Corydecusines A-H, new phthalideisoquinoline hemicetal alkaloids from the bulbs of Corydalis decumbens inhibit Tau pathology by activating autophagy mediated by AMPK-ULK1 pathway.

Twelve phthalideisoquinoline hemiacetal alkaloids including eight new ones (1-8) and one natural alkaloid characterized by an aziridine moiety with unassigned NMR data (9), were isolated and identified from the bulbs of Corydalis decumbens. Their structures were established by comprehensive analyses of HRESIMS, NMR, X-ray crystallography, and ECD analyses. The unambiguously established structures of the phthalideisoquinoline hemiacetal alkaloids indicated that the absolute configurations of C-1, C-9, and C-7' were confusable only relied on coupling constants. A summary of their ECD spectra was concluded and provided an insight for C-1, C-9, and C-7' absolute configuration assignment. These new compounds were evaluated to induce autophagy flux through flow cytometry analysis. Moreover, compounds 2 and 6 could significantly induce autophagy and inhibit Tau pathology by AMPK-ULK1 pathway activation, which provided an avenue for anti-AD lead compounds discovery.

Maternal tobacco exposure during pregnancy and atopic dermatitis in offspring: A systematic review and meta-analysis.

The main purpose of this review was to examine the evidence of the relationship between active smoking or passive smoking during pregnancy and atopic dermatitis in offspring. The protocol was written following the PRISMA Checklist and was registered in the PROSPERO database (registration number CRD42022381136). We implemented a comprehensive search in PubMed, Embase and Web of Science databases to identify all potentially related articles from inception through 1 December 2022. We assessed cohort studies and case-control studies using the Newcastle-Ottawa Scale (NOS), and the Joanna Briggs Institute (JBI) critical appraisal tool to assess the quality of cross-sectional studies. Heterogeneity was investigated by using Cochrane Q tests and I2 statistics. In addition, according to the research design, population source and population size, the reasons for the heterogeneity were analysed. A total of 15 observational studies were included in this analysis. Our meta-analysis suggests that atopic dermatitis in offspring is not associated with active smoking during pregnancy (pooled OR, 0.96 [95% CI 0.86-1.07]); however, it is related to passive smoking (OR, 1.52 [95% CI 1.36-1.70]). Passive smoking during pregnancy is associated with an increased risk of eczema development in offspring. More research is needed to explore the risk of active smoking and eczema development in offspring, especially the association between measurements of pregnancy cotinine levels in maternal body fluids and AD in offspring.

Cathepsin H Knockdown Reverses Radioresistance of Hepatocellular Carcinoma via Metabolic Switch Followed by Apoptosis.

Despite the wide application of radiotherapy in HCC, radiotherapy efficacy is sometimes limited due to radioresistance. Although radioresistance is reported with high glycolysis, the underlying mechanism between radioresistance and cancer metabolism, as well as the role of cathepsin H (CTSH) within it, remain unclear. In this study, tumor-bearing models and HCC cell lines were used to observe the effect of CTSH on radioresistance. Proteome mass spectrometry, followed by enrichment analysis, were used to investigate the cascades and targets regulated by CTSH. Technologies such as immunofluorescence co-localization flow cytometry and Western blot were used for further detection and verification. Through these methods, we originally found CTSH knockdown (KD) perturbed aerobic glycolysis and enhanced aerobic respiration, and thus promoted apoptosis through up-regulation and the release of proapoptotic factors such as AIFM1, HTRA2, and DIABLO, consequently reducing radioresistance. We also found that CTSH, together with its regulatory targets (such as PFKL, HK2, LDH, and AIFM1), was correlated with tumorigenesis and poor prognosis. In summary, our study found that the cancer metabolic switch and apoptosis were regulated by CTSH signaling, leading to the occurrence of radioresistance in HCC cells and suggesting the potential value of HCC diagnosis and therapy.

ESR1 inhibits ionizing radiation-induced ferroptosis in breast cancer cells via the NEDD4L/CD71 pathway.

