Single-cell transcriptomic sequencing analysis of mechanistic insights into the IFN-γ signaling pathway in different tumor cells.

PURPOSE: This study aimed to investigate the relationship between the interferon-gamma (IFN-γ) pathway in different tumor microenvironments (TME) and patients' prognosis, as well as the regulatory mechanisms of this pathway in tumor cells. METHODS: Using RNA-seq data from the TCGA database, we analyzed the predictive value of the IFN-γ pathway across various tumors. We employed a univariate Cox regression model to assess the prognostic significance of IFN-γ signaling in different tumor types. Additionally, we analyzed single-cell RNA sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) database to examine the distribution characteristics of the IFN-γ pathway and explore its regulatory mechanisms, highlighting how IFN-γ influenced cellular interactions within the TME. RESULTS: Our analysis revealed a significant association between the IFN-γ pathway and adverse prognosis in pan-cancer tissues (P < 0.001). Interestingly, this correlation varied regarding positive and negative regulation across different tumor types. Through a detailed examination of scRNA-seq data, we found that the IFN-γ pathway exerted substantial regulatory effects on stromal and immune cells. In contrast, its expression and regulatory patterns in tumor cells exhibited diversity and heterogeneity. Further analysis indicated that the IFN-γ pathway not only enhanced the immunogenicity of tumor cells but also inhibited their proliferation. Cell-cell interaction analysis confirmed the pivotal role of the IFN-γ pathway within the overall regulatory network. Moreover, we identified HMGB2 (high mobility group box 2) in T cells as a potential key regulator of tumor cell proliferation. CONCLUSIONS: The IFN-γ pathway exhibited a dual function by both suppressing tumor cell proliferation and enhancing their immunogenicity, positioning it as a pivotal target for refined cancer diagnosis and cancer strategies.

Epidemiology and Triggers of Severe Perioperative Anaphylaxis: An 8-Year Single-Center Study.

OBJECTIVE: To determine the features, rescue measures, outcomes, re-allergic reactions, and independent risk factors associated with severe anaphylaxis during surgery. DESIGN: Instances of severe perioperative anaphylaxis were identified through perioperative electronic records, adverse event reporting records, and surveys of anesthesiologists. Confirmed cases were randomly matched 4:1 with control cases on the same operation day. Patient risk factors, surgery type, anesthetic technique, and perioperative medications, fluids, and blood transfusions were given in instances of severe perioperative anaphylaxis were compared with control cases. SETTING: A tertiary hospital in China. PATIENTS: All patients undergoing surgery and anesthesia in the operating room from January 2014 to February 2022. MEASUREMENTS: Incidence and the independent risk factors for severe perioperative anaphylaxis. MAIN RESULTS: Ninety-seven patients experienced severe perioperative allergic responses during the 266,033 surgeries performed, with an incidence rate of 3.6 per 10,000. Three of 97 anaphylaxis patients experienced a severe allergic reaction again during the second surgery. The nested case-control study revealed that the independent triggers during surgery were allergy history (odds ratio 5.23; 95% confidence interval [CI], 2.35-11.68; p < 0.001), cisatracurium use (odds ratio 5.03; 95% CI, 1.22-20.70; p < 0.001), hydroxyethyl starch 130/0.4 use (odds ratio 5.36; 95% CI, 2.99-9.60; p =0.025), and allogeneic plasma (odds ratio 11.02; 95% CI, 3.78-35.95; p < 0.001). CONCLUSIONS: Perioperative severe anaphylaxis is a rare but life-threatening complication. Previous allergic history, cisatracurium, hydroxyethyl starch 130/0.4, and allogeneic plasma may be the independent triggers. Early diagnosis of anaphylaxis and the timely administration of epinephrine are critical to allergic treatment. Avoiding exposure to allergens is effective for preventing severe allergic responses and the efficacy of glucocorticoids and antihistamines is controversial.

HSP70 protects against acute pancreatitis-elicited intestinal barrier damage in rats.

