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Aim: To evaluate the prediction of peritumoral and intratumoral radiomics for visceral pleural invasion (VPI) in lung adenocarcinoma cancer (LAC) based on preoperative computed tomography (CT) radiomics., Materials and Methods: In total, 350 patients with LAC confirmed by surgery pathology were enrolled in The Second Hospital of Hebei Medical University, including 281 VPI negative patients and 69 VPI positive patients, were divided into the training cohort (n = 280) and validation cohort (n=70) at random with a ratio of 8:2. We extracted the radiomics features from the 3 region of interest (ROI), including gross tumor volume (GTV), the gross peritumoral tumor volume (GPTV) and the gross volume of the tumor rim (included the outer 4 mm of the tumor and 4mm of the tumor adjacent lung tissue on either side of the tumor contour boundary, GTR).The maximal redundancy minimal relevance (mMRM) algorithm and the least absolute shrinkage and selection operator (LASSO) was performed to reduce feature dimensionality and the radiomics score (Rad score) of the best radiomics model was combined with CT morphological characteristics with statistical significance in the univariable analysis to construct the combined model. The performance of the models was evaluated based on receiver operating characteristics (ROC) curve, calibration, and clinical usefulness. DeLong's test was used to assess differences in area under curve (AUC) between different models., Results: There were no statistically significant differences in patient's gender, age, and BMI between the VPI positive group and VPI negative group (all p＞0.05). There were statistically significant differences in the tumor maximum diameter, tumor CT image type, vacuole sign, and pleural indentation sign between the VPI positive group and VPI negative group (all p < 0.05). The models of radiomics of GTV, GPTV, and GTR showed high predictive value in the training cohort (All AUC > 0.75). Compared with GTV, GTR radiomics models, the GPTV radiomics model constructed via the logistic regression (LR) method exhibited better prediction performance with the AUCs of 0.819, 0.827; accuracy of 0.757,0.743; sensitivity of 0.800,0.786; specificity of 0.747,0.732 in the training and validation cohorts, respectively. The LR model of GPTV radiomics was defined as the optimal model for predicting VPI, since its excellent performance in both ROC, calibration curve and decision curve analysis (DCA)., Conclusion: Preoperative CT-based radiomics models can predict VPI in patients with LAC; the LR algorithm combined the GPTV radiomics was the optimal choice, demonstrating high sensitivity, specificity, accuracy and clinical usefulness., Competing Interests: Conflict of interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Jing-jing Cui reports a relationship with United Imaging Intelligence (Beijing) Co., Ltd that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The human body contains trillions of cells, classified into specific cell types, with diverse morphologies and functions. In addition, cells of the same type can assume different states within an individual's body during their lifetime. Understanding the complexities of the proteome in the context of a human organism and its many potential states is a necessary requirement to understanding human biology, but these complexities can neither be predicted from the genome, nor have they been systematically measurable with available technologies. Recent advances in proteomic technology and computational sciences now provide opportunities to investigate the intricate biology of the human body at unprecedented resolution and scale. Here we introduce a big-science endeavour called π-HuB (proteomic navigator of the human body). The aim of the π-HuB project is to (1) generate and harness multimodality proteomic datasets to enhance our understanding of human biology; (2) facilitate disease risk assessment and diagnosis; (3) uncover new drug targets; (4) optimize appropriate therapeutic strategies; and (5) enable intelligent healthcare, thereby ushering in a new era of proteomics-driven phronesis medicine. This ambitious mission will be implemented by an international collaborative force of multidisciplinary research teams worldwide across academic, industrial and government sectors., Competing Interests: Competing interests:  R.A. holds shares of Biognosys AG, which operates in the field covered by the article. D.F. is co-founder of MedBiome Inc., a precision nutrition company. K.G. is a shareholder of CYBO, LucasLand, and FlyWorks. T.G. is the founder of Westlake Omics Inc. M.M. is an indirect investor in EvoSep. R.T. is a founder of BayOmics. The other authors declare no competing interests., (© 2024. Springer Nature Limited.)

Background: Over the past two decades, modern spine surgery has become increasingly intellectualized and minimally invasive. However, whether using robots in spine surgery results in more accurate pedicle screw placement remains a topic of debate. This study aimed to evaluate the certainty and quality of the available evidence on the efficacy of robot-assisted pedicle screw placement., Methods: We performed an overview of reviews including systematic reviews (SRs) and meta-analyses (MAs) regarding the accuracy of robot-assisted pedicle screw placement. Regarding the SRs/MAs, five electronic databases were searched from inception to 28 April 2023. There were no restrictions on the language or population. The quality and certainty of the evidence were evaluated with PRISMA, AMSTAR-2, ROBIS, Veritas plot, and GRADE tools., Results: Fifteen SRs/MAs were analyzed. The findings indicated that the accuracy of pedicle screw placement in the robot-assisted group was not superior to that in the freehand group. All the SRs/MAs were of low or critically low quality. The main reasons for this include missing data, lack of transparency, lack of sensitivity analysis, and measurement of heterogeneity in the included studies, registration of reporting protocols, and deficiencies in the study inclusion methods and selection criteria., Conclusions: While there is potential for robot-assisted pedicle screw placement to offer superior accuracy compared to conventional surgery, the current evidence is limited by methodological shortcomings. The quality of the studies analyzed was insufficient to provide a robust basis for developing clinical guidelines. Further high-quality research is necessary to confirm the benefits and establish clearer recommendations.

The human body possesses natural barriers, such as skin and mucosa, which limit the effective delivery of therapeutics and integration of medical devices to target tissues. Various strategies have been deployed to breach these barriers mechanically, chemically, or electronically. The development of various penetration enhancers (PEs) offers a promising solution due to their ability to increase tissue permeability using readily available reagents. However, existing PE-mediated delivery methods often rely on weak gel or liquid drug formulations, which are not ideal for sustained local delivery. Hydrogel adhesives that can seamlessly interface biological tissues with controlled drug delivery could potentially resolve these issues. Here, we demonstrate that tough adhesion between drug-laden hydrogels and biological tissue ( e.g. skin and tumours) can lead to effective local delivery of drugs deep into targeted tissues by leveraging the enhanced tissue penetration mediated by PEs. The drug release profile of the hydrogel adhesives can be fine-tuned by further engineering the nanocomposite hydrogel matrix to elute chemotherapeutics from 2 weeks to 2 months. Using a 3D tumour spheroid model, we demonstrated that PEs increased the cancer-killing effectiveness of doxorubicin by facilitating its delivery into tumour microtissues. Therefore, the proposed tough bioadhesion and drug delivery strategy modulated by PEs holds promise as a platform technique to develop next-generation wearable and implantable devices for cancer management and regenerative medicine.