Ferroptosis is the name given to the type of non-apoptotic cell death that is caused by iron accumulation and subsequent lipid peroxidation. However, how ionizing radiation (IR)-induced ferroptosis is regulated in estrogen receptor-positive (ER+) breast cancer cells remains unclear. To attempt to resolve this issue, bioinformatics analysis was performed to evaluate the prognostic value of estrogen receptor 1 (ESR1) in breast cancer tissues. A total of four breast cancer cell lines and an MCF10A non-malignant counterpart were used. Western blotting was used to analyze the levels of protein expression, whereas immunoprecipitation (IP) and ubiquitination experiments were used to test protein binding and ubiquitination levels, respectively. Flow cytometry was subsequently used to analyze cell death and lipid peroxidation levels. The results showed that a high expression level of ESR1 was significantly correlated with poor overall survival in breast cancer. ESR1 knockdown significantly enhanced IR-induced ferroptosis and increased the CD71 protein level. The IP results showed that ESR1 enhanced the binding of the E3 ubiquitin ligase NEDD4L to CD71, promoting the ubiquitination and degradation of CD71, suggesting that CD71 expression was regulated by both ESR1 and NEDD4L. Taken together, the findings in the present study have demonstrated a regulatory relationship between ESR1 and NEDD4L/CD71 in IR-induced ferroptosis. In addition, the ESR1/NEDD4L/CD71 axis may be a potential target for the radiotherapy of breast cancer.

SRSF3 and HNRNPH1 Regulate Radiation-Induced Alternative Splicing of Protein Arginine Methyltransferase 5 in Hepatocellular Carcinoma.

Protein arginine methyltransferase 5 (PRMT5) is an epigenetic regulator which has been proven to be a potential target for cancer therapy. We observed that PRMT5 underwent alternative splicing (AS) and generated a spliced isoform PRMT5-ISO5 in hepatocellular carcinoma (HCC) patients after radiotherapy. However, the regulatory mechanism and the clinical implications of IR-induced PRMT5 AS are unclear. This work revealed that serine and arginine rich splicing factor 3 (SRSF3) silencing increased PRMT5-ISO5 level, whereas heterogeneous nuclear ribonucleoprotein H 1 (HNRNPH1) silencing reduced it. Then, we found that SRSF3 and HNRNPH1 competitively combined with PRMT5 pre-mRNA located at the region around the 3'- splicing site on intron 2 and the alternative 3'- splicing site on exon 4. IR-induced SRSF3 downregulation led to an elevated level of PRMT5-ISO5, and exogenous expression of PRMT5-ISO5 enhanced cell radiosensitivity. Finally, we confirmed in vivo that IR induced the increased level of PRMT5-ISO5 which in turn enhanced tumor killing and regression, and liver-specific Prmt5 depletion reduced hepatic steatosis and delayed tumor progression of spontaneous HCC. In conclusion, our data uncover the competitive antagonistic interaction of SRSF3 and HNRNPH1 in regulating PRMT5 splicing induced by IR, providing potentially effective radiotherapy by modulating PRMT5 splicing against HCC.

Transcriptomics and Proteomics Characterizing the Anticancer Mechanisms of Natural Rebeccamycin Analog Loonamycin in Breast Cancer Cells.

The present study is to explore the anticancer effect of loonamycin (LM) in vitro and in vivo, and investigate the underlying mechanism with combined multi-omics. LM exhibited anticancer activity in human triple negative breast cancer cells by promoting cell apoptosis. LM administration inhibited the growth of MDA-MB-468 tumors in a murine xenograft model of breast cancer. Mechanistic studies suggested that LM could inhibit the topoisomerase I in a dose-dependent manner in vitro experiments. Combined with the transcriptomics and proteomic analysis, LM has a significant effect on O-glycan, p53-related signal pathway and EGFR/PI3K/AKT/mTOR signal pathway in enrichment of the KEGG pathway. The GSEA data also suggests that the TNBC cells treated with LM may be regulated by p53, O-glycan and EGFR/PI3K/AKT/mTOR signaling pathway. Taken together, our findings predicted that LM may target p53 and EGFR/PI3K/AKT/mTOR signaling pathway, inhibiting topoisomerase to exhibit its anticancer effect.

Clinicopathological and Prognostic Significance of PRMT5 in Cancers: A System Review and Meta-Analysis.