Acute pancreatitis (AP) is a frequent but severe abdominal emergency in general surgery with intestinal barrier dysfunction. Heat shock protein 70 (HSP70) is a ubiquitous molecular chaperone that has been proposed to exert favorable effects on AP. Nonetheless, the detailed impacts of HSP70 on the intestinal barrier function in AP are unknown, which will be investigated here. After the injection of sodium taurocholate into the biliopancreatic duct, the rat models of AP were established. After modeling, HSP70 expression was up-regulated through lentivirus infection. Western blot was used to detect HSP70 expression. H&E staining was used to examine the histological changes in the pancreatic and intestinal tissues. The levels of pancreatic biochemical markers and oxidative stress markers were detected using corresponding assay kits. ELISA was used to detect the levels of inflammatory cytokines and gastrointestinal function indicators. Immunofluorescence staining and Western blot were used to detect the expression of tight junction proteins. DCFH-DA probe and MitoSOX Red probe were used to detect total reactive oxygen species (ROS) and mitochondrial ROS (mtROS), respectively. TUNEL assay and Western blot were used to detect apoptosis. During the model construction, severe pancreatic and abnormal intestinal tissue abnormalities were observed, inflammatory response was activated and the intestinal barrier was disrupted. HSP70 expression was down-regulated in the intestinal tissues AP rat models. HSP70 ameliorated the morphological damage of pancreatic and intestinal tissues of AP rats. In addition, HSP70 significantly reduced intestinal barrier damage, inflammatory response, oxidative stress and apoptosis in the intestinal tissues of AP rat models. Collectively, HSP70 might attenuate AP through exerting anti-inflammatory, anti-oxidant, anti-apoptotic effects and inhibiting intestinal barrier disruption.

Development and validation of an early mortality risk model for pediatric hemophagocytic lymphohistiocytosis: a comparison with HScore, PELOD-2, P-MODS, and pSOFA.

There has been no severity evaluation model for pediatric patients with hemophagocytic lymphohistiocytosis (HLH) that uses readily available parameters. This study aimed to develop a novel model for predicting the early mortality risk in pediatric patients with HLH using easily obtained parameters whatever etiologic subtype. Patients from one center were divided into training and validation sets for model derivation. The developed model was validated using an independent validation cohort from the second center. The prediction model with nomogram was developed based on logistic regression. The model performance underwent internal and external evaluation and validation using the area under the receiver operating characteristic curve (AUC), calibration curve with 1000 bootstrap resampling, and decision curve analysis (DCA). Model performance was compared with the most prevalent severity evaluation scores, including the PELOD-2, P-MODS, and pSOFA scores. The prediction model included nine variables: glutamic-pyruvic transaminase, albumin, globulin, myohemoglobin, creatine kinase, serum potassium, procalcitonin, serum ferritin, and interval between onset and diagnosis. The AUC of the model for predicting the 28-day mortality was 0.933 and 0.932 in the training and validation sets, respectively. The AUC values of the HScore, PELOD-2, P-MODS and pSOFA were 0.815, 0.745, 0.659 and 0.788, respectively. The DCA of the 28-day mortality prediction exhibited a greater net benefit than the HScore, PELOD-2, P-MODS and pSOFA. Subgroup analyses demonstrated good model performance across HLH subtypes. The novel mortality prediction model in this study can contribute to the rapid assessment of early mortality risk after diagnosis with readily available parameters.

[Mechanism of Shenling Baizhu Powder on treatment of alcoholic liver disease by regulating TLR4/NLRP3 pathway].

This study aims to investigate the regulatory effects of Shenling Baizhu Powder(SBP) on cellular autophagy in alcoholic liver disease(ALD) and its intervention effect through the TLR4/NLRP3 pathway. A rat model of chronic ALD was established by gavage of spirits. An ALD cell model was established by stimulating BRL3A cells with alcohol. High-performance liquid chromatography(HPLC) was utilized for the compositional analysis of SBP. Liver tissue from ALD rats underwent hematoxylin-eosin(HE) and oil red O staining for pathological evaluation. Enzyme-linked immunosorbent assay(ELISA) was applied to quantify lipopolysaccharides(LPS), tumor necrosis factor-alpha(TNF-α), interleukin-1 beta(IL-1ß), and interleukin-18(IL-18) levels. Quantitative reverse transcription polymerase chain reaction(qRT-PCR) was conducted to evaluate the mRNA expression of myeloid differentiation factor 88(MyD88) and Toll-like receptor 4(TLR4). The effect of different drugs on BRL3A cell proliferation activity was assessed through CCK-8 analysis. Western blot analysis was performed to examine the protein expression of NOD-like receptor pyrin domain-containing 3(NLRP3), nuclear factor-kappa B P65(NF-κB P65), phosphorylated nuclear factor-kappa B P65(p-P65), caspase-1, P62, Beclin1, and microtubule-associated protein 1 light chain 3(LC3Ⅱ). The results showed that SBP effectively ameliorated hepatic lipid accumulation, reduced liver function, mitigated hepatic tissue inflammation, and reduced levels of LPS, TNF-α, IL-1ß, and IL-18. Moreover, SBP exhibited the capacity to modulate hepatic autophagy induced by prolonged alcohol intake through the TLR4/NLRP3 signaling pathway. This modulation resulted in decreased expression of LC3Ⅱ and Beclin1, an elevation in P62 expression, and the promotion of autolysosome formation. These research findings imply that SBP can substantially enhance liver function and mitigate lipid irregularities in the context of chronic ALD. It achieves this by regulating excessive autophagic responses caused by prolonged spirit consumption, primarily through the inhibition of the TLR4/NLRP3 pathway.

