High-pressure strengthening in ultrafine-grained metals.

The Hall-Petch relationship, according to which the strength of a metal increases as the grain size decreases, has been reported to break down at a critical grain size of around 10 to 15 nanometres1,2. As the grain size decreases beyond this point, the dominant mechanism of deformation switches from a dislocation-mediated process to grain boundary sliding, leading to material softening. In one previous approach, stabilization of grain boundaries through relaxation and molybdenum segregation was used to prevent this softening effect in nickel-molybdenum alloys with grain sizes below 10 nanometres3. Here we track in situ the yield stress and deformation texturing of pure nickel samples of various average grain sizes using a diamond anvil cell coupled with radial X-ray diffraction. Our high-pressure experiments reveal continuous strengthening in samples with grain sizes from 200 nanometres down to 3 nanometres, with the strengthening enhanced (rather than reduced) at grain sizes smaller than 20 nanometres. We achieve a yield strength of approximately 4.2 gigapascals in our 3-nanometre-grain-size samples, ten times stronger than that of a commercial nickel material. A maximum flow stress of 10.2 gigapascals is obtained in nickel of grain size 3 nanometres for the pressure range studied here. We see similar patterns of compression strengthening in gold and palladium samples down to the smallest grain sizes. Simulations and transmission electron microscopy reveal that the high strength observed in nickel of grain size 3 nanometres is caused by the superposition of strengthening mechanisms: both partial and full dislocation hardening plus suppression of grain boundary plasticity. These insights contribute to the ongoing search for ultrastrong metals via materials engineering.

The influence of male HBV infection on sperm quality, embryonic development, and assisted reproductive outcomes.

STUDY QUESTION: What is the impact of male hepatitis B virus (HBV) infection on sperm quality, embryonic development, and assisted reproductive outcomes? SUMMARY ANSWER: Male HBV infection did not affect assisted reproductive outcomes, but HBV is capable of impairing human sperm and embryo formation in the early stages following fertilization. WHAT IS KNOWN ALREADY: HBV is found in germ cells and early embryos of patients with HBV. HBV may impair human sperm function via increasing reactive oxygen species. STUDY DESIGN, SIZE, DURATION: We conducted a retrospective cohort study of 1581 infertile couples, including 496 male patients clinically confirmed to have hepatitis B infection, and a laboratory study of effects of HBV proteins on early embryos, using human embryonic stem cells (hESCs), human sperm, and golden hamster oocytes. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 1581 infertile couples (24-40 years of age) who were admitted to a reproductive medicine center to undergo ART for the first time from January 2019 to November 2021 were selected as the study subjects. The case group was composed of 469 couples with hepatitis B surface antigen (HBsAg)-seropositive men and seronegative women (368 for IVF and 101 for ICSI treatment). The negative control group was composed of 1112 couples where both men and women were seronegative for hepatitis B antigen. We divided these couples into three comparison groups (IVF/ICSI, IVF, and ICSI). IVF of human sperm and hamster oocytes was used to evaluate the influence of the HBV HBs protein on formation of 2-cell embryos. Mitochondrial membrane potential (MMP) of hESCs was assayed via a fluorescence intensity system. Immunofluorescence staining of the phosphorylated histone H2A.X was applied to identify DNA damage to hESCs caused by the HBV X (HBx) protein. MAIN RESULTS AND THE ROLE OF CHANCE: Sperm concentration, total sperm number, and sperm with normal morphology were decreased in the couples with HBV-infected males in couples who were undergoing IVF/ICSI (male HBV(+) vs control: 469 vs 1112 individuals; sperm number, P < 0.01; normal sperm morphology, P < 0.01), IVF (368 vs 792; sperm number, P < 0.01; normal sperm morphology, P ≤ 0.05), and ICSI (101 vs 306; sperm number, P < 0.01; normal sperm morphology, P < 0.001). There was no significant difference in the number of embryo cleavages, blastocyst formation, biochemical pregnancy rate, clinical pregnancy rate, and live-birth rate between case and control groups. The 2PN fertilization rate in IVF/ICSI (P < 0.01) and ICSI (P < 0.05) couples, and the number of 2PN-fertilized oocytes in IVF (P < 0.001) couples were lower in couples with male HBV infection compared to control couples. HBV HBs protein reduced the MMP of human sperm and decreased 2-cell embryo formation in IVF of human sperm and zona-free-hamster oocyte. A reduction in fluorescence intensity and immunofluorescence staining of phosphorylated histone H2A.X indicated that HBx caused MMP impairment and DNA damage in human early embryonic cells, respectively. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: HBV can be examined in samples of sperm or discarded IVF early embryos from HBsAg-seropositive men and seronegative women. The hESC model in vitro may not fully mimic the natural embryos in vivo. WIDER IMPLICATIONS OF THE FINDINGS: This study furthers our understanding of the influence of male HBV infection on embryonic development. Our results suggest that a semen-washing process may be necessary for male patients with HBV undergoing ART to minimize the potential negative effects of HBV infection on the early embryo. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by grants from the National Natural Science Foundation of China, grant numbers 81870432 and 81570567 to X.Z., 81571994 to P.S., and 81950410640, the Natural Science Foundation of Guangdong Province, China (No. 2023A1515010660 to X.Z.), and the Li Ka Shing Shantou University Foundation (Grant No. L11112008). The authors have no conflicts of interest.