PURPOSE: Since protein arginine methyltransferase 5 (PRMT5) is abnormally expressed in various tumors, in this study we aim to assess the association between PRMT5 and clinicopathological and prognostic features. METHODS: Electronic databases including PubMed, Web of Science, Scopus, ScienceDirect, and the Cochrane Library were searched until July 25, 2021. The critical appraisal of the eligible studies was performed using the Newcastle-Ottawa Quality Assessment Scale. Pooled hazard ratios (HR) and pooled odds ratios (OR) were calculated to assess the effect. Engauge Digitizer version 12.1, STATA version 15.1, and R version 4.0.5 were used to obtain and analysis the data. RESULTS: A total of 32 original studies covering 15,583 patients were included. In our data, it indicated that high level of PRMT5 was significantly correlated with advanced tumor stage (OR = 2.12, 95% CI: 1.22-3.70, P =.008; I2 = 80.7%) and positively correlated with poor overall survival (HR = 1.59, 95% CI: 1.46-1.73, P < .001; I2 = 50%) and progression-free survival (HR = 1.53, 95% CI: 1.24-1.88, P < .001; I2 = 0%). In addition, sub-group analysis showed that high level of PRMT5 was associated with poor overall survival for such 5 kinds of cancers as hepatocellular carcinoma, pancreatic cancer, breast cancer, gastric cancer, and lung cancer. CONCLUSION: For the first time we found PRMT5 was pan-cancerous as a prognostic biomarker and high level of PRMT5 was associated with poor prognosis for certain cancers.

Comparison of Venous Thromboembolism Risks Between COVID-19 Pneumonia and Community-Acquired Pneumonia Patients.

OBJECTIVE: The objectives were to investigate and compare the risks and incidences of venous thromboembolism (VTE) between the 2 groups of patients with coronavirus disease 2019 (COVID-19) pneumonia and community-acquired pneumonia (CAP). Approach and Results: Medical records of 616 pneumonia patients who were admitted to the Yichang Central People's Hospital in Hubei, China, from January 1 to March 23, 2020, were retrospectively reviewed. The patients with COVID-19 pneumonia were treated in the dedicated COVID-19 units, and the patients with CAP were admitted to regular hospital campus. Risks of VTE were assessed using the Padua prediction score. All the patients received pharmaceutical or mechanical VTE prophylaxis. VTE was diagnosed using Duplex ultrasound or computed tomography pulmonary angiogram. Differences between COVID-19 and CAP groups were compared statistically. All statistical tests were 2 sided, and P<0.05 was considered as statistically significant. All data managements and analyses were performed by IBM SPSS, version 24, software (SPSS, Inc, Chicago, IL). Of the 616 patients, 256 had COVID-19 pneumonia and 360 patients had CAP. The overall rate of VTE was 2% in COVID-19 pneumonia group and 3.6% in CAP group, respectively (P=0.229). In these two groups, 15.6% of the COVID-19 pneumonia patients and 10% of the CAP patients were categorized as high risk for VTE (Padua score, >4), which were significantly different (P=0.036). In those high-risk patients, the incidence of VTE was 12.5% in COVID-19 pneumonia group and 16.7% in CAP group (P=0.606). Subgroup analysis of the critically ill patients showed that VTE rate was 6.7% in COVID-19 group versus 13% in CAP group (P=0.484). In-hospital mortality of COVID-19 and CAP was 6.3% and 3.9%, respectively (P=0.180). CONCLUSIONS: Our study suggested that COVID-19 pneumonia was associated with hypercoagulable state. However, the rate of VTE in COVID-19 pneumonia patients was not significantly higher than that in CAP patients.

DIAGNOSTIC VALUE OF ANTI-MÜLLERIAN HORMONE AS A BIOMARKER FOR POLYCYSTIC OVARY SYNDROME: A META-ANALYSIS UPDATE.

