 (CO2RR). In particular, grain boundaries on the catalysts contribute to the generation of various Cu coordination environments, which have been found essential for C—C coupling. However, smooth‐surfaced Cu2O nanocrystals generally lack the ability for the surface reorganization to form multiple grain boundaries and desired Cu undercoordination sites. Flow chemistry armed with the unparalleled ability to mix reaction mixture can achieve a very high concentration of unstable reaction intermediates, which in turn are used up rapidly to lead to kinetics‐driven nanocrystal growth. Herein, the synthesis of a unique hierarchical structure of Cu2O with numerous steps (h‐Cu2O ONS) via flow chemistry‐assisted modulation of nanocrystal growth kinetics is reported. The surface of h‐Cu2O ONS underwent rapid surface reconstruction under CO2RR conditions to exhibit multiple heterointerfaces between Cu2O and Cu phases, setting the preferable condition to facilitate C—C bond formation. Notably, the h‐Cu2O ONS obtained the increased C2H4 Faradaic efficiency from 31.9% to 43.5% during electrocatalysis concurrent with the morphological reorganization, showing the role of the stepped surface. Also, the h‐Cu2O ONS demonstrated a 3.8‐fold higher ethylene production rate as compared to the Cu2O nanocube. [ABSTRACT FROM AUTHOR]

To probe the mechanism of dopamine receptors in drug addiction and look for potential new methods for treating this disease, we have designed and synthesized benzothiophene morpholine analogues that were considered as dopamine D3 receptor‐selective ligands. Radioligand binding assay was used to determine the binding affinity of target compounds. Members of this class have great selectivity and binding affinity in D3 receptor. In addition, the ability of these compounds to mitigate the symptoms of addiction from opioids was investigated in animal behavior patterns, and we have found that two compounds (18a and 18d) have good affinity in the D3R and exhibit the efficacy of anti‐drug addiction in morphine‐dependent mice induced by naloxone. [ABSTRACT FROM AUTHOR]

Oligonol is a low‐molecular‐weight polyphenol product derived from lychee (Litchi chinensis Sonn.) fruits. This study was focused on the effects of oligonol on the skeletal muscle of ovariectomized rats. We randomly divided female Sprague–Dawley rats into three groups: a sham surgery control group (Sham), an ovariectomy (OVX) group, and an OVX group treated with oligonol (OVX + Oligonol). Oligonol was intraperitoneally administrated at 30 mg/kg daily for 6 weeks. Oligonol treatment after OVX decreased body weight and fat mass, regulated lipid metabolism in skeletal muscle, without loss of lean mass and bone. Bone turnover was not affected by oligonol. In protein synthesis and degradation, oligonol increased the levels of the mammalian target of rapamycin and its downstream targets, eukaryotic initiation factor 4E‐binding protein 1 and 70‐kDa ribosomal protein S6 kinase, and it stimulated the expression of ubiquitin‐proteasome pathway proteins, the forkhead box transcription factors of the class O and the muscle ring‐finger protein‐1. Moreover, oligonol treatment enhanced mitochondrial biogenesis and dynamics. Thus, our results indicated that oligonol treatment had beneficial effects on the skeletal muscle in an estrogen‐deficiency rat model. [ABSTRACT FROM AUTHOR]

Aims/Introduction: The purpose of this study was to investigate the impact of vision and hearing impairments on the risk of adverse cardiovascular outcomes and mortality in patients with type 2 diabetes using a nationwide longitudinal cohort. Materials and Methods: We enrolled 771,128 patients with type 2 diabetes who underwent the National Health Screening Program in 2009. We carried out Cox proportional hazards regression analyses to calculate the hazard ratios (HR) of myocardial infarction (MI), stroke, and mortality in those with or without vision and hearing impairments. Subgroup analyses of patients stratified by age, sex and diabetic retinopathy were carried out. Results: Diabetes patients with either vision or hearing impairment showed higher risk of MI, stroke or death compared with those without. Among the combinations of impairments, patients with both vision and hearing impairments had the highest risk for MI (adjusted HR [aHR] 1.362, 95% confidence interval [CI] 1.252–1.481) and mortality (aHR 1.591, 95% CI 1.532–1.651). Those with only vision impairment showed higher risk of MI (aHR 1.324, 95% CI 1.275–1.375 and aHR 1.117, 95% CI 1.066–1.170, respectively), stroke (aHR 1.318, 95% CI 1.276–1.362 and aHR 1.134 95% CI 1.089–1.180, respectively) and mortality (aHR 1.417, 95% CI 1.390–1.446 and aHR 1.163, 95% CI 1.135–1.191, respectively) compared with those with only hearing impairment. Conclusions: Vision and hearing impairments are independently important risk factors for adverse cardiovascular events and mortality in patients with type 2 diabetes. Vision and hearing impairments synergistically increased the risk of MI and all‐cause deaths, but not stroke. In addition, in patients aged <65 years, the HR of vision impairment was higher than those with vision and hearing impairments. [ABSTRACT FROM AUTHOR]