Comparison of clinical efficacy of robot-assisted and freehand core decompression in the treatment of osteonecrosis of the femoral head: a systematic review and meta-analysis.

OBJECTIVE: At present, the core decompression (CD) has become the main surgical procedure for the treatment of osteonecrosis of the femoral head (ONFH); however, the CD surgery requires high operator experience and repeated fluoroscopy increases the radiation damage to patients, and medical staff. This article compares the clinical efficacy of robot-assisted and freehand CD for ONFH by meta-analysis. METHODS: Computer searches of PubMed, Web of Science, Embase, Cochrane Library, Chinese National Knowledge Infrastructure, China Science and Technology Journal Database, WanFang, and Chinese BioMedical Literature Database were conducted from the time of database inception to November 15, 2023. The literature on the clinical efficacy of robot-assisted and freehand CD in the treatment of ONFH was collected. Two researchers independently screened the literature according to the inclusion and exclusion criteria, extracted data, and strictly evaluated the quality of the included literature. Outcome measures encompassed operative duration, intraoperative blood loss volume, frequency of intraoperative fluoroscopies, visual analog scale (VAS) score, Harris hip score (HHS), complications, and radiographic progression. Data synthesis was carried out using Review Manager 5.4.1 software. The quality of evidence was evaluated according to Grades of Recommendation Assessment Development and Evaluation (GRADE) standards. RESULTS: Seven retrospective cohort studies involving 355 patients were included in the study. The results of meta-analysis showed that in the robot-assisted group, the operative duration (MD = -17.60, 95% CI: -23.41 to -11.78, P < 0.001), intraoperative blood loss volume (MD = -19.98, 95% CI: -28.84 to -11.11, P < 0.001), frequency of intraoperative fluoroscopies (MD = -6.60, 95% CI: -9.01 to -4.20, P < 0.001), and ΔVAS score (MD = -0.45, 95% CI: -0.67 to -0.22, P < 0.001) were significantly better than those in the freehand group. The GRADE evidence evaluation showed ΔVAS score as low quality and other indicators as very low quality. There was no significant difference in the terms of ΔHHS (MD = 0.51, 95% CI: -1.34 to 2.35, P = 0.59), complications (RR = 0.30, 95% CI: 0.03 to 2.74, P = 0.29), and radiographic progression (RR = 0.50, 95% CI: 0.25 to 1.02, P = 0.06) between the two groups. CONCLUSION: There is limited evidence showing the benefit of robot-assisted therapy for treatment of ONFH patients, and much of it is of low quality. Therefore, caution should be exercised in interpreting these results. It is recommended that more high-quality studies be conducted to validate these findings in future studies. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/ #recordDetails, CRD42023420593.

SIRT6 Inhibits Anoikis of Colorectal Cancer Cells by Down-Regulating NDRG1.