Objective: A previous meta-analysis carried out on the predictive ability of anti-Müllerian hormone (AMH) for polycystic ovary syndrome (PCOS) showed that independent AMH may be a useful initial diagnostic test for PCOS. The aims of this study were to update the meta-analysis and to evaluate the diagnostic efficacy of AMH when it replaces polycystic ovary morphology (PCOM) in the Rotterdam criteria. Methods: Two independent reviewers searched PubMed, Cochrane Library, and the Web of Science databases systematically to identify relevant articles by using the key words "anti-Müllerian hormone" and "polycystic ovary syndrome." The deadline for manuscript inclusion was July 31, 2018. A random effects model was used and subgroup analysis and meta regression were performed to identify possible sources of heterogeneity. The methodologic quality of each study was assessed by QUADAS-2 and funnel plot asymmetry test. Results: According to the inclusion criteria, 29 studies were included in this meta-analysis. The pooled sensitivity, specificity, and diagnostic odds ratio (DOR) for AMH alone detecting PCOS were 0.76 (95% confidence interval [CI] 0.71 to 0.81), 0.86 (95% CI 0.82 to 0.90) and 20 (95% CI 12 to 33), respectively. When AMH replaces polycystic ovary morphology (PCOM) for the diagnosis of PCOS, the pooled sensitivity, specificity, and DOR rose to 0.93 (95% CI 0.89 to 0.96), 0.99 (95% CI 0.95 to 1.00), and 1,634 (95% CI 217 to 12,324), respectively. The area under the summary receiver-operating characteristic curve for AMH alone and for AMH replacing PCOM detecting PCOS were 0.88 (95% CI 0.85 to 0.91) and 0.97 (95% CI 0.95 to 0.98), respectively, which was found to be significantly different (Z = 4.89, P<.01). Conclusion: When AMH replaces PCOM in the Rotterdam criteria, the diagnostic efficacy for polycystic ovary syndrome is better. Abbreviations: AMH = anti-Müllerian hormone; AUC = area under the summary receiver operating characteristic curve; BMI = body mass index; CI = confidence interval; DOR = diagnostic odds ratio; HA = hyperandrogenism; IBC = Immunotech-Beckman Coulter; NLR = negative likelihood ratio; OA = oligo-anovulation; PCOM = polycystic ovary morphology; PCOS = polycystic ovary syndrome; PLR = positive likelihood ratio; QUADAS = the Quality Assessment of Diagnostic Accuracy Studies; SENS = sensitivity; SPEC = specificity.

Diagnostic accuracy of optical coherence tomography angiography for choroidal neovascularization: a systematic review and meta-analysis.

BACKGROUND: Optical coherence tomography angiography (OCTA), an innovative image technique, renders visualization of ocular neovascularization through non-invasive means, which has been applied in recent years. Therefore, the present study was designed to assess the diagnostic value of OCTA in detecting the choroidal neovascularization (CNV). METHODS: In brief, PubMed, Web of Science and Cochrane Library databases were systematically searched from January 2014 to June 2019. Afterwards, a meta-analysis was performed to determine the pooled diagnostic accuracy in a random-effects model using STATA 15.1 and Meta-Disc 1.4 software. Quality Assessment of diagnostic Accuracy Version 2 was used to evaluate the risk of bias of each study by Revman 5.3 software. In addition, a meta-regression model was further conducted to explore potential sources of heterogeneity. RESULTS: According to pre-set inclusion and exclusion criteria, 16 eligible studies were enrolled in this study. A total of 447 CNV eyes and 414 non-CNV eyes were included to investigate the diagnostic accuracy of OCTA. As a result, the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (PLR), diagnostic odds ratio (DOR) and the area under the summary receiver operating characteristic curve (sROC-AUC) were 0.87 (95% CI 0.81-0.92), 0.97 (95% CI 0.92-0.99), 32.7 (95% CI 10.1-105.5), 0.13 (95% CI 0.08-0.20), 252 (95% CI 63-1011) and 0.96 (95% CI 0.94-0.97), respectively. CONCLUSIONS: In summary, we demonstrated that OCTA was of high diagnostic value for detecting intraocular CNV.

The effect of surgery on the survival status of patients with locally advanced cervical cancer after radiotherapy/chemoradiotherapy: a meta-analysis.