Objective: To compare the associations of three surrogate markers of insulin resistance (IR) [glucose and triglycerides (TyG index), TyG index with BMI (TyG-BMI), and the ratio of triglycerides divided by HDL-C (TG/HDL-C)] with hypertensive patients (HTN) plus hyperuricemia (HUA) (HTN-HUA) in young, non-obese individuals., Methods: Data from a cross-sectional epidemiological study of an annual health check-up population aged younger than 66 years were used to calculate the three IR surrogate indexes. The association with HTN-HUA and insulin resistance surrogates was examined with multinomial logistic regression and a receiver operating characteristic (ROC) curve., Results: A total of 6952 participants were included, including 671 (9.65%) participants with HTN alone, 272 (3.91%) participants with HUA alone, and 62 (0.90%) participants with HTN and HUA. Binary multiple-logistic regression results showed that TG/HDL-C was significantly correlated with HTN, HUA, and HTN-HUA. Compared with the lowest quartile, the odds ratios (95% CI) of the highest quartile of TG/HDL-C for HTN-HUA were 3.462 (1.138~10.530). TG/HDL-C and TyG-BMI had moderate discriminative abilities for HTN-HUA, and the area under the curve was 0.748 (0.682~0.815), 0.746 (0.694~0.798)., Conclusion: Our study suggests that TG/HDL-C had a significant correlation with HTN-HUA and that TG/HDL-C had moderate discriminative abilities for HTN-HUA., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Zuo et al.)

Introduction: Colorectal cancer liver metastasis (CRCLM) remains a lethal diagnosis, with an overall 5-year survival rate of 5-10%. Two distinct histopathological growth patterns (HGPs) of CRCLM are known to have significantly differing rates of patient survival and response to treatment. We set out to review the results of 275 patients who underwent liver resection for CRCLM at the McGill University Health Center (MUHC) and analyze their clinical outcome, mutational burden, and pattern of cancer progression in light of their HGPs, and to consider their potential effect on surgical decision making., Methods: We performed a retrospective multivariate analysis on clinical data from patients with CRCLM ( n = 275) who underwent liver resection at the McGill University Health Center (MUHC). All tumors were scored using international consensus guidelines by pathologists trained in HGP scoring., Results: A total of 109 patients (42.2%) were classified as desmoplastic and angiogenic, whereas 149 patients (57.7%) were non-desmoplastic and vessel co-opting. The 5-year survival rates for angiogenic patients compared with vessel co-opting patients were 47.1% and 13%, respectively ( p < 0.0001). Multivariate analysis showed patients with vessel co-opting CRCLM had a higher incidence of extrahepatic metastatic disease ( p = 0.0215) compared with angiogenic CRCLM. Additionally, KRAS mutation status was a marker of increased likelihood of disease recurrence ( p = 0.0434), as was increased number of liver tumors ( p = 0.0071) and multiple sites of extrahepatic metastatic disease ( p < 0.0001)., Conclusions: Multivariate analysis identified key clinical prognostic and molecular features correlating with the two HGPs. Determining liver tumor HGPs is essential for patient prognostication and treatment optimization.

Background: Infection with Neisseria gonorrhoeae in adults usually leads to vaginitis and acute urethritis, and infection through the birth canal in newborns can lead to acute neonatal conjunctivitis. In view of certain factors such as a high missed detection rate of N.gonorrhoeae from staining microscopy method, the time-consuming nature and limited sensitivity of bacterial culture method, complicated and inability of absolute quantification from the ordinary PCR method., Methods: This study aims to establish a ddPCR system to detect N.gonorrhoeae in a absolute quantification, high specificity, high stability and accurate way. We selected the pgi1 gene as the target gene for the detection of N.gonorrhoeae., Results: The amplification efficiency was good in the ddPCR reaction, and the whole detection process could be completed in 94 min. It has a high sensitivity of up to 5.8 pg/μL. With a high specificity, no positive microdroplets were detected in 9 negative control pathogens in this experiment. In addition, ddPCR detection of N.gonorrhoeae has good repeatability, and the calculated CV is 4.2 %., Conclusions: DdPCR detection technology has the characteristics of absolute quantification, high stability, high specificity and high accuracy of N.gonorrhoeae. It can promote the accuracy of the detecting of N.gonorrhoeae, providing a more scientific basis for clinical diagnosis and treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Gastric cancer is the most common malignancy worldwide and is the third leading cause of cancer-related deaths, urgently requiring an early and non-invasive diagnosis. Circulating extracellular vesicles may emerge as promising biomarkers for the rapid diagnosis in a non-invasive manner., Methods: Using high-throughput small RNA sequencing, we profiled the small RNA population of serum-derived extracellular vesicles from healthy controls and gastric cancer patients. Differentially expressed microRNAs (miRNAs) were randomly selected and validated by reverse transcription-quantitative real-time polymerase chain reaction. Receiver operating characteristic curves were employed to assess the predictive value of miRNAs for gastric cancer., Results: In this study, 193 differentially expressed miRNAs were identified, of which 152 were upregulated and 41 were significantly downregulated. Among the differently expressed miRNA, the expression levels of miR-21-5p, miR-26a-5p, and miR-27a-3p were significantly elevated in serum-derived extracellular vesicles of gastric cancer patients. The miR-21-5p and miR-27a-3p were closely correlated with the tumor size. Moreover, the expression levels of serum miR-21-5p and miR-26a-5p were significantly decreased in gastric cancer patients after surgery., Conclusions: The present study discovered the potential of serum miR-21-5p and miR-26a-5p as promising candidates for the diagnostic and prognostic markers of gastric cancer., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

A textile bandwidth-enhanced half-mode substrate-integrated cavity (HMSIC) antenna based on embroidered shorting vias is designed. Based on the simulated results of the basic HMSIC antenna, two embroidered hollow posts with square cross-sections are added as shorting vias at the intersections of the zero-E traces of the TM210HM and TM020HM modes to shift the TM010HM-mode band to merge with the bands of the higher-order modes for bandwidth enhancement. A prototype is practically fabricated based on computerized embroidery techniques. Measurement results show that the prototype is of an expanded -10 dB impedance band of 4.87~6.17 GHz (23.5% fractional bandwidth), which fully covers the 5 GHz wireless local area network (WLAN) band. The simulated radiation efficiency and maximum gain of the proposed antenna are above 97% and 7.6 dBi, respectively. Furthermore, simulations and measurements prove its robust frequency response characteristic in the proximity of the human tissues or in bending conditions, and the simulations of the specific absorption rate (SAR) prove its electromagnetic safety on the human body.