Anoikis, a form of apoptosis resulting from the loss of cell-extracellular matrix interaction, is a significant barrier to cancer cell metastasis. However, the epigenetic regulation of this process remains to be explored. Here, we demonstrate that the histone deacetylase sirtuin 6 (SIRT6) plays a pivotal role in conferring anoikis resistance to colorectal cancer (CRC) cells. The protein level of SIRT6 is negatively correlated with anoikis in CRC cells. The overexpression of SIRT6 decreases while the knockdown of SIRT6 increases detachment-induced anoikis. Mechanistically, SIRT6 inhibits the transcription of N-myc downstream-regulated gene 1 (NDRG1), a negative regulator of the AKT signaling pathway. We observed the up-regulation of SIRT6 in advanced-stage CRC samples. Together, our findings unveil a novel epigenetic program regulating the anoikis of CRC cells.

Discovery of the hidden coding information in cancers: Mechanisms and biological functions.

Most proteins are derived from the translation of coding sequence (CDS) in messenger RNAs (mRNAs). However, accumulating evidence has revealed an unexpected abundance of translation in putative non-coding genomes, especially 5' untranslated region (5' UTR) of mRNAs or non-coding RNA species (ncRNA) such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). Notably, many of these UTR- or ncRNA-encoded micropeptides/proteins play important roles in human malignancies. In this review, we describe recent advances in our understanding of the mechanisms underlying the translation of non-coding regions or ncRNAs and the methods to discover the hidden coding information. Furthermore, we summarize the biological functions of UTR- or ncRNA-encoded micropeptides/proteins in cancers and discuss their potential as clinical biomarkers for cancer diagnosis and as therapeutic targets for cancer treatment.

CD22 is a potential target of CAR-NK cell therapy for esophageal squamous cell carcinoma.

BACKGROUND: Chimeric antigen receptor NK (CAR-NK) cell therapy is one of the most promising immunotherapies. Although it has shown a significant therapeutic effect in hematologic malignancies, few successes have been obtained in solid tumors including esophageal squamous cell carcinoma (ESCC). The major reasons are lack of specific cell surface antigens and complex tumor microenvironment. Here we identify CD22, a well-known tumor surface marker in hematologic malignancies, is expressed in ESCC, possibly serving as a potential target of CAR-NK cell therapy. METHODS: The expression of 13 tumor cell surface antigens used clinically was analyzed in patients from The Cancer Genome Atlas (TCGA) database. Also, mRNA expression were detected in 2 ESCC cell lines and 2 patients samples by qCPR. Then according to Venn diagram, CD22 was selected for further investigation. Following this, the expression of CD22 by immunofluorescence (IF) in ESCC cell lines and by immunohistochemistry (IHC) in 87 cases of human ESCC samples was detected respectively. On the basis of H-score results, the correlation between CD22 expression and clinical parameters was analyzed. As a proof, the efficacy of CD22-targeted CAR-NK cells against ESCC cell lines was performed by a real-time cell analyzer (RTCA) platform. RESULTS: KYSE-140 and KYSE-150 cell lines displayed surface expression of CD22. IHC showed an 80.46% (70/87) positive rate in ESCC patient samples. Among these, cell membranous expression of CD22 was observed in 27.59% (24/87) patient samples. Through chi-square test, expression of CD22 in ESCC was associated with lymph node metastasis while it was no related to the depth of tumor invasion and clinical stage. Engineered CD22-targeted CAR-NK cells exhibited inhibitory growth capability against ESCC cell lines (p < 0.0001). CONCLUSIONS: CD22 is a potential tumor surface antigen capable of being targeted by CAR-NK cells in ESCC. And potential therapeutics for ESCC may be developed based on immune cells expressing anti-CD22 CAR. The study also indicates that CD22 CAR-NK cells could be used in other cancers and more in vivo experiments are needed.

Association between myasthenia gravis and cognitive disorders: a PRISMA-compliant meta-analysis.