BACKGROUND: To determine the effect of surgery on the survival status of patients with locally advanced cervical cancer after radiotherapy/chemoradiotherapy. METHODS: PubMed, Web of Science, ProQuest and Medline were searched using the key words "cervical cancer", "locally advanced disease", "radiotherapy" and "surgery or hysterectomy". Eight articles were selected and analysed using the STATA 12.0 software package. The log hazard ratio (HR) and its standard error for overall survival were calculated to assess the effect of surgery on patients with locally advanced cervical cancer after radiotherapy/chemoradiotherapy. RESULTS: In total, 2176 patients with locally advanced cervical cancer were identified. The pooled HR for overall survival was 1.13 (95% confidence interval (CI) 0.906-1.409), and there were no differences among the eight manuscripts (z = 1.08, p = 0.278). In the subgroup analysis, the pooled HR for overall survival was 1.169 (95% CI 0.924-1.480), and no differences among patients with stage IB-IIB disease were found in six articles (z = 1.30, p = 0.193). There was no publication bias regarding overall survival or stage IB-IIB disease. CONCLUSIONS: This meta-analysis suggested that surgery had no effect on overall survival after radiotherapy/chemoradiotherapy; therefore, it is not recommended for patients with locally advanced cervical cancer.

Diagnostic value of urinary survivin as a biomarker for bladder cancer: a systematic review and meta-analysis of published studies.

OBJECTIVE: This study is a meta-analysis and aims to determine the value of urinary survivin for detecting bladder cancer (BC) on the basis of preceding statistical performance and to compare their diagnostic value. MATERIALS AND METHODS: Considering that the urinary survivin data were from both RNA and protein levels, the key words "bladder cancer" AND "survivin" and "bladder cancer" AND "survivin RNA" were used; and PubMed, Web of Science, and Cochrane Library were systematically searched to identify relevant articles. The methodological quality of each study was assessed by QUADAS-2. Data were analyzed by STATA 12.0 and Meta-disc v.1.4 software package. A random-effects model was used and subgroup analysis was carried out to identify possible sources of heterogeneity. RESULTS: Nine articles for survivin protein test with 789 patients and 684 controls, and 12 articles for survivin RNA test with 880 patients and 922 controls were identified. The results showed that the pooled sensitivity was 0.79 (95% CI 0.73, 0.84), specificity was 0.87 (95% CI 0.79, 0.92) of the survivin protein test for bladder cancer, and the sensitivity and specificity was 0.84 (95% CI 0.79, 0.88) and 0.94 (95% CI 0.89, 0.97) of the survivin RNA test. The AUC of the two approaches was 0.89 (95% CI 0.86, 0.91) and 0.94 (95% CI 0.92, 0.96), respectively. CONCLUSIONS: The survivin protein and survivin RNA both had great potential as biomarkers for BC detection, and survivin RNA showed higher accuracy than survivin protein on BC diagnosis.

One-step nucleic acid amplification assay is an accurate technique for sentinel lymph node biopsy of breast cancer patients: a meta-analysis.

BACKGROUND: To estimate the accuracy of one-step nucleic acid amplification (OSNA) assay as an intra-operative sentinel lymph node biopsy (SLNB) for sentinel lymph node (SLN) metastasis in breast cancer. METHODS: PubMed, Cochrane Library and Web of Science databases were searched by two independent reviewers to retrieve literature with per-patient analysis. The deadline was up until December 2016. A meta-analysis was performed using STATA, Meta-Disc, and Revman software. A random-effects model was used and subgroup analysis was carried out to identify possible sources of heterogeneity. RESULTS: According to the inclusion criteria, 2833 patients from 12 studies were included in this meta-analysis. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and the area under the sROC curve (AUC) for detecting SLN metastasis were 0.87 (95% CI 0.81-0.91), 0.92 (95% CI 0.86-0.95), 10.65 (95% CI 6.18-18.34), 0.14 (95% CI 0.10-0.20), 75.08 (95% CI 37.77-149.22) and 0.94 (95% CI 0.91-0.95), respectively. CONCLUSIONS: The present study adds the evidence that OSNA assay is an accurate molecular diagnostic tool for intra-operatively detecting SLN metastasis in breast cancer. One-step nucleic acid amplification assay might be introduced into clinical usage for replacing traditional intro-operative diagnostic methods of SLNB.