Shape-Scale Co-Awareness Network for 3D Brain Tumor Segmentation.

The accurate segmentation of brain tumor is significant in clinical practice. Convolutional Neural Network (CNN)-based methods have made great progress in brain tumor segmentation due to powerful local modeling ability. However, brain tumors are frequently pattern-agnostic, i.e. variable in shape, size and location, which can not be effectively matched by traditional CNN-based methods with local and regular receptive fields. To address the above issues, we propose a shape-scale co-awareness network (S2CA-Net) for brain tumor segmentation, which can efficiently learn shape-aware and scale-aware features simultaneously to enhance pattern-agnostic representations. Primarily, three key components are proposed to accomplish the co-awareness of shape and scale. The Local-Global Scale Mixer (LGSM) decouples the extraction of local and global context by adopting the CNN-Former parallel structure, which contributes to obtaining finer hierarchical features. The Multi-level Context Aggregator (MCA) enriches the scale diversity of input patches by modeling global features across multiple receptive fields. The Multi-Scale Attentive Deformable Convolution (MS-ADC) learns the target deformation based on the multiscale inputs, which motivates the network to enforce feature constraints both in terms of scale and shape for optimal feature matching. Overall, LGSM and MCA focus on enhancing the scale-awareness of the network to cope with the size and location variations, while MS-ADC focuses on capturing deformation information for optimal shape matching. Finally, their effective integration prompts the network to perceive variations in shape and scale simultaneously, which can robustly tackle the variations in patterns of brain tumors. The experimental results on BraTS 2019, BraTS 2020, MSD BTS Task and BraTS2023-MEN show that S2CA-Net has superior overall performance in accuracy and efficiency compared to other state-of-the-art methods. Code: https://github.com/jiangyu945/S2CA-Net.

Effects of penehyclidine hydrochloride combined with dexmedetomidine on pulmonary function in patients undergoing heart valve surgery: a double-blind, randomized trial.

AIM: To investigate the effects of penehyclidine hydrochloride combined with dexmedetomidine on pulmonary function in patients undergoing heart valve surgery with cardiopulmonary bypass (CPB). METHODS: A total of 180 patients undergoing elective heart valve surgery with CPB were randomly divided into four groups: 45 in group P (intravenous penehyclidine hydrochloride 0.02 mg/kg 10 min before anesthesia induction and at the beginning of CPB, total 0.04 mg/kg); 43 in group D (dexmedetomidine 0.5 µg/kg/h after induction of anesthesia until the end of anesthesia); 44 in group PD ( penehyclidine hydrochloride 0.04 mg/kg combined with dexmedetomidine 0.5 µg/kg/h intravenously during anesthesia); and 43 in group C (same amount of normal saline 10 min before and after anesthesia induction, to the end of anesthesia, and at the beginning of CPB). The main outcomes were the incidence and severity of postoperative pulmonary complications (PPCs). The secondary outcomes were: (1) extubation time, length of stay in intensive care, and postoperative hospital stay, and adverse events; and (2) pulmonary function evaluation indices (oxygenation index and respiratory index) and plasma inflammatory factor concentrations (tumor necrosis factor-α, interleukin-6, C-reactive protein and procalcitonin) during the perioperative period. RESULTS: The incidence of PPCs in groups P, D and PD after CPB was lower than that in group C (P < 0.05), and the incidence in group PD was significantly lower than that in groups P and D (P < 0.05). The scores for PPCs in groups P, D and PD were lower than those in group C (P < 0.05). CONCLUSION: Combined use of penehyclidine hydrochloride and dexmedetomidine during anesthesia reduced the occurrence of postoperative pulmonary dysfunction, and improved the prognosis of patients undergoing heart valve surgery with CPB. TRIAL REGISTRATION: The trial was registered in the Chinese Clinical Trial Registry on 3/11/2020 (Registration No.: ChiCTR2000039610).