OBJECTIVE: This meta-analysis assessed the association between myasthenia gravis (MG) and cognitive disorders. METHODS: The PubMed, Web of Science, OVID, EMBASE, CNKI and Wanfang electronic databases were comprehensively searched from inception to October 2020 for relevant studies. The primary outcomes were scores of the cognitive function battery. A random effects model was used to evaluate the cognitive function of patients with MG. RESULTS: Eight cross-sectional studies containing 381 patients and 220 healthy controls were included in this meta-analysis. In relation to global cognitive function, patients with MG performed significantly worse than healthy individuals (SMD = -0.4, 95% CI = -0.63 to -0.16, p < 0.001, I2 = 10%). Specifically, the impaired cognitive domains included language, visuospatial function, information processing, verbal immediate and delayed recall memory, visual immediate recall memory, and response fluency, while attention, executive function, and visual delayed recall memory were unimpaired. The patients with early-onset (SMD= -0.527, 95% CI = -0.855 to -0.199, p = 0.002) and generalized MG (SMD= -0.577, 95% CI = -1.047 to -0.107, p = 0.016) had poorer global cognitive performance than the healthy population. CONCLUSIONS: Patients with MG may have cognitive disorders, including those associated with the domains of language, visuospatial function, information processing, verbal immediate and delayed recall memory, visual immediate recall memory and response fluency. Furthermore, the age of onset and disease severity may be associated with cognitive disorders in patients with MG.

Modeling Liver Development and Disease in a Dish.

Historically, biological research has relied primarily on animal models. While this led to the understanding of numerous human biological processes, inherent species-specific differences make it difficult to answer certain liver-related developmental and disease-specific questions. The advent of 3D organoid models that are either derived from pluripotent stem cells or generated from healthy or diseased tissue-derived stem cells have made it possible to recapitulate the biological aspects of human organs. Organoid technology has been instrumental in understanding the disease mechanism and complements animal models. This review underscores the advances in organoid technology and specifically how liver organoids are used to better understand human-specific biological processes in development and disease. We also discuss advances made in the application of organoid models in drug screening and personalized medicine.

Expression of CD22 in Triple-Negative Breast Cancer: A Novel Prognostic Biomarker and Potential Target for CAR Therapy.

Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancer cases. Due to the lack of expression of well-known molecular targets [estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)], there is a need for more alternative treatment approaches in TNBC. Chimeric antigen receptor (CAR)-T cell-based immunotherapy treatment is one of the latest treatment technologies with outstanding therapeutic advances in the past decade, especially in the treatment of hematologic malignancies, but the therapeutic effects of CAR-T cells against solid tumors have not yet shown significant clinical benefits. Identification of highly specific CAR-T targets in solid tumors is also crucial for its successful treatment. CD22 is reported to be a multifunctional receptor that is mainly expressed on the surface of mature B-cells (lymphocytes) and is also highly expressed in most B-cell malignancies. This study aimed to investigate the expression of CD22 in TNBC. Bioinformatic analysis was performed to evaluate the expression of CD22 in breast carcinoma and normal tissues. RNA-seq data of normal and breast carcinoma patients were downloaded from The Cancer Genome Atlas (TCGA), and differential gene expression was performed using R language. Additionally, online bioinformatics web tools (GEPIA and TNM plot) were used to evaluate the expression of CD22 in breast carcinoma and normal tissues. Western blot (WB) analysis and immunofluorescence (IF) were performed to characterize the expression of CD22 in TNBC cell lines. Immunohistochemical (IHC) staining was performed on tumor specimens from 97 TNBC patients for CD22 expression. Moreover, statistical analysis was performed to analyze the association of clinical pathological parameters with CD22 expression. Correlation analysis between overall survival data of TNBC patients and CD22 expression was also performed. Differential gene expression analysis of TCGA data revealed that CD22 is among the upregulated differentially expressed genes (DEGs) with high expression in breast cancer, as compared to normal breast tissues. WB and IF analysis revealed high expression of CD22 in TNBC cell lines. IHC results also showed that approximately 62.89% (61/97) of TNBC specimens were stained positive for CD22. Cell membrane expression of CD22 was evident in 23.71% (23/97) of TNBC specimens, and 39.18% (38/97) of TNBC specimens showed cytoplasmic/membrane expression, while 37.11% (36/97) specimens were negative for CD22. Furthermore, significant associations were found between the size of tumors in TNBC patients and CD22 expression, which unveils its potential as a prognostic biomarker. No significant correlation was found between the overall survival of TNBC patients and CD22 expression. In conclusion, we demonstrated for the first time that CD22 is highly expressed in TNBC. Based on our findings, we anticipated that CD22 could be used as a prognostic biomarker in TNBC, and it might be a potential CAR-T target in TNBC for whom few therapeutic options exist. However, more large-scale studies and clinical trials will ensure its potential usefulness as a CAR-T target in TNBC.

Endoscopic submucosal excavation of a rectal submucosal tumor assisted by a curvilinear echoendoscope.