Identification and functional evaluation of the reductases and dehydrogenases from Saccharomyces cerevisiae involved in vanillin resistance.

BACKGROUND: Vanillin, a type of phenolic released during the pre-treatment of lignocellulosic materials, is toxic to microorganisms and therefore its presence inhibits the fermentation. The vanillin can be reduced to vanillyl alcohol, which is much less toxic, by the ethanol producer Saccharomyces cerevisiae. The reducing capacity of S. cerevisiae and its vanillin resistance are strongly correlated. However, the specific enzymes and their contribution to the vanillin reduction are not extensively studied. In our previous work, an evolved vanillin-resistant strain showed an increased vanillin reduction capacity compared with its parent strain. The transcriptome analysis suggested the reductases and dehydrogenases of this vanillin resistant strain were up-regulated. Using this as a starting point, 11 significantly regulated reductases and dehydrogenases were selected in the present work for further study. The roles of these reductases and dehydrogenases in the vanillin tolerance and detoxification abilities of S. cerevisiae are described. RESULTS: Among the candidate genes, the overexpression of the alcohol dehydrogenase gene ADH6, acetaldehyde dehydrogenase gene ALD6, glucose-6-phosphate 1-dehydrogenase gene ZWF1, NADH-dependent aldehyde reductase gene YNL134C, and aldo-keto reductase gene YJR096W increased 177, 25, 6, 15, and 18 % of the strain µmax in the medium containing 1 g L(-1) vanillin. The in vitro detected vanillin reductase activities of strain overexpressing ADH6, YNL134C and YJR096W were notably higher than control. The vanillin specific reduction rate increased by 8 times in ADH6 overexpressed strain but not in YNL134C and YJR096W overexpressed strain. This suggested that the enzymes encoded by YNL134C and YJR096W might prefer other substrate and/or could not show their effects on vanillin on the high background of Adh6p in vivo. Overexpressing ALD6 and ZWF1 mainly increased the [NADPH]/[NADP(+)] and [GSH]/[GSSG] ratios but not the vanillin reductase activities. Their contribution to strain growth and vanillin reduction were balancing the redox state of strain when vanillin was presented. CONCLUSIONS: Beside the reported Adh6p, the enzymes encoded by YNL134C and YJR096W were proved to have vanillin reduction activity in present study. While ALD6 and ZWF1 did not directly reduce vanillin to vanillyl alcohol, their contribution to vanillin resistance primarily depended on the enhancement of the reducing equivalent supply.

Synthesis and biological evaluation of peptide-conjugated phthalocyanine photosensitizers with highly hydrophilic modifications.

The selectivity of targeted photosensitizer delivery is a constant challenge for photodynamic therapy (PDT). Herein, with the aim of optimizing the affinity, selectivity and activity of peptide-conjugated photosensitizers for PDT therapy and fluorescence imaging, we designed a solid-phase strategy for the efficient synthesis of peptide-phthalocyanine (Pc) conjugates with two types of highly hydrophilic modifications to the Pc rings. The peptide conjugation clearly increased the photodynamic efficacy and selectivity of Pcs against cancer cells with different receptor expression levels. A highly hydrophilic modification to the Pc rings can block non-specific interactions between the Pcs and biological molecules while minimally influencing peptide ligand affinity with target receptors. Compared with the triethyleneglycol monomethyl ether group modification, the glycerol group modification exhibited a stronger capability to decrease the Pc aggregation tendency in aqueous medium, reduce non-specific binding and non-specific, light-induced cytotoxicity towards cells with low receptor expression in vitro; increased targeting selectivity was observed in the in vivo distribution experiments via the obvious reduction of background signals. Highly hydrophilic modifications to the Pc rings may be very useful for improving targeting selectivity for PDT with the construction of peptide-conjugated photosensitizers.

1H NMR guided isolation of 3-arylisoquinoline alkaloids from Hypecoum erectum L. and their anti-inflammation activity.