Succinate dehydrogenase (SDH) has been considered an ideal target for discovering fungicides. To develop novel SDH inhibitors, in this work, 31 novel benzothiazol-2-ylthiophenylpyrazole-4-carboxamides were designed and synthesized using active fragment exchange and a link approach as promising SDH inhibitors. The findings from the tests on antifungal activity indicated that most of the synthesized compounds displayed remarkable inhibition against the fungi tested. Compound Ig N -(2-(((5-chlorobenzo[ d ]thiazol-2-yl)thio)methyl)phenyl)-3-(difluoromethyl)-1-methyl-1 H -yrazole-4-carboxamide, with EC 50 values against four kinds of fungi tested below 10 μg/mL and against Cercospora arachidicola even below 2 μg/mL, showed superior antifungal activity than that of commercial fungicide thifluzamide, and specifically compounds Ig and Im were found to show preventative potency of 90.6% and 81.3% against Rhizoctonia solani Kühn , respectively, similar to the positive fungicide thifluzamide. The molecular simulation studies suggested that hydrophobic interactions were the main driving forces between ligands and SDH. Encouragingly, we found that compound Ig can effectively promote the wheat seedlings and the growth of Arabidopsis thaliana . Our further studies indicated that compound Ig could stimulate nitrate reductase activity in planta and increase the biomass of plants.

Background: Ticks, which are obligate blood-feeding parasites, transmit a wide range of pathogens during their hematophagic process. Certain enzymes and macromolecules play a crucial role in inhibition of several tick physiological processes, including digestion and reproduction. In the present study, genes encoding type 2 cystatin were cloned and characterized from Haemaphysalis doenitzi, and the potential role of cystatin in tick control was further assessed., Results: Two cystatin genes, HDcyst-1 and HDcyst-2, were successfully cloned from the tick H. doenitzi. Their open reading frames are 390 and 426 base pairs, and the number of coding amino acids are 129 and 141, respectively. In the midgut, salivary glands, Malpighian tubules and ovaries of ticks, the relative expression of HDcyst-1 was higher in the midgut and Malpighian tubules, and HDcyst-2 was higher in the salivary glands of H. doenitzi, respectively. Lipopolysaccharide (LPS) injection and low-temperature stress elevated cystatin expression in ticks. Enzyme-linked immunosorbent assay showed that both rHDcyst-1 and rHDcyst-2 protein vaccines increased antibody levels in immunized rabbits. A vaccination trial in rabbits infected with H. doenitzi showed that both recombinant cystatin proteins significantly reduced tick engorgement weights and egg mass weight, in particular, rHDcyst-1 significantly prolonged tick engorgement time by 1 day and reduced egg hatching rates by 16.9%. In total, rHDcyst-1 and rHDcyst-2 protein vaccinations provided 64.1% and 51.8% protection to adult female ticks, respectively., Conclusion: This is the first report on the immunological characterization of the cystatin protein and sequencing of the cystatin gene in H. doenitzi. Cystatin proteins are promising antigens that have the potential to be used as vaccines for infestation of H. doenitzi control. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Context.—: Changes in Paneth cell numbers can be associated with chronic inflammatory diseases of the gastrointestinal tract. So far, no consensus has been achieved on the number of Paneth cells and their relevance to celiac disease (CD)., Objectives.—: To compare crypt and Paneth cell granule areas between patients with CD and those without CD (non-CD) using an artificial intelligence-based solution., Design.—: Hematoxylin-eosin-stained sections of duodenal biopsies from 349 patients at the McGill University Health Centre were analyzed. Of these, 185 had a history of CD and 164 were controls. Slides were digitized, and NoCodeSeg, a code-free workflow using open-source software (QuPath, DeepMIB), was implemented to train deep learning models to segment crypts and Paneth cell granules. The total area of the entire analyzed tissue, epithelium, crypts, and Paneth cell granules was documented for all slides, and comparisons were performed., Results.—: A mean intersection-over-union score of 88.76% and 91.30% was achieved for crypt areas and Paneth cell granule segmentations, respectively. On normalization to total tissue area, the crypt to total tissue area in CD was increased and the Paneth cell granule area to total tissue area decreased when compared to non-CD controls., Conclusions.—: Crypt hyperplasia was confirmed in CD compared to non-CD controls. The area of Paneth cell granules, an indirect measure of Paneth cell function, decreased with increasing severity of CD. More importantly, our study analyzed complete hematoxylin-eosin slide sections using an efficient and easy to use coding-free artificial intelligence workflow., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2024 College of American Pathologists.)

A phytochemical study of the ethanol extract from Ailanthus altissima (Mill.) Swingle leaves resulted in the isolation of four new monoterpenoids (1-3, 5). The structures were elucidated using HRESIMS data, NMR spectroscopic data, quantum chemical calculations for NMR and ECD, and custom DP4+ probability analysis. Additionally, the absolute configuration of sugar was determined by acid hydrolysis. Compounds 1-4 are cyclogeraniane monocyclic monoterpenes, while compound 5 contains an acyclic mycrane monoterpenes skeleton. Anti-tyrosinase, anti-acetylcholinesterase, and anti-butyrylcholinesterase activities were tested. Compound 1 showed notable anti-acetylcholinesterase activity, and compound 3 exhibited significant inhibitory effects on anti-tyrosinase activity. Furthermore, the potential binding sites of compounds 1 and 3 were predicted by molecular docking., Competing Interests: Declaration of competing interest Qi Song, Zhi-Kang Duan, Ya-Nuo Tan, Zhi-Heng Gao, Dai Liu, Jin-Le Hao, Bin Lin, Xiao-Xiao Huang, and Shao-Jiang Song declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Demand for the exploration of botanical pesticides continues to increase due to the detrimental effects of synthetic chemicals on human health and the environment and the development of resistance by pests. Under the guidance of a bioactivity-guided approach and HSQC-based DeepSAT, 16 coumarin derivatives were discovered from the leaves of Ailanthus altissima (Mill.) Swingle, including seven undescribed monoterpenoid coumarins, three undescribed monoterpenoid phenylpropanoids, and two new coumarin derivatives. The structure and configurations of these compounds were established and validated via extensive spectroscopic analysis, acetonide analysis, and quantum chemical calculations. Biologically, 5 exhibited significant antifeedant activity toward the Plutella xylostella . Moreover, tyrosinase being closely related to the growth and development of larva, the inhibitory potentials of 5 against tyrosinase was evaluated in vitro and in silico . The bioactivity evaluation results highlight the prospect of 5 as a novel category of botanical insecticide.

