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Genome sequencing of filamentous fungi has demonstrated that most secondary metabolite biosynthetic gene clusters (BGCs) are silent under standard laboratory conditions. In this work, we have established an in vitro CRISPR-Cas9 system in

The nickel chloride complex of the Schiff base N 2,N 2′-propanediylbis(2,3-butanedione-2-imine-3-oxime), namely, chlorido(3,9-dimethylundeca-3,8-diene-2,10-dione 10-oxime 2-oximato-κ4 N,N′,N′′,N′′′)nickel(II), [NiCl(C11H19N4O2)], at 100 K crystallizes in the orthorhombic space group Cmce. The structure exhibits mirror disorder of the main molecule that is not present in the bromide analogue. The relatively small number of unique reflections in the data set and the disorder imposed by the crystallographic mirror plane present a challenging educational case study.

Isolated superior mesenteric artery dissection (ISMAD) has attracted more and more clinicians' attention in recent years. Patients onset of ISMAD often present with abdominal pain. The misdiagnosis or miss diagnosis is common because of the non-specific symptoms and signs, which even can endanger lives in serious cases. Imaging classification is of great significance for diagnosis and treatment of ISMAD. The Sakamoto classification and the Yun classification are two classical classified methods. However, with the further study of ISMAD, various new classifications emerge. Conservative treatment was once considered as the preferred. As the rapid development of endovascular therapy and the great progress of new devices, stenting therapy can significantly improve symptoms and achieve satisfactory long-term effects, and be even expected to become the preferred method for clinical therapy of ISMAD. However, the long-term effects of endovascular therapy still need a large number of follow-up data, and complications after stent implantation can't be ignored.近年来，孤立性肠系膜上动脉夹层被越来越多的临床医师关注。患者发病时常表现为腹痛，其症状、体征无特异性，易被误诊、漏诊，严重时可危及患者生命。影像学分型对该疾病的诊断和指导治疗有着重要意义，Sakamoto分型和Yun分型是两种经典的分型方式。随着对该病了解的不断深入，各种新分型不断出现，各有千秋。保守治疗曾被认为是孤立性肠系膜上动脉夹层的首选治疗方式，但随着血管腔内治疗的迅速发展和新器械的不断出现，支架成形术后患者症状改善明显，中长期效果满意，有望成为该疾病的首选治疗方法。然而，腔内治疗的远期效果仍需大样本随访资料支持，支架植入后并发症同样不可忽视。.

Waste plastics represent major environmental and economic burdens due to their ubiquity, slow breakdown rates, and inadequacy of current recycling routes. Polyethylenes are particularly problematic, because they lack robust recycling approaches despite being the most abundant plastics in use today. We report a novel chemical and biological approach for the rapid conversion of polyethylenes into structurally complex and pharmacologically active compounds. We present conditions for aerobic, catalytic digestion of polyethylenes collected from post-consumer and oceanic waste streams, creating carboxylic diacids that can then be used as a carbon source by the fungus Aspergillus nidulans. As a proof of principle, we have engineered strains of A. nidulans to synthesize the fungal secondary metabolites asperbenzaldehyde, citreoviridin, and mutilin when grown on these digestion products. This hybrid approach considerably expands the range of products to which polyethylenes can be upcycled.