Nine 3-arylisoquinoline alkaloids including five undescribed ones, hypectumines A-E (1-5), were isolated from the whole herb of Hypecoum erectum L. with the guidance of 1H-NMR. Their structures were established by a combination of 1D, 2D NMR, and HRESIMS spectrometry. Among them, hypectumines A and B possessed rare urea moieties while hypectumines C and D were characterized by 3-(methylamino)propanoic acid scaffolds. Biological assay demonstrated that alkaloids hypectumine B and 2,3-dimethoxy-N-formylcorydamine had anti-inflammatory effects by inhibiting NO production on LPS-induced RAW264.7 cells with IC50 values of 24.4 and 44.2 µM, respectively. Furthermore, hypectumine B could reduce the expression of pro-inflammatory cytokines TNF-α and IL-6, suggesting it might be a potential candidate for treating inflammatory disease.

Radioprotective countermeasures for radiation injury (Review).

A series of physiological and pathological changes occur after radiotherapy and accidental exposure to ionizing radiation (IR). These changes cause serious damage to human tissues and can lead to death. Radioprotective countermeasures are radioprotective agents that prevent and reduce IR injury or have therapeutic effects. Based on a good understanding of radiobiology, a number of protective agents have achieved positive results in early clinical trials. The present review grouped known radioprotective agents according to biochemical categories and potential clinical use, and reviewed radiation countermeasures, i.e., radioprotectors, radiation mitigators and radiotherapeutic agents, with an emphasis on their current status and research progress. The aim of the present review is to facilitate the selection and application of suitable radioprotectors for clinicians and researchers, to prevent or reduce IR injury.

Safety, immunogenicity and immune-persistence of heterologous prime-boost immunization with BBIBP-CorV and ZF2001 against SARS-CoV-2 in healthy adults aged 18 years or older.

BACKGROUND: Because SARS-CoV-2 mutations and immunity wane over time, a third dose of heterologous COVID-19 vaccine is proposed for individuals primed with inactivated COVID-19 vaccine. RESEARCH DESIGN AND METHODS: We conducted a single-center, open-label trial to assess the safety, immunogenicity, and immune-persistence of a heterologous BBIBP-CorV/ZF2001 prime-boost vaccination in Chinese adults. 480 participants who had been primed with two doses of BBIBP-CorV, received a third dose of ZF2001 after an interval of 3-4, 5-6, or 7-9 months. RESULTS: The overall incidence of adverse reactions within 30 days after vaccination was 5.83%. No serious adverse reactions were reported. The respective geometric mean titers (GMTs) of neutralizing antibodies for 3-4, 5-6, and 7-9 months groups at baseline were 2.06, 2.02, and 2.10; which increased to 55.42, 63.45, and 62.06 on day 14; then decreased to 17.53, 23.79, and 26.73 on day 30; before finally waning to 8.29, 9.24, and 9.51 on day 180. After the booster, the three groups showed no significant differences in GMTs. GMTs were lower in older participants than younger participants. CONCLUSIONS: A heterologous BBIBP-CorV/ZF2001 prime-boost vaccination was safe and immunogenic. Prime-boost intervals did not affect the immune response. The immune response was weaker in older adults than younger adults. CLINICAL TRIAL IDENTIFIER: NCT05205083.

Establishing chromosomal design-build-test-learn through a synthetic chromosome and its combinatorial reconfiguration.

Chromosome-level design-build-test-learn cycles (chrDBTLs) allow systematic combinatorial reconfiguration of chromosomes with ease. Here, we established chrDBTL with a redesigned synthetic Saccharomyces cerevisiae chromosome XV, synXV. We designed and built synXV to harbor strategically inserted features, modified elements, and synonymously recoded genes throughout the chromosome. Based on the recoded chromosome, we developed a method to enable chrDBTL: CRISPR-Cas9-mediated mitotic recombination with endoreduplication (CRIMiRE). CRIMiRE allowed the creation of customized wild-type/synthetic combinations, accelerating genotype-phenotype mapping and synthetic chromosome redesign. We also leveraged synXV as a "build-to-learn" model organism for translation studies by ribosome profiling. We conducted a locus-to-locus comparison of ribosome occupancy between synXV and the wild-type chromosome, providing insight into the effects of codon changes and redesigned features on translation dynamics in vivo. Overall, we established synXV as a versatile reconfigurable system that advances chrDBTL for understanding biological mechanisms and engineering strains.