A 62-year-old woman undergoing screening colonoscopy was found to have a submucosal protrusion in the mid-rectum. Evaluation with a curvilinear echoendoscope revealed it to be a 1.8×1.1cm, hypoechoic mass originating from muscularis propria (MP) . Endoscopic submucosal excavation (ESE) was attempted, but despite adequate dissection of the submucosa, the mass remained poorly defined appearing as a slight elevation in the background of flat muscle. Repeat visualization of the lesion status post submucosal dissection was performed with the curvilinear echoendoscope. A biopsy forceps was introduced as a movable landmark which could be visualized on both synchronized endosonographic and optical views, so as to clearly identify the margin of the lesion . Incision of the MP overlying the identified margin allowed for precise exposure of the mass, which was further excavated and finally resected.

Tremella fuciformis Crude Polysaccharides Attenuates Steatosis and Suppresses Inflammation in Diet-Induced NAFLD Mice.

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disorder characterized by an enhanced accumulation of lipids, which affects around 40% of the world's population. The T. fuciformis fungus possesses immunomodulatory activity and other beneficial properties that may alleviate steatosis through a different mechanism. The present study was designed to evaluate the effect T. fuciformis crude polysaccharides (TFCP) on inflammatory and lipid metabolism gene expression, oxidative stress, and lipid profile. Mice were divided into groups receiving (a) a normal chow diet (NCD), (b) a methionine-choline-deficient (MCD) diet, and (c) a MCD diet with TFCP. Liver histopathology was performed, and the hepatic gene expression levels were estimated using qRT-PCR. The lipid profiles, ALT, AST, and efficient oxidative enzymes were analyzed using ELISA. The TFCP administration in the MCD-fed mice suppressed hepatic lipid accumulation, lipid metabolism-associated genes (HMGCR, FABP, SREBP, ACC, and FAS), and inflammation-associated genes (IL-1ß, TLR4, TNF-α, and IL-6) whilst enhancing the expression of HNF4α genes. TFCP mitigated against oxidative stress and normalized healthy lipid profiles. These results highlighted that TFCP prevents NAFLD through the inhibition of oxidative stress and inflammation, suggesting TFCP would potentially be an effective therapeutic agent against NAFLD progression.

Antibacterial and anti-biofilm activities of probiotic Lactobacillus curvatus BSF206 and Pediococcus pentosaceus AC1-2 against Streptococcus mutans.

Streptococcus mutans (S. mutans) is the most important oral pathogenic bacterial cause of dental caries. Here we investigated the abilities of probiotic lactobacillus strains of Lactobacillus curvatus (L. curvatus) BSF206 and Pediococcus pentosaceus (P. pentosaceus) AC1-2 to control S. mutans. Both probiotic strains are acid and bile salt tolerant and are resistant to hydrogen peroxide and lysozyme to promote their survival within the oral environment. In addition, both strains are highly hydrophobic and are also capable of engaging in electrostatic interactions. These properties enhance abilities of both strains to adhere to gingival epithelial cells and HT-29 for improved colonization of oral tissues, while also enabling these probiotics auto-aggregate and to form aggregates with S. mutans that both may prevent S. mutans from colonizing oral tissues and facilitate the clearance of the cariogenic bacteria from the mouth during swallowing of food and saliva. Furthermore, results presented herein revealed that L. curvatus BSF206 and P. pentosaceus AC1-2 effectively inhibited S. mutans activities (biofilm formation, secretion of extracellular matrix components, synthesis of water-insoluble glucans) and led to downregulation of expression of key S. mutans genes involved in biofilm production (gtfA, gtfB, ftf, brpA). Taken together, these results indicate that L. curvatus BSF206 and P. pentosaceus AC1-2 can inhibit S. mutans biofilm formation as a new strategy for preventing dental caries.

Comparative Effectiveness and Safety of Polyethylene Glycol Electrolyte Solution Versus Lactulose for Treatment of Hepatic Encephalopathy: A Systematic Review and Meta-analysis.