Due to the complexity and heterogeneity of obesity, the diagnosis and treatment of obesity vary greatly. Five to 10 percent of body weight can be lost through lifestyle modifications, nutritional and behavioral counseling, and the use of approved weight reduction medicines for obesity and diabetes; however, these non-surgical treatments are not effective for all patients. Compared to medical therapy, bariatric surgery is associated with higher rates of type 2 diabetes remission, lower mortality from vascular complications, and long-term, sustained weight loss. With the advent of precision medicine in surgical therapy, bariatric surgeons' fundamental understanding of laparoscopic Roux-en-Y gastric bypass surgery has evolved in recent years. The objective of surgery has shifted from short-term weight loss to the safe and successful long-term management of patient weight and comorbidities. In laparoscopic Roux-en-Y gastric bypass surgery, the concept of precision bariatric and metabolic surgery is mainly reflected in three aspects: accurate preoperative assessment, precise intraoperative operation, and comprehensive postoperative management. A new direction for the future development of precision laparoscopic Roux-en-Y gastric bypass surgery and obesity metabolic surgery is to formulate precise and individualized surgical treatment plans for patients and to use artificial intelligence and big data technology to improve the standardization of specialist data.由于肥胖本身的复杂性和异质性，导致肥胖症的诊疗方法个体化差异较大。通过改变生活方式和饮食结构、采用行为疗法以及使用已经批准的减肥药物治疗肥胖和糖尿病患者，可以实现5%~10%的体质量减轻，但并非所有患者都可以通过这些非手术的治疗手段获益。与药物治疗相比，减重代谢手术有更高的2型糖尿病缓解率和更低的血管并发症病死率并且可以长期持续减轻体质量。近些年来，随着精准医学在外科治疗中的发展，减重外科医生对腹腔镜Roux-en-Y胃旁路手术的核心理念也发生了改变。手术目的从强调短期体质量大幅下降转变为安全有效地长期控制患者的体质量和并发症。在腹腔镜Roux-en-Y胃旁路手术中，精准减重代谢外科理念主要体现在3个方面：术前的精准评估、术中的精细操作和术后的综合管理。为患者制定精准、个体化的手术治疗方案，同时利用人工智能和大数据技术，提高专科数据的标准化是精准腹腔镜Roux-en-Y胃旁路手术和减重代谢外科未来发展的新方向。.

Background Heart failure (HF) occurs in approximately 26% of patients with atrial fibrillation (AF). Real-world data of oral anticoagulation with edoxaban in AF patients with HF history are limited. Purpose To compare edoxaban effectiveness and safety in AF patients with or without HF history. Methods The Global ETNA-AF programme (EU: NCT02944019, Japan: UMIN000017011, South Korea/Taiwan: NCT02951039) integrates data from multiple prospective, observational, noninterventional regional studies of AF patients receiving edoxaban for stroke prevention. This snapshot analysis summarises baseline characteristics and 2-year annualised rates of all-cause death, cardiovascular (CV) death, stroke (haemorrhagic, ischaemic, any), and bleeding (major bleeding [MB], major gastrointestinal [GI] bleeding, intracranial haemorrhage [ICH], clinically relevant nonmajor bleeding [CRNMB], and any bleeding) in patients with or without HF history. Univariate Cox regression models assessed clinical outcomes. Results Data from 27,333 patients (5258 with HF history) from Europe, Japan, South Korea, and Taiwan were analysed. Patients with HF history were significantly older and had lower mean body weight and creatinine clearance (P Conclusions In AF patients receiving edoxaban, the rates of MB, major GI bleeding, and CV or all-cause death were higher when comparing those with versus without HF history. The higher incidence of MB and major GI bleeding in patients with HF history did not lead to proportionally higher fatal bleeding rates among all-cause deaths. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo

Background Atrial fibrillation (AF) patients with a history of ischaemic stroke (IS) have a higher risk for recurrent IS events and were largely excluded from the pivotal, randomised, controlled phase 3 trials on oral anticoagulants. Thus, the effectiveness and safety of edoxaban in these patients need to be studied in a real-world setting. Purpose To compare edoxaban real-world effectiveness and safety in AF patients with or without an IS history. Methods The Global ETNA-AF programme (EU: NCT02944019, Japan: UMIN000017011, South Korea/Taiwan: NCT02951039) integrates data from multiple prospective, observational, noninterventional regional studies of AF patients receiving edoxaban for stroke prevention. This snapshot analysis summarises baseline characteristics with medical history and 2-year annualised rates of all-cause death, cardiovascular (CV) death, stroke (haemorrhagic, ischaemic, any), and bleeding (including major bleeding [MB], major gastrointestinal [GI] bleeding, intracranial haemorrhage [ICH], clinically relevant nonmajor bleeding [CRNMB], and any bleeding) in patients with or without IS history. Results Data from 27,333 patients (3215 with prior IS and 24,118 without) from Europe, Japan, South Korea, and Taiwan were analysed. Patients with IS history were significantly older, more likely ≥75 years of age, and had a lower mean body weight and creatinine clearance (P Conclusions Patients with AF who have a history of IS are more likely elderly; have histories of MB, ICH, and TIA; and have high baseline stroke and bleeding risk scores. Patients with IS history receiving edoxaban have a considerably higher likelihood of experiencing IS or TIA, whereas the risk of experiencing any bleeding event (with the exception of ICH) is only modestly higher than in those without IS history. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo

Background Atrial fibrillation patients with a history of major bleeding (MB) are at high risk of future bleeding events; this history was an exclusion criterion in pivotal phase 3 trials of anticoagulation for stroke prevention. Real-world edoxaban effectiveness and safety in patients with a history of MB were analysed from the global ETNA programme. Purpose To compare edoxaban effectiveness and safety in AF patients with or without an MB history. Methods The Global ETNA-AF programme (EU: NCT02944019, Japan: UMIN000017011, South Korea/Taiwan: NCT02951039) integrates data from multiple prospective, observational, noninterventional regional studies of AF patients treated with edoxaban for stroke prevention. This snapshot analysis summarises global baseline characteristics and 2-year annualised rates of all-cause death, cardiovascular death, stroke (haemorrhagic, ischaemic, any), and bleeding (including MB, major gastrointestinal bleeding [MGIB], intracranial haemorrhage [ICH], clinically relevant nonmajor bleeding, and any bleeding) in patients with or without MB history. Results Data from 27,333 patients (479 with MB history and 26,854 without) from Europe, Japan, South Korea, and Taiwan were analysed. Patients with MB history were significantly older (P Conclusions Patients with AF receiving edoxaban and who have a history of MB are more likely elderly, male, and have comorbidities, including HF. These patients are also more susceptible to any adverse cardiovascular event. ICH event rates were not higher in patients with prior ICH than those with non-ICH major bleedings, whereas history of MGIB was associated with a high risk of MGIB recurrence. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo

The reconstruction of tactile function during the repair of skin damage caused by factors including burns is inseparable from the functional regeneration of tactile receptor Merkel cells. Merkel cells mainly exist in the basal layer of the epidermis and are closely connected with nerves to form Merkel cell-nerve complexes, which play an important role in biological organisms. A large number of studies have shown that Merkel cells conduct precise transmission of mechanical force stimuli through the mechanically gated ion channels PIEZO2, and perform the function of tactile receptors. In this paper, we discussed the characteristics of Merkel cells and analyzed the different subgroups that may possibly exist in this type of cells and their functions, at the same time, we investigated the animal model research of touch-related diseases and the clinical diseases related to touch, revealing the importance of Merkel cell function research.在由烧伤等因素导致的皮肤损伤修复过程中，触觉功能的重建离不开触觉感受器默克尔细胞的功能再生。默克尔细胞主要存在于表皮基底层，与神经紧密相连形成默克尔细胞-神经复合体，在生物机体内发挥重要作用。大量研究表明默克尔细胞通过机械门控离子通道PIEZO2对机械力刺激进行精确传导，行使触觉感受器的功能。该文通过论述默克尔细胞的特征，分析该类细胞可能存在的不同亚群及其功能，同时调研了触觉相关疾病的动物模型研究和触觉相关的临床疾病，揭示了默克尔细胞功能研究的重要性。.