Herein, we report the phosphonylacylation of alkenes via visible-light-induced N-heterocyclic carbene (NHC) catalysis to afford a series of γ-ketophosphonates in moderate to good yields. This protocol features mild conditions, free of photocatalyst, and good compatibility of functional groups. The excited Breslow enolate intermediate was proposed to undergo single-electron transfer with oxime phosphonate to generate the corresponding ketyl radical and phosphonyl radical.

Objective: This study investigates the incidence of urinary incontinence following transurethral thulium laser prostatectomy with three different prostate apex disconnection techniques: semi-separation, pre-separation, and post-separation. The findings aim to provide references for clinical treatment., Patients and Methods: A retrospective analysis was conducted on 74 patients treated with transurethral thulium laser prostatectomy for prostatic hyperplasia from April 2022 to March 2023. Complete clinical and follow-up data were available for 52 patients. Clinical and follow-up data were collected for these patients. A comparison was made of urinary incontinence following the three different types of prostate apex disconnection in transurethral thulium laser prostatectomy., Results: In this study, the immediate postoperative urinary incontinence rate for transurethral thulium laser prostatectomy was 9.62% (5/52), the short-term incontinence rate was 11.54% (5/52), and the long-term incontinence rate was 9.62% (5/52). The immediate postoperative incontinence rates for semi-separation, pre-separation, and post- separation were 8.33% (1/12), 8.33% (2/24), and 12.5% (2/16), respectively. The short-term incontinence rates for semi-separation, pre-separation, and post-separation were 8.33% (1/12), 8.33% (2/24), and 18.75% (3/16), respectively. The long-term incontinence rates for semi-separation, pre-separation, and post-separation were 8.33% (1/12), 8.33% (2/24), and 12.5% (2/16), respectively., Conclusions: The incidence of urinary incontinence following transurethral thulium laser prostatectomy was lower with semi-separation and pre-separation compared to post-separation.

The Chinese government adjusted its national epidemic prevention and control policy in December 2022 after the worldwide declaration of COVID-19 as a common influenza. After the policy adjustment, there has been widespread infection in China, which has brought a lot of uncertainty to the lives and studies of Chinese university students. This study focused on the impact of the intolerance of uncertainty for COVID-19 (IUC) on the emotional and mental health of college students in China "Post-pandemic" age. This study examined the mediating role of difficulties in emotion regulation (DER) between IUC and mental health (MH). 1,281 university students in China were surveyed using the intolerance of uncertainty for COVID-19 scale, the difficulties in emotion regulation scale and the mental health scale. A structural equation model was used to test the hypothesis model, and it was shown that IUC had a significant negative effect on the MH of college students and a significant positive effect on the DER. DER had a significant negative effect on the MH, and DER had a complete mediation effect between IUC and MH. The findings of this study enrich our understanding of the influencing factors of mental health of university students under the background of post-epidemic in China, and provide practical reference for universities on how to prevent mental health problems under the current uncertain environment in China., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Gao, Li. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Context: Ma Xing Shi Gan Decoction (MXSGD) is a traditional remedy for treating lung injuries that was developed by the Typhoid and Fever School of Pharmaceutical Biology. It has antitussive and expectorant effects, anti-inflammatory, antiviral, regulates the body's immunity, etc., Aim: The aim of this study is to investigate whether MXSGD can ameliorate cyclosporine A (CsA)-induced hypoimmunity lung injury by regulating microflora metabolism. Methods: Establishment of a model for CsA-induced hypoimmunity lung injury. Using 16S rRNA high-throughput sequencing and LC-MS, the effects of MXSGD on gut flora and lung tissue microecology of mice with CsA-induced hypoimmunity were investigated., Results: MXSGD was able to preserve lung tissue morphology and structure, reduce serum inflammatory marker expression and protect against CsA-induced lung tissue damage. Compared to the model, MXSGD increased beneficial gut bacteria: Eubacterium ventriosum group and Eubacterium nodatum group ; decreased intestinal pathogens: Rikenellaceae RC9 intestinal group ; reduced the abundance of Chryseobacterium and Acinetobacter , promoted the production of Lactobacillus and Streptococcus , and then promoted the lung flora to produce short-chain fatty acids. MXSGD was able to enhance the expression of serum metabolites such as Americine, 2-hydroxyhexadecanoylcarnitine, Emetine, All-trans-decaprenyl diphosphate, Biliverdin-IX-alpha, Hordatin A and N-demethyl mifepristone in the CsA-induced hypoimmunity lung injury model., Conclusion: MXSGD can restore gut and lung microbiota diversity and serum metabolite changes to inhibit inflammation, ameliorate CsA-induced hypoimmunity lung injury., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ye, Gao, Bie, Chen, Lu and Wei.)