BACKGROUND: Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome associated with liver failure and/or portal systemic shunting. Polyethylene glycol (PEG) electrolyte solution is a commonly used for catharsis of gut, which has been demonstrated to relieve HE in a number of randomized controlled trials. The aim of this paper was to evaluate the comparative efficacy and safety of PEG with lactulose for current HE treatment. METHODS: PEG electrolyte solution versus lactulose of HE was deeply studied by conducting a systematic search in electronic databases and other sources until December 31, 2020. The PRISMA statement recommended the use of meta-analysis with 95% confidence interval (CI), relative risk (RR), and weighted mean deviation (WMD) as the estimated effect size. A sensitivity analysis was performed comprehensively to present the risk of bias and the source of heterogeneity. RESULTS: A total of 434 patients were involved in 7 randomized studies. It is found that there was a significant advantage of PEG therapy in the increase of clinical efficacy (RR=1.46; 95% CI: 1.26-1.68; P=0.000; I2=0.0%) and the decrease of hospital stay (WMD=-1.78; 95% CI: -2.72 to 0.85; P=0.000; I2=90.1%). There was no significant difference in the incidence of adverse events (RR=0.75; 95% CI: 0.48-1.19; P=0.222>0.05; I2=7.2%) and the level of serum ammonia (WMD=9.02; 95% CI: -14.39 to 32.43; P=0.45>0.05; I2=84.9%) after 24 hours between the 2 groups. CONCLUSIONS: The results prove that PEG has a beneficial effect on the treatment of HE. Compared with lactulose, PEG can lead to more rapid HE resolution during the first 24 hours and shorten the length of stay without increasing the rate of adverse effects.

Different dosage regimens of erenumab for the treatment of migraine: A systematic review and meta-analysis of the efficacy and safety of randomized controlled trials.

BACKGROUND: Migraine is a worldwide epidemic neurological disorder that has a significant influence on the quality of life. Migraine attacks are considered to be related to a calcitonin gene-related peptide (CGRP) signaling molecule, and anti-CGRP medications are used to abort and prevent migraine attacks. Erenumab, a monoclonal antibody that targets the CGRP receptor, is the first migraine preventive medication approved by the US Food and Drug Administration. In the present study, we evaluate the efficacy and safety of erenumab. OBJECTIVE: This study aims to systematically assess the efficacy and safety of erenumab as a migraine preventive treatment compared to a placebo. METHODS: Randomized, placebo-controlled, single or double-blind trials were searched through MEDLINE, Embase, Cochrane Library, and ClinicalTrials.gov up to May 2022. The efficacy outcomes we collected include changes from baseline on monthly migraine days, monthly acute migraine-specific medication days, ≥50% responder rate, ≥75% responder rate, and 100% responder rate at week 12. Safety outcomes include treatment emergent adverse events, serious adverse events, and any adverse event that leads to discontinuation of treatment. The study was registered with PROSPERO (Registry number: CRD42022338861). RESULT: In all eight included trials, we found that erenumab (28, 70, and 140 mg) is very effective and has a significantly greater reduction in baseline monthly migraine days (28 mg: mean difference [MD] = -1.1, 95% confidence interval [CI]: -2.0 to -0.2, p = 0.020; 70 mg: MD = -1.4, 95% CI: -1.8 to -1.1, p < 0.001, I2  = 26%; 140 mg: MD = -1.8, 95% CI: -2.1 to -1.4, p < 0.001, I2  = 0%) than placebo at week 12, especially with 140 mg. Otherwise, we found that there were no statistical differences in the occurrence of adverse events (7 mg: risk ratio [RR] = 0.9, 95% CI: 0.7 to 1.2, p = 0.570; 21 mg: RR = 1.0, 95% CI: 0.8 to 1.2, p = 0.730; 28 mg: RR = 0.9, 95% CI: 0.7 to 1.1, p = 0.340; 70 mg: RR = 1.0, 95% CI: 0.9 to 1.0, p = 0.230, I2  = 0%; 140 mg: RR = 1.0, 95% CI: 0.9 to 1.1, p = 0.880, I2  = 40%) between the erenumab and placebo groups. CONCLUSIONS: In our study, we found that erenumab, especially at the dose of 140 mg, is an effective and well-tolerated preventive treatment for migraine.

Chiral 2-phenyl-3-hydroxypropyl esters as PKC-alpha modulators: HPLC enantioseparation, NMR absolute configuration assignment, and molecular docking studies.