Laparoscopic Roux-en-Y gastric bypass (RYGB) is an important obesity surgery. The risk of remnant gastric cancer after RYGB for obesity is gaining growing attention from bariatric surgeons and patients with obesity. This systematic review included articles from major databases internationally and domestically that specifically described the remnant gastric cancer after RYGB intervention, a total of 21 cases was subsequently analyzed. The average median time from post-operative RYGB to diagnosis of gastric cancer was 11 years (1-28 years), the duration of gastric cancer symptoms lasted 7 days to 6 years, abdominal pain is the most common (71.4%), especially in the upper abdomen (33.3%), followed by nausea and vomiting (33.3%), over-weight loss (33.3%), and abdominal bloating (28.6%), etc. Neoplasm location was reported to occur in the antrum or the pre-pyloric region (71.4%), with adenocarcinoma being the most common tumor histology observed (71.4%), tumor stage III-IV as the most diagnosed, 38.1% of tumor were deemed to be unresectable, 52.4% of the patients performed subtotal gastrectomy and lymphadenectomy. In addition, a global article investigating the occurrence of esophageal gastric cancer after RYGB in 64 cases revealed the common preoperative medical history include smoking habits (37.5%), alcohol issues (14.0%), GERD (86.0%), presence with Barret esophagus (10.9%), patients that has other malignant tumor medical history (6.3%), first-degree relatives (6.3%), or other family members with gastric esophagus cancer family history. Although the incidence of gastric cancer after RYGB is rare, the increasing prevalence of gastric cancer development is one of great concern. A rise in clinical cases of patients treated with RYGB presents a target for future studies. Risk of gastric cancer after RYGB should be evaluated and considered in high-risk cases.腹腔镜Roux-en-Y胃旁路术（RYGB）是重要的减重术式之一。RYGB与残胃癌发生风险之间的关系，越来越受到减重外科医生以及肥胖症人群的关注。本文系统分析国内外主要医学数据平台与RYGB术后发生胃癌相关的文献发现，21例RYGB胃旁路术后相关胃癌的患者从接受RYGB到诊断为肿瘤的中位时间为11（1~28）年，症状的持续时间为7 d至6年，其中最常见的症状是腹痛（71.4%），尤其是上腹部（33.3%），其次为恶心和呕吐（33.3%）、体质量过度减轻（33.3%）以及腹胀（28.6%）等。肿瘤多位于胃窦或幽门（71.4%），腺癌是最常见的肿瘤组织类型（71.4%），以Ⅲ~Ⅳ期为主，38.1%的患者肿瘤无法完全切除，52.4%患者接受了胃次全切除术和淋巴结切除术。关于RYGB术后发生胃癌的术前病史，一项有关64例食管胃癌患者的全球性报道发现，常见术前病史包括抽烟（37.5%）、饮酒史（14.0%）、胃食管反流病症状（86.0%）、存在Barrett食管（10.9%）、有其他恶性肿瘤的个人病史（6.3%）、一级亲属（6.3%）或其他家族成员（1.6%）有胃食管恶性肿瘤的家族史。虽然RYGB术后胃癌的发生很少见，但随着越来越多的患者采用RYGB来治疗肥胖及其代谢病，需警惕高危患者术后发生肿瘤的风险。.

Due to immense phenotypic plasticity and adaptability, Aspergillus niger is a cosmopolitan fungus that thrives in versatile environments, including the International Space Station (ISS). This is the first report of genomic, proteomic, and metabolomic alterations observed in A. niger strain JSC-093350089 grown in a controlled experiment aboard the ISS. Whole-genome sequencing (WGS) revealed that ISS conditions, including microgravity and enhanced irradiation, triggered non-synonymous point mutations in specific regions, chromosomes VIII and XII of the JSC-093350089 genome when compared to the ground-grown control. Proteome analysis showed altered abundance of proteins involved in carbohydrate metabolism, stress response, and cellular amino acid and protein catabolic processes following growth aboard the ISS. Metabolome analysis further confirmed that space conditions altered molecular suite of ISS-grown A. niger JSC-093350089. After regrowing both strains on Earth, production of antioxidant—Pyranonigrin A was significantly induced in the ISS-flown, but not the ground control strain. In summary, the microgravity and enhanced irradiation triggered unique molecular responses in the A. niger JSC-093350089 suggesting adaptive responses.