Background: Epidemiological evidence links the proprotein convertase subtilisin/kexin 7 (PCSK7) to triglyceride (TG) metabolism. We associated the known PCSK7 gain-of-function non-coding SNP rs236918 with higher levels of plasma apolipoprotein B (apoB) and the loss-of-function coding variant p.Pro777Leu (SNP rs201598301) with lower apoB and TG. Herein, we aimed to unravel the in vivo role of liver PCSK7., Methods: We biochemically defined the functional role of PCSK7 in lipid metabolism using hepatic cell lines and Pcsk7 -/- mice. Our findings were validated following subcutaneous administration of hepatocyte-targeted N-acetylgalactosamine (GalNAc)-antisense oligonucleotides (ASOs) against Pcsk7., Results: Independent of its proteolytic activity, membrane-bound PCSK7 binds apoB100 in the endoplasmic reticulum and enhances its secretion. Mechanistically, the loss of PCSK7/Pcsk7 leads to apoB100 degradation, triggering an unfolded protein response, autophagy, and β-oxidation, eventually reducing lipid accumulation in hepatocytes. Non-alcoholic fatty liver disease (NAFLD) was induced by a 12-week high fat/fructose/cholesterol diet in wild type (WT) and Pcsk7 -/- mice that were then allowed to recover on a 4-week control diet. Pcsk7 -/- mice recovered more effectively than WT mice from all NAFLD-related liver phenotypes. Finally, subcutaneous administration of GalNAc-ASOs targeting hepatic Pcsk7 to WT mice validated the above results., Conclusions: Our data reveal hepatic PCSK7 as one of the major regulators of apoB, and its absence reduces apoB secretion from hepatocytes favoring its ubiquitination and degradation by the proteasome. This results in a cascade of events, eventually reducing hepatic lipid accumulation, thus supporting the notion of silencing PCSK7 mRNA in hepatocytes for targeting NAFLD., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nabil G Seidah has patent METHOD FOR REDUCING HEPATIC TRIGLYCERIDES pending to Nabil G Seidah., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Birth defects have always been one of the most important diseases in medical research as they affect the quality of the birth population. Orofacial clefts (OFCs) are common birth defects that place a huge burden on families and society. Early screening and prevention of OFCs can promote better natal and prenatal care and help to solve the problem of birth defects. OFCs are the result of genetic and environmental interactions; many genes are involved, but the current research has not clarified the specific pathogenesis. The mouse animal model is commonly used for research into OFCs; common methods of constructing OFC mouse models include transgenic, chemical induction, gene knockout, gene knock-in and conditional gene knockout models. Several main signal pathways are involved in the pathogenesis of OFCs, including the Sonic hedgehog (SHH) and transforming growth factor (TGF)-β pathways. The genes and proteins in each molecular pathway form a complex network to jointly regulate the formation and development of the lip and palate. When one or more genes, proteins or interactions is abnormal, OFCs will form. This paper summarises the mouse models of OFCs formed by different modelling methods, as well as the key pathogenic genes from the SHH and TGF-β pathways, to help to clarify the pathogenesis of OFCs and develop targets for early screening and prevention.

Objective: This study aims to explore the risk factors for stone remnants and recurrence after lateral decubitus percutaneous nephrolithotomy (PCNL), providing insights to enhance the stone-free rate and reduce the stone recurrence rate., Patients and Methods: A retrospective analysis was conducted on 356 patients with renal or upper ureteral stones who underwent lateral decubitus PCNL from January 2015 to August 2022. Among them, 271 patients had complete clinical and follow-up data. General clinical information, perioperative data, and follow-up data were collected. Univariate and multivariate logistic regression analyses were performed to identify risk factors for stone remnants and recurrence after lateral decubitus PCNL., Results: The stone-free rate after lateral decubitus PCNL was 88.6% (195/271), and the stone recurrence rate within three years was 28.1% (76/271). Stone size (p<0.001) and stone co-infection (p=0.047) were identified as independent risk factors for stone remnants after lateral decubitus PCNL. Multiple stones (p=0.003) were an independent risk factor for stone recurrence after lateral decubitus PCNL., Conclusions: Stone size and stone co-infection are independent risk factors for stone remnants after lateral decubitus PCNL. Multiple stones are an independent risk factor for stone recurrence after lateral decubitus PCNL.

Two Gram-stain negative, aerobic and rod-shaped bacterial strains, DHOD12 T and 7GSK02 T , were isolated from forest soil of Dinghushan Biosphere Reserve, Guangdong Province, PR China. Strain DHOD12 T grew at 4-42 °C (optimum, 28-33 °C), pH 4.0-8.5 (optimum, pH 5.5-6.5) and in the presence of 0-1.5 % (w/v; optimum, 0-0.5 %)NaCl; while strain 7GSK02 T grew at 12-42 °C (optimum, 28-33 °C), pH 4.0-8.5 (optimum, pH 5.0-6.0) and in the presence of 0-0.5 % (w/v; optimum, 0 %) NaCl. Strains DHOD12 T and 7GSK02 T had the highest 16S rRNA sequence similarities of 98.0 and 98.3 % with the same species Trinickia mobilis DHG64 T , respectively, and 98.4 % between themselves. In the 16S rRNA phylogeny, they formed a clade that was sister to a major cluster consisting of all described Trinickia species. Phylogenomic analyses with the UBCG and PhyloPhlAn methods consistently showed that strains DHOD12 T and 7GSK02 T formed a clade with T. mobilis DHG64 T that was a sister of a cluster containing the remainder of the Trinickia species. The DNA G+C contents of strains DHOD12 T and 7GSK02 T were 63.1 and 64.6 mol%, respectively. Digital DNA-DNA hybridization and average nucleotide identity values of strains DHOD12 T , 7GSK02 T and their closely related strains were in the ranges of 21.6-31.4 % and 77.1-86.9 %, respectively. These two strains had the same major respiratory quinone, ubiquinone-8, and both had C 16 : 0 , C 17 : 0 cyclo and summed feature 8 (C 18 : 1  ω 7 c /C 18 : 1  ω 6 c ) as their major fatty acids. Their major polar lipids were phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. Genomic analysis indicated that the two strains could have the potential to degrade aromatic compounds like other Trinickia species. On the basis of phenotypic and phylogenetic results, strains DHOD12 T and 7GSK02 T represent two novel species of the genus Trinickia , for which the names Trinickia violacea sp. nov. (type strain DHOD12 T =LMG 30258 T =CGMCC 1.15436 T ) and Trinickia terrae sp. nov. (type strain 7GSK02 T =CGMCC 1.15432 T =KCTC 62468 T ) are proposed.

Structural characteristics-guided investigation of Ailanthus altissima (Mill.) Swingle resulted in the isolation and identification of seven undescribed potential Michael reaction acceptors (1-7). Ailanlactone A (1) possesses an unusual 1,7-epoxy-11,12-seco quassinoid core. Ailanterpene B (6) was a rare guaianolide-type sesquiterpene with a 5/6/6/6-fused skeleton. Their structures were determined through extensive analysis of physiochemical and spectroscopic data, quantum chemical calculations, and single crystal X-ray crystallographic technology using Cu Kα radiation. The cytotoxic activities of isolates on HepG2 and Hep3B cells were evaluated in vitro. Encouragingly, ailanaltiolide K (4) showed significant cytotoxicity against Hep3B cells with IC 50 values of 1.41 ± 0.21 μM, whose covalent binding mode was uncovered in silico., Competing Interests: Declaration of competing interest No declaration of interest statement exists in the submission of this manuscript., (Copyright © 2023. Published by Elsevier Ltd.)