Objectives: AXL‐mediated activation of aberrant tyrosine kinase drives various oncogenic processes and facilitates an immunosuppressive microenvironment. We evaluated the anti‐tumor and anti‐metastatic activities of SKI‐G‐801, a small‐molecule inhibitor of AXL, alone and in combination with anti‐PD‐1 therapy. Methods: In vitro pAXL inhibition by SKI‐G‐801 was performed in both human and mouse cancer cell lines. Immunocompetent mouse models of tumor were established to measure anti‐metastatic potential of SKI‐G‐801. Furthermore, SKI‐G‐801, anti‐PD‐1 or their combination was administered as an adjuvant or neoadjuvant in the 4T1 tumor model to assess their potential for clinical application. Results: SKI‐G‐801 robustly inhibited pAXL expression in various cell lines. SKI‐G‐801 alone or in combination with anti‐PD‐1 potently inhibited metastasis in B16F10 melanoma, CT26 colon and 4T1 breast models. SKI‐G‐801 inhibited the growth of B16F10 and 4T1 tumor‐bearing mice but not immune‐deficient mice. An antibody depletion assay revealed that CD8+ T cells significantly contributed to SKI‐G‐801‐mediated survival. Anti‐PD‐1 and combination group were observed the increased CD8+Ki67+ and effector T cells and M1 macrophage and decreased M2 macrophage, and granulocytic myeloid‐derived suppressor cell (G‐MDSC) compared to the control group. The neoadjuvant combination of SKI‐G‐801 and anti‐PD‐1 therapy achieved superior survival benefits by inducing more profound T‐cell responses in the 4T1 syngeneic mouse model. Conclusion: SKI‐G‐801 significantly suppressed tumor metastasis and growth by enhancing anti‐tumor immune responses. Our results suggest that SKI‐G‐801 has the potential to overcome anti‐PD‐1 therapy resistance and allow more patients to benefit from anti‐PD‐1 therapy. [ABSTRACT FROM AUTHOR]

Objectives: Many interventions have been attempted to improve adenoma detection rate (ADR) and sessile serrated lesion detection rate (SDR), and one of these interventions is educational training to recognize polyp characteristics. This study aimed to investigate the change in polyp detection rates of endoscopists before and after comprehensive training through the Gangnam‐Real Time Optical Diagnosis (Gangnam‐READI) program. Methods: Fifteen gastroenterologists participated in a 1‐year comprehensive training program that consisted of ex vivo and in vivo training that encompasses knowledge and skills in endoscopic characterization of colonic polyps using the Workgroup serrAted polypS and Polyposis (WASP) classification. We evaluated the impact of the training program by comparing the overall and individual ADR and SDR 6 months before and after the training. Results: Overall, 18,280 polyps (9337 adenomas and 855 sessile serrated lesion) were collected. The optical diagnosis training had no significant impact on the difference in ADR after training compared to before training (47.7% vs. 46.5%, P = 0.608). A tendency for a decrease in ADR variance was noted among the endoscopists after training (74.9 vs. 32.7, P = 0.121). The overall pre‐training period SDR was 4.5% and showed a statistically significant increase to 5.6%, 8.0%, and 7.1% in the first and second half of the training period, and post‐training period, respectively (P = 0.003). The optical diagnosis training did not decrease variance in SDR (8.9 vs. 8.8, P = 0.985). Conclusion: Comprehensive optical diagnosis training with WASP classification has a significant impact on increasing the overall SDR of expert endoscopists. [ABSTRACT FROM AUTHOR]