Targeted, programmable, and precise tandem duplication in the mammalian genome.

Tandem duplications are frequent structural variations of the genome and play important roles in genetic disease and cancer. However, interpreting the phenotypic consequences of tandem duplications remains challenging, in part owing to the lack of genetic tools to model such variations. Here, we developed a strategy, tandem duplication via prime editing (TD-PE), to create targeted, programmable, and precise tandem duplication in the mammalian genome. In this strategy, we design a pair of in trans prime editing guide RNAs (pegRNAs) for each targeted tandem duplication, which encode the same edits but prime the single-stranded DNA (ssDNA) extension in opposite directions. The reverse transcriptase (RT) template of each extension is designed homologous to the target region of the other single guide RNA (sgRNA) to promote the reannealing of the edited DNA strands and the duplication of the fragment in between. We showed that TD-PE produced robust and precise in situ tandem duplications of genomic fragments ranging from ∼50 bp to ∼10 kb, with a maximal efficiency up to 28.33%. By fine-tuning the pegRNAs, we achieved simultaneous targeted duplication and fragment insertion. Finally, we successfully produced multiple disease-relevant tandem duplications, showing the general utility of TD-PE in genetic research.

Bioinformatics analysis based on high-throughput sequencing data to identify hub genes related to different clinical types of COVID-19.

This article aims to explore hub genes related to different clinical types of cases with COVID-19 and predict the therapeutic drugs related to severe cases. The expression profile of GSE166424 was divided into four data sets according to different clinical types of COVID-19 and then calculated the differential expression genes (DEGs). The specific genes of four clinical types of COVID-19 were obtained by Venn diagram and conducted enrichment analysis, protein-protein interaction (PPI) networks analysis, screening hub genes, and ROC curve analysis. The hub genes related to severe cases were verified in GSE171110, their RNA-specific expression tissues were obtained from the HPA database, and potential therapeutic drugs were predicted through the DGIdb database. There were 536, 266, 944, and 506 specific genes related to asymptomatic infections, mild, moderate, and severe cases, respectively. The hub genes of severe specific genes were AURKB, BRCA1, BUB1, CCNB1, CCNB2, CDC20, CDC6, KIF11, TOP2A, UBE2C, and RPL11, and also differentially expressed in GSE171110 (P < 0.05), and their AUC values were greater than 0.955. The RNA tissue specificity of AURKB, CDC6, KIF11, UBE2C, CCNB2, CDC20, TOP2A, BUB1, and CCNB1 specifically enhanced on lymphoid tissue; CCNB2, CDC20, TOP2A, and BUB1 specifically expressed on the testis. Finally, 55 drugs related to severe COVID-19 were obtained from the DGIdb database. Summary, AURKB, BRCA1, BUB1, CCNB1, CCNB2, CDC20, CDC6, KIF11, TOP2A, UBE2C, and RPL11 may be potential diagnostic biomarkers for severe COVID-19, which may affect immune and male reproductive systems. 55 drugs may be potential therapeutic drugs for severe COVID-19.

Effectiveness of Kurtosis-Adjusted Cumulative Noise Exposure in Assessing Occupational Hearing Loss Associated With Complex Noise.

OBJECTIVES: Occupational noise-induced hearing loss (NIHL) is one of the most prevalent occupational diseases worldwide. Few studies have been reported on applying kurtosis-adjusted noise energy (e.g., kurtosis-adjusted cumulative noise exposure, CNE-K) as a joint indicator for assessing NIHL. This study aimed to analyze the effectiveness of CNE-K in assessing occupational hearing loss associated with complex noise in typical manufacturing industries. DESIGN: A cross-sectional survey of 1404 Chinese manufacturing workers from typical manufacturing industries was conducted. General demographic characteristics, noise exposure data, and noise-induced permanent threshold shifts (NIPTS) at 3, 4, and 6 kHz (NIPTS 346 ) were collected and analyzed. The role of kurtosis in high-frequency noise-induced hearing loss (HFNIHL) was also analyzed. The degree of overlap of the two logistic curves (i.e., between complex noise CNE-K and HFNIHL%, and between Gaussian noise CNE and