Fluvastatin (FLV), the first synthetically derived 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, is a potent inhibitor of cholesterol biosynthesis. While its primary mechanism of action is to reduce cholesterol levels, there is some evidence suggesting that it may also have effects on K + channels. However, the overall effects of fluvastatin on ionic currents are not yet well understood. The whole-cell clamp recordings were applied to evaluate the ionic currents and action potentials of cells. Here, we have demonstrated that FLV can effectively inhibit the amplitude of erg-mediated K + current (I K(erg) ) in pituitary tumor (GH 3 ) cells, with an IC 50 of approximately 3.2 µM. In the presence of FLV, the midpoint in the activation curve of I K(erg) was distinctly shifted to a less negative potential by 10 mV, with minimal modification of the gating charge. However, the magnitude of hyperpolarization-activated cation current (I h ) elicited by long-lasting membrane hyperpolarization was progressively decreased, with an IC 50 value of 8.7 µM, upon exposure to FLV. More interestingly, we also found that FLV (5 µM) could regulate the action potential and afterhyperpolarization properties in primary embryonic mouse cortical neurons. Our study presents compelling evidence indicating that FLV has the potential to impact both the amplitude and gating of the ion channels I K(erg) and I h . We also provide credible evidence suggesting that this drug has the potential to modify the properties of action potentials and the afterhyperpolarization current in electrically excitable cells. However, the assumption that these findings translate to similar in-vivo results remains unclear., (Copyright © 2023 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: To investigate the relationship between intimal thickness on ultrasonography and long-term patency of arteriovenous fistula restenosis after cutting balloon and high pressure balloon angioplasty., Methods: We retrospectively compared the outcomes between cutting balloon angioplasty and high pressure balloon angioplasty in 149 patients with hemodialysis access restenosis. The relationship of intimal thickness and primary assisted patency of hemodialysis access on ultrasonography was investigated as the primary outcome, using Kaplan-Meier survival analysis and Cox proportional hazards model. The second outcomes included residual diameter, blood flow, and venous pressure of hemodialysis access before and after angiography and balloon diameter and inflation pressure., Results: Primary assisted patency in cutting balloon angioplasty was 90.6%, which was significantly (P = 0.001) more than that of 37.9% in high pressure balloon angioplasty during the 20-month follow-up period. Cox proportional hazards model screened significant factors including procedure type (high pressure or cutting, P = 0.004), inflation pressure (P = 0.013), preoperative intimal thickness (P = 0.009), and difference of intimal thickness (P = 0.029). Finally, procedure type (P = 0.012) and preoperative intimal thickness (P = 0.033) were identified for predicting primary assisted patency by multivariate Cox proportional hazards model., Conclusions: Compared to high pressure balloon angioplasty for treating patients with hemodialysis access restenosis, cutting balloon angioplasty had a better primary assisted patency. The increase of intimal thickness on ultrasonography after angiography was inversely correlated with primary assisted patency., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Rodents and shrews are major reservoirs of various pathogens that are related to zoonotic infectious diseases. The purpose of this study was to investigate co-infections of zoonotic pathogens in rodents and shrews trapped in four provinces of China. We sampled different rodent and shrew communities within and around human settlements in four provinces of China and characterised several important zoonotic viral, bacterial, and parasitic pathogens by PCR methods and phylogenetic analysis. A total of 864 rodents and shrews belonging to 24 and 13 species from RODENTIA and EULIPOTYPHLA orders were captured, respectively. For viral pathogens, two species of hantavirus (Hantaan orthohantavirus and Caobang orthohantavirus) were identified in 3.47% of rodents and shrews. The overall prevalence of Bartonella spp., Anaplasmataceae, Babesia spp., Leptospira spp., Spotted fever group Rickettsiae, Borrelia spp., and Coxiella burnetii were 31.25%, 8.91%, 4.17%, 3.94%, 3.59%, 3.47%, and 0.58%, respectively. Furthermore, the highest co-infection status of three pathogens was observed among Bartonella spp., Leptospira spp., and Anaplasmataceae with a co-infection rate of 0.46%. Our results suggested that species distribution and co-infections of zoonotic pathogens were prevalent in rodents and shrews, highlighting the necessity of active surveillance for zoonotic pathogens in wild mammals in wider regions.

Pachymaran (PCP), the major medicinal constituent of Poria cocos, has a regulatory effect on immunosuppressive lung injury, but its mechanism of action with respect to gut microorganisms and their metabolites is not clear. The aim of this study was to investigate the protective effect of PCP against immunosuppressive lung injury caused by cyclosporine A (CsA), and to reveal its possible mechanism of action via the comprehensive analysis of 16S rRNA and LC-MS. We demonstrated that PCP was effective at alleviating CsA-induced immunosuppressive lung injury by restoring the organ indices and lung tissue morphology and structure. PCP significantly altered the composition of the gut and lung microbiota in mice with CsA-induced immunosuppressive lung injury by increasing the number of beneficial bacteria from the Eubacterium nodatum group , Eubacterium ventriosum group , Akkermansia , and Ruminococcus , and reducing the pathogenic Rikenellaceae RC9 gut group to fulfill its immunomodulatory role. In lung tissue microecology, PCP intervention significantly reduced the abundance of Chryseobacterium , Lawsonella , Paracoccus , and Sediminibacterium and increased the abundance of Alloprevotella . The LC-MS results showed that PCP alleviated the CsA-induced immunosuppression of lung tissue injury. The model serum metabolite Americine decreased the expression of PC(O-18:1(4Z)/0:0). Our results suggest that PCP may be involved in regulating the composition, function, and metabolism of the gut and lung microbiota to reverse CsA-induced immunosuppressive lung injury.

An ultra-compact low-pass spoof surface plasmon polariton (SSPP) filter based on an interdigital structure (IS) is designed. Simulated dispersion curves show that adding the interdigital structure in an SSPP unit effectively reduces its asymptotic frequency compared with traditional and T-shaped SSPP geometries, and the unit dimensions can be conversely reduced. Based on that, three IS-based SSPP units are, respectively, designed with different maximum intrinsic frequencies and similar asymptotic frequencies to constitute the matching and waveguide sections of the proposed filter, and the unit number in the waveguide section is adjusted to improve the out-of-band suppression. Simulation results illustrate the efficient transmission in the 0~5.66 GHz passband, excellent out-of-band suppression (over 24 dB) in the 5.95~12 GHz stopband and ultra-shape roll-off at 5.74 GHz of the proposed filter. Measurement results on a fabricated prototype validate the design, with a measured cut-off frequency of 5.53 GHz and an ultra-compact geometry of 0.5 × 0.16 λ 0 2 .