Protein kinase C (PKC) isoforms play a pivotal role in the regulation of numerous cellular functions, making them extensively studied and highly attractive drug targets. In our previous work, we identified in racemate 1-2, based on the 2-benzyl-3-hydroxypropyl ester scaffold, two new potent and promising PKCα and PKCδ ligands, targeting the C1 domain of these two kinases. Herein, we report the resolution of the racemates by enantioselective semi-preparative HPLC. The attribution of the absolute configuration (AC) of homochirals 1 was performed by NMR, via methoxy-α-trifluoromethyl-α-phenylacetic acid derivatization (MTPA or Mosher's acid). Moreover, the match between the experimental and predicted electronic circular dichroism (ECD) spectra confirmed the assigned AC. These results proved that Mosher's esters can be properly exploited for the determination of the AC also for chiral primary alcohols. Lastly, homochiral 1 and 2 were assessed for binding affinity and functional activity against PKCα. No significative differences in the Ki of the enantiopure compounds was observed, thus suggesting that chirality does not seem to play a significant role in targeting PKC C1 domain. These results are in accordance with the molecular docking studies performed using a new homology model for the human PKCαC1B domain.

[CiteSpace knowledge mapping of traditional Chinese medicine in treatment of premature ovarian failure].

This study aimed to investigate the research trend of traditional Chinese medicine(TCM) against premature ovarian fai-lure(POF) from 1989 to 2021 by bibliometrics and explore the research status, research hotspots, and advances in international co-operation, knowledge structure, and active topics.The research articles on POF published from database inception to December 28, 2021, were retrieved from Web of Science and China National Knowledge Infrastructure(CNKI) and visually analyzed for countries, journals, authors, institutions, and keywords by CiteSpace 5.8.R3.A total of 1 468 articles were included, including 217 in English and 1 251 in Chinese.Since 1989, there has been an overall upward trend in the number of articles, with China serving as the main contributor.The core authors of Chinese articles are from a cooperative team represented by FENG Yi-xuan, REN Yu-lan, LING Le-le, and TENG Xiu-xiang.BETTERLE C is the author with the highest number of published articles in this international research field.The articles are mainly published by TCM journals and universities, and Human Reproduction accounts for the highest proportion of publications in the international research(11 articles, 5.07%).In the retrieved research articles, the research contents mainly focus on the treatment methods, research methods, and mechanism of action of TCM in the treatment of POF, where "Zuogui Pills" "gene" "cell" "model" "expression", etc.are the current research hotspots. "Acupuncture" "data mining" "systematic review" "oxidative stress" "activation" may be the potential topics in the follow-up research development.Future development should focus on the scientific interpretation and analysis of the theory and practice of TCM by modern scientific and technological methods.The research on informatization, digitization, and knowledge of TCM theory and practice is pivotal to promoting the internationalization and modernization of TCM, which can help researchers explore new directions for future research and identify new perspectives for potential collaboration in the field.

Analysis of clinical characteristics and genetic testing in patients with acute fatty liver of pregnancy: a retrospective study.

BACKGROUND: Acute fatty liver of pregnancy (AFLP) is an acute, rare and potentially lethal disease typically occurring in the third trimester of pregnancy. So far, there is no effective means of prevention. Therefore, in this study, we retrospectively analyzed the clinical features of AFLP patients for a better understanding. Meanwhile, for the first time, the genetic background associated with the onset of AFLP was discussed by high-throughput sequencing, hoping to provide evidence for genetic counseling and prenatal diagnosis of AFLP. METHODS: Thirteen AFLP patients admitted to our hospital and other hospital from March 2012 to February 2020 were selected. Clinical data about general condition, laboratory test, liver biopsy and the prognosis of mother and fetus were collected for retrospective analysis. In addition, the peripheral blood of five patients with AFLP and one newborn infant of his mother with AFLP was sequenced with whole-exome sequencing and gene mutation was analyzed by bioinformatics methods. RESULTS: The initial symptoms of AFLP varied differently, with jaundice (9/13, 69%), fatigue (8/13, 62%) and nausea and vomiting (6/13, 46%) being the most common. Moreover, the main maternal complications were coagulopathy (13/13, 100%), followed by acute renal dysfunction (10/13, 77%). Raised serum bilirubin, transaminases and uric acid were found in all patients (100%), hypoglycemia was found in six patients (46%) and fatty liver on ultrasound was seen in five patients (5/12, 42%). One (7%) maternal death occurred and all neonates survived delivery. In addition, to our surprise, whole-exome sequencing showed that no gene mutation in related enzymes involved in fatty acid metabolism was noted in the pregnant women and children receiving genetic testing. CONCLUSIONS: Early visit, early detection, early termination of pregnancy and multidisciplinary comprehensive treatment are the key factors to improve the prognosis of AFLP patients and their newborn infants. Furthermore, although limited size of study, to our knowledge, this report is the first to present the lack of common mutation involved in fatty acid oxidation in Chinese patients with AFLP via whole-exome sequencing. Thus, further studies are needed with larger and more varied samples to validate the conclusion.