Flowering plants (angiosperms) perform a unique double fertilization in which two sperm cells fuse with two female gamete cells in the embryo sac to develop a seed. Furthermore, during land plant evolution, the mode of sexual reproduction has been modified dramatically from motile sperm in the early‐diverging land plants, such as mosses and ferns as well as some gymnosperms (Ginkgo and cycads) to nonmotile sperm that are delivered to female gametes by the pollen tube in flowering plants. Recent studies have revealed the cellular dynamics and molecular mechanisms for the complex series of double fertilization processes and elucidated differences and similarities between animals and plants. Here, together with a brief comparison with animals, we review the current understanding of flowering plant zygote dynamics, covering from gamete nuclear migration, karyogamy, and polyspermy block, to zygotic genome activation as well as asymmetrical division of the zygote. Further analyses of the detailed molecular and cellular mechanisms of flowering plant fertilization should shed light on the evolution of the unique sexual reproduction of flowering plants. Research Highlights: With a comparison to animal systems, this review highlights cellular dynamics of flowering plant zygote, from gamete nuclear migration, karyogamy and polyspermy block, to zygotic genome activation as well as asymmetrical division of the zygote. [ABSTRACT FROM AUTHOR]

Three conjugated polymers (CPs) containing indolocarbazole‐based similar conjugated frameworks are designed to investigate the NO2 detection capability of field‐effect transistor (FET) sensors. The partly linear aliphatic side chain strengthens the crystallization tendency of the CPs, but the crystallinity is critically degraded when introducing an ethylene oxide (EO)‐modified side chain to the same conjugated framework. Although the highly crystalline morphology of the CP helps to achieve high hole mobility, the NO2 response rate of the CP‐based FET sensor is severely deteriorated because of the suppression of NO2 diffusion into the CP matrix. The polar and flexible EO‐modified side chain is helpful to improve the NO2‐affinity of the CPs and induce favorable pathways for NO2 diffusion, ultimately providing enhanced detectivity with better NO2‐response characteristics. As a result, despite low charge carrier mobility due to pure amorphous nature, the CP with EO‐modified side chains provides an exceptional sensitivity of 180%/ppm upon NO2 (100 ppb) exposure for 50 s, including distinct detectivity toward other environmentally abundant harmful polar gases, such as SO2, NO, and NH3. [ABSTRACT FROM AUTHOR]

Background: To compare the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) between non‐vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation (AF), this retrospective study was conducted using the Korean Health Insurance Review & Assessment Service (HIRA) claims database. Methods: Patients with AF who initiated NOACs (apixaban, dabigatran, and rivaroxaban) from July 1, 2015 to November 30, 2016 were included. We applied inverse probability of treatment weighting (IPTW) method using propensity score to make weighted populations having similar characteristics between groups. Hazard ratio (HR) of S/SE and MB were estimated by Cox proportional hazard model. Results: Of the 39 783 patients with AF, 10 564; 11 418; and 17 801 used apixaban, dabigatran, and rivaroxaban, respectively. The mean CHA2DS2‐VASc and HAS‐BLED scores were 4.59 ~ 4.69 and 3.58 ~ 3.62, respectively, among all patients after applying IPTW. For S/SE, there were no significant differences between NOACs (HR [95% confidence interval (CI)]): apixaban vs dabigatran (0.99 [0.87‐1.13]), apixaban vs rivaroxaban (0.95 [0.84‐1.07]), and dabigatran vs rivaroxaban (0.96 [0.85‐1.08]). For MB (HR [95% CI]), both apixaban (0.77 [0.68‐0.86]) and dabigatran (0.88 [0.79‐0.98]) had a significantly lower risk compared with rivaroxaban. Apixaban also had a significantly lower risk of MB compared with dabigatran (0.87 [0.76‐0.99]). Conclusions: In real‐world practice among Korean AF patients with relatively high risk of stroke and bleeding, there were no significant differences in the risk of S/SE between all NOAC comparisons. Apixaban was associated with lower risk of MB than dabigatran and rivaroxaban. [ABSTRACT FROM AUTHOR]