Background: Metastasis is the principal cause of cancer treatment failure and an area of dire diagnostic needs. Colorectal cancer metastases to the liver (CRCLMs) are predominantly classified into desmoplastic and replacement based on their histological growth patterns (HGPs). Desmoplastic responds well to current treatments, while replacement HGP has a poor prognosis with low overall survival rates., Methods: We hypothesised that complex cellular response underlying HGPs may be reflected in the proteome of circulating extracellular vesicles (EVs). EV proteomics data was generated through LC-MS/MS and analysed with Maxquant and Perseus. To validate the S100A9 signature, ELISA was performed, and IHC and IF were conducted on tissue for marker detection and colocalization study., Results: Plasma EV proteome signature distinguished desmoplastic from the replacement in patients with 22 differentially expressed proteins, including immune related markers. Unsupervised PCA analysis revealed clear separation of the two lesions. The marker with the highest confidence level to stratify the two HGPs was S100A9, which was traced in CRCLM lesions and found to colocalize with macrophages and neutrophils. EV-associated S100A9 in plasma may reflect the innate immunity status of metastatic lesions and their differential therapeutic responses., Conclusion: Plasma EV-derived S100A9 could be useful in personalising therapy in patients with CRCLM., (© 2023. The Author(s).)

Bats are reservoir hosts for many zoonotic viruses. Despite this, relatively little is known about the diversity and abundance of viruses within individual bats, and hence the frequency of virus co-infection and spillover among them. We characterize the mammal-associated viruses in 149 individual bats sampled from Yunnan province, China, using an unbiased meta-transcriptomics approach. This reveals a high frequency of virus co-infection (simultaneous infection of bat individuals by multiple viral species) and spillover among the animals studied, which may in turn facilitate virus recombination and reassortment. Of note, we identify five viral species that are likely to be pathogenic to humans or livestock, based on phylogenetic relatedness to known pathogens or in vitro receptor binding assays. This includes a novel recombinant SARS-like coronavirus that is closely related to both SARS-CoV and SARS-CoV-2. In vitro assays indicate that this recombinant virus can utilize the human ACE2 receptor such that it is likely to be of increased emergence risk. Our study highlights the common occurrence of co-infection and spillover of bat viruses and their implications for virus emergence., (© 2023. The Author(s).)

Deuterium incorporation at selective sites of organic compounds has long attracted the interest of the pharmaceutical industry. Here, we present a distal p -benzylic deuteration via N-heterocyclic carbene catalyzed ring-opening of cyclopropylbenzaldehydes with MeOD as the deuterium source. The corresponding 4-alkylbenzoates with high deuterium incorporation at the benzylic position were obtained in good yields. The stable benzylic deuterium remained intact for further chemical transformations.

Neuregulin 4 (NRG4) is an important adipocytokine, which plays crucial roles in maintaining energy balance, regulating glucose and lipid metabolism, and preventing non-alcoholic fatty liver disease in mammals. At present, the genomic organization, transcript and protein isoforms of human NRG4 gene have been fully explored. Previous studies in our laboratory have shown that the NRG4 gene is expressed in chicken adipose tissue, but the chicken NRG4 (cNRG4) genomic structure, transcript and protein isoforms are still unknown. To this end, in this study, the genomic and transcriptional structure of the cNRG4 gene were systematically investigated using rapid amplification of cDNA ends (RACE) and reverse transcription-polymerase chain reaction (RT-PCR). The results showed that the coding region (CDS) of the cNRG4 gene was small, but it had a very complex transcriptional structure characterized by multiple transcription start sites, alternative splicing, intron retention, cryptic exons, and alternative polyadenylation, thus leading to production of four 5?UTR isoforms (cNRG4 A, cNRG4 B, cNRG4 C, and cNRG4 D) and six 3?UTR isoforms (cNRG4 a, cNRG4 b, cNRG4 c, cNRG4 d, cNRG4 e, and cNRG4 f) of the cNRG4 gene. The cNRG4 gene spanned 21,969 bp of genomic DNA (Chr.10:3,490,314~3,512,282) and consisted of 11 exons and 10 introns. Compared with the cNRG4 gene mRNA sequence (NM&#95;001030544.4), two novel exons and one cryptic exon of the cNRG4 gene were identified in this study. Bioinformatics analysis, RT-PCR, cloning and sequencing analysis showed that the cNRG4 gene could encode three protein isoforms (cNRG4-1, cNRG4-2 and cNRG4-3). This study lays a foundation for further research on the function and regulation of the cNRG4 gene.

N-heterocyclic carbene (NHC)-catalyzed enantioselective Mannich-type reactions of the biomass-derived platform compound 5-(chloromethyl)furfural (CMF) with imines were developed. A series of high-value-added chiral amines were afforded in good to high yields with excellent regio- and enantioselectivities. The bifunctional NHC derived from ʟ-pyroglutamic acid efficiently steered the remote addition of the trienolate intermediate to the imine in a highly stereocontrolled manner. This represents the first enantioselective reaction proceeding via an NHC-bound trienolate intermediate., (© 2023 Wiley-VCH GmbH.)

The enantioselective α-oxidative coupling of enals with carboxylic acids was developed via the umpolung of an NHC-bound enolate with an iodine(III) reagent. The corresponding α-acyloxyl-β,γ-unsaturated esters were afforded in good yields, with high regio- and enantioselectivities. The key step of the reaction involves the formation of enol iodine(III) intermediate from the enolate with iodosobenzene, which changes the polarity of α-carbon of the enal from nucleophilic to electrophilic, and thus facilitates the subsequent addition of carboxylate., (© 2023 Wiley-VCH GmbH.)

Background: Robotic surgery may be advantageous in neurogenic sacral tumor resection but only a few studies reported robotic-assisted neurogenic sacral tumor resection., Objective: To propose a new surgical strategy for robotic-assisted benign sacral neurogenic tumor resection and introduce the ultrasonic osteotomy surgical system in robotic surgery., Methods: Twelve patients who had robotic-assisted primary benign sacral neurogenic tumor resection between May 2015 and March 2021 were included. Our surgical strategy divides tumors into 4 types. Type I: Presacral tumors with diameter <10 cm. Type II: Narrow-base tumors involving the sacrum with diameter <10 cm. Type III: Broad-base tumors involving the sacrum with diameter <10 cm. Type IV: Tumors involving sacral nerve roots ≥2 levels and/or with diameter ≥10 cm., Results: Five type I, 5 type II, and 1 type III patients underwent tumor resection via an anterior approach, and 1 type IV patient via a combined approach. The median operation time, blood loss, and postoperative hospital stay of type I and II were much less than those of type IV. The ultrasonic osteotomy surgical system facilitated osteotomy in 2 type II and 1 type III patients. Eleven patients had total resections, and 1 type III patient had a partial resection. During the follow-up period of 7.9 to 70.9 months (median: 28.5 months), no local recurrences or deaths were noted., Conclusion: With the largest single-center series to our knowledge, this surgical strategy helped to guide robotic-assisted benign sacral neurogenic tumor resection. The ultrasonic osteotomy surgical system was effective for type II and III., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc on behalf of Congress of Neurological Surgeons.)