Protective Effect of Tuna Bioactive Peptide on Dextran Sulfate Sodium-Induced Colitis in Mice.

Bioactive peptides isolated from marine organisms have shown to have potential anti-inflammatory effects. This study aimed to investigate the intestinal protection effect of low molecular peptides (Mw < 1 kDa) produced through enzymatic hydrolysis of tuna processing waste (tuna bioactive peptides (TBP)) on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in BALB/c mice. Here, we randomly divided twenty-four male BALB/c mice into four groups: (i) normal (untreated), (ii) DSS-induced model colitis, (iii) low dose TBP+DSS-treated (200 mg/kg/d), and (iv) high dose TBP+DSS-treated groups (500 mg/kg/d). The results showed that TBP significantly reduced mice weight loss and improved morphological and pathological characteristics of colon tissues. In addition, it increased the activities of antioxidant enzymes (SOD and GSH-Px) and decreased inflammatory factors (LPS, IL-6, and TNF-α) expression. TBP increased the gene expression levels of some tight junction (TJ) proteins. Moreover, TBP increased the short-chain fatty acids (SCFAs) levels and the diversity and imbalance of intestinal flora. Therefore, TBP plays some protective roles in the intestinal tract by enhancing antioxidant and anti-inflammatory abilities of the body, improving the intestinal barrier and metabolic abnormalities, and adjusting intestinal flora imbalance.

The optimal range of serum intact parathyroid hormone for a lower risk of mortality in the incident hemodialysis patients.

The serum intact parathyroid hormone (iPTH) is associated with the prognosis of hemodialysis (HD) patients, however, its optimal range for reducing mortality remains inconsistent. We designed a prospective cohort study of 346 incident HD patients to assess the association between different serum iPTH level and mortality. According to the Kidney Disease Outcomes Quality Initiative (K/DOQI) international guidelines (2003), we divided patients into three groups (iPTH < 150 pg/mL, 150-300 pg/mL and >300 pg/mL). During the median follow-up of 58 months, 157 patients (45.38%) died. Multivariate Cox regression analysis showed that iPTH < 150 pg/mL and >300 pg/mL were associated with all-cause and cardiovascular mortality. Then, we performed a sensitivity analysis of patients divided into 6 serum PTH levels groups according to the folds of the K/DOQI target range. Multivariate Cox regression analysis showed that patients with serum iPTH ≥750 pg/mL, 600-749 pg/mL, 450-599 pg/mL had significantly higher risk of all-cause and cardiovascular mortality compared with those with serum iPTH in the range of 150-299 pg/mL. The association between serum iPTH and mortality shows a U-shaped curve. The optimal serum iPTH level which confers the lowest risk of all-cause and cardiovascular mortality could range from 150 pg/mL to 450 pg/mL in this group of incident HD patients.

Defined host factors support HBV infection in non-hepatic 293T cells.

Hepatitis B virus (HBV) is a human hepatotropic virus. However, HBV infection also occurs at extrahepatic sites, but the relevant host factors required for HBV infection in non-hepatic cells are only partially understood. In this article, a non-hepatic cell culture model is constructed by exogenous expression of four host genes (NTCP, HNF4α, RXRα and PPARα) in human non-hepatic 293T cells. This cell culture model supports HBV entry, transcription and replication, as evidenced by the detection of HBV pgRNA, HBV cccDNA, HBsAg, HBeAg, HBcAg and HBVDNA. Our results suggest that the above cellular factors may play a key role in HBV infection of non-hepatic cells. This model will facilitate the identification of host genes that support extrahepatic HBV infection.