Fungal natural products (NPs) comprise a vast number of bioactive molecules with diverse activities, and among them are many important drugs. However, the yields of fungal NPs from native producers are usually low, and total synthesis of structurally complex NPs is challenging. As such, downstream derivatization and optimization of lead fungal NPs can be impeded by the high cost of obtaining sufficient starting material. In recent years, reconstitution of NP biosynthetic pathways in heterologous hosts has become an attractive alternative approach to produce complex NPs. Here, we present an efficient, cloning-free strategy for the cluster refactoring and total biosynthesis of fungal NPs in Aspergillus nidulans. Our platform places our genes of interest (GOIs) under the regulation of the robust asperfuranone afo biosynthesis gene machinery, allowing for their concerted activation upon induction. We demonstrated the utility of our system by creating strains that can synthesize high-value NPs, citreoviridin (1), mutilin (2), and pleuromutilin (3), with good to high yield and purity. This platform can be used not only for producing NPs of interests (i.e., total biosynthesis) but also for elucidating cryptic biosynthesis pathways.

Natural products derived from microorganisms play a key role in the discovery and development of drug candidates. Several drugs have originated from secondary metabolites or their derivatives from microorganisms in clinical therapy, such as penicillin, cyclosporine, and lovastatin. Application of epigenetic methodology on modulation and stimulation of secondary metabolites from fungi provides a practical way to investigate fungal natural products. Addition of enzyme inhibitors such as histone deacetylase (HDAC) or DNA methyltransferase (DNMT) inhibitors to activate silent biosynthetic gene clusters result in the potential for generating a variety of secondary metabolites with novel skeletons and diversity of stereochemistry, as well as unprecedented heterocyclic rings. After triggering the epigenetic modifiers, some species were affected and produced several uncovered secondary metabolites. Although this strategy has been successfully carried out for few reports, the results of this research field have demonstrated high potential for engineering the secondary metabolites from fungi. By utilizing the above strategy, modulation and characterization of the secondary metabolites from fungi make them able to generate several novel or bioactive natural products that will provide sources for discovering new candidates. Furthermore, the epigenetic modulation technique integrated with pharmacological assays for further investigation becomes a promising avenue for improvement of natural products research and development. This review summarizes the progression and development of epigenetic manipulation in fungal natural product research.

To thoroughly explore the relationship between precipitation and corrosion in a precipitation-strengthened Al-4.47Zn-2.13Mg-1.20Cu (wt%) wrought alloy plate after a nonisothermal aging (NIA) treatment, specifically, a heating-aging treatment (HAT), electrochemical testing and transmission electron microscopy (TEM) were conducted in the present work. The H(5) process exhibited excellent corrosion resistance with a low corrosion current density (icorr) and a high corrosion potential (Ecorr) compared to those for the T6 treatment. After the HAT, the precipitates at the grain boundaries (GBs) gradually became intermittent with a narrow precipitate-free zone (PFZ), effectively preventing GBs precipitates from anodic dissolution. The HAT enabled the rapid diffusion and enrichment of Cu at the GBs and reduced the potential difference between the grain boundary and matrix, thereby decreasing the intergranular corrosion (IGC) susceptibility. Moreover, the time spent for a HAT can be decreased by approximately 70% in comparison with that for a T6 treatment. The current results indicate that NIAs could improve the mechanical properties and production efficiency with a decreased energy consumption.

Sphingomonas is ubiquitous in nature, including the anthropogenically contaminated extreme environments. Members of the Sphingomonas genus have been identified as potential candidates for space biomining beyond earth.