The iminoacylation of alkenes via photoredox N-heterocyclic carbene catalysis is developed with the employment of alkene-tethered α-imino-oxy acids and acyl imidazoles. The corresponding substituted 3,4-dihydro-2 H -pyrroles were afforded in moderate to good yields with good to high diastereoselectivities in most cases. The reaction involves the 5- exo -trig radical cyclization of an alkene-tethered iminyl radical and the following coupling with a ketyl radical from acyl imidazole under NHC catalysis.

The objective of this study was to evaluate the effect of the level of wheat substitution for corn on the fat metabolism of Tibetan lamb. A total of 90 Tibetan lambs [body weight (BW) of 19.78 ± 2.45 kg] were arranged with three substitution levels of wheat: WC (100 % corn), WL (10 % wheat substitution for corn), and WH (15 % wheat substitution for corn) on a dry matter basis. After the experiment, cry section technology was used to scrutinize the subcutaneous adipose tissue morphology, and genes related to fat metabolism were excavated using high-throughput sequencing technology. According to the study results, fat diameter and fat biovolume of the WL and WH groups were less than the WC group. A total of 506 differentially expressed genes (DEGs) were identified by RNA sequencing (RNA-Seq) technology. Compared with the WC group, 66 DEGs were upregulated and 59 DEGs were downregulated in the WL group, and 179 DEGs were upregulated and 269 DEGs were downregulated in the WH group. The top 20 DEGs were analyzed by Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathway, indicating significant differences in the fat metabolism pathway. Five DEGs were randomly screened for quantitative reverse transcription-polymerase chain reaction (qRT-PCR) verification, and the results were consistent with the RNA-Seq results, which proved the accuracy of sequencing. In summary, with the increase in the proportion of supplemental wheat, the fat cells became smaller, and the genes related to fat decomposition were significantly upregulated., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Many people experience high burden by the outbreak of the coronavirus disease (COVID-19) and its consequences for health and everyday life. The present cross-national study investigated potential factors that can reduce the burden by COVID-19 in China and Germany. Cross-sectional and longitudinal (China: N  = 474, baseline, BL: 2015, follow-up, FU: 2020; Germany: N  = 359, BL: 2019, FU: 2020) data on physical activity (e.g., jogging) (BL/FU), positive mental health (PMH) (BL/FU), and burden by COVID-19 (FU) were collected via online surveys. In both countries, physical activity was positively associated with PMH, and both variables were negatively related to burden by COVID-19. Furthermore, PMH mediated the link between physical activity and burden. The mediation model was significant when physical activity and PMH were assessed at the BL, while burden was measured at the FU; and it was also significant when all variables were assessed at the FU. The present findings reveal that physical activity in combination with PMH can reduce the experience of burden by COVID-19. Conscious fostering of physical activity and PMH is supported as an effective strategy to reduce the negative impact of the pandemic outbreak on mental and physical health. Additional benefits such as increased adherence to governmental measures around COVID-19 are discussed., Competing Interests: Conflict of InterestThe author declare no competing interests., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021.)

β decay of proton-rich nuclei plays an important role in exploring isospin mixing. The β decay of ^{26}P at the proton drip line is studied using double-sided silicon strip detectors operating in conjunction with high-purity germanium detectors. The T=2 isobaric analog state (IAS) at 13 055 keV and two new high-lying states at 13 380 and 11 912 keV in ^{26}Si are unambiguously identified through β-delayed two-proton emission (β2p). Angular correlations of two protons emitted from ^{26}Si excited states populated by ^{26}P β decay are measured, which suggests that the two protons are emitted mainly sequentially. We report the first observation of a strongly isospin-mixed doublet that deexcites mainly via two-proton decay. The isospin mixing matrix element between the ^{26}Si IAS and the nearby 13 380-keV state is determined to be 130(21) keV, and this result represents the strongest mixing, highest excitation energy, and largest level spacing of a doublet ever observed in β-decay experiments.

Hemophilia A gene therapy targets hepatocytes to express B domain deleted (BDD) clotting factor VIII (FVIII) to permit viral encapsidation. Since BDD is prone to misfolding in the endoplasmic reticulum (ER) and ER protein misfolding in hepatocytes followed by high-fat diet (HFD) can cause hepatocellular carcinoma (HCC), we studied how FVIII misfolding impacts HCC development using hepatocyte DNA delivery to express three proteins from the same parental vector: (1) well-folded cytosolic dihydrofolate reductase (DHFR); (2) BDD-FVIII, which is prone to misfolding in the ER; and (3) N6-FVIII, which folds more efficiently than BDD-FVIII. One week after DNA delivery, when FVIII expression was undetectable, mice were fed HFD for 65 weeks. Remarkably, all mice that received BDD-FVIII vector developed liver tumors, whereas only 58% of mice that received N6 and no mice that received DHFR vector developed liver tumors, suggesting that the degree of protein misfolding in the ER increases predisposition to HCC in the context of an HFD and in the absence of viral transduction. Our findings raise concerns of ectopic BDD-FVIII expression in hepatocytes in the clinic, which poses risks independent of viral vector integration. Limited expression per hepatocyte and/or use of proteins that avoid misfolding may enhance safety., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Four new steroids, chouchunsteride A-D (1-4), together with four known steroids (5-8), were isolated from the leaves of Ailanthus altissima (Mill.) Swingle. Their structures were elucidated based on spectroscopic data analysis, while the relative and absolute configurations were determined via acetonide analysis and quantum chemical ECD calculations. All isolated steroids were evaluated for their cytotoxic activity against two hepatoma carcinoma cell lines (HepG2, Hep3B). Among them, 1 exhibited the most potent cytotoxicity against HepG2 cells with an IC 50 value of 4.03 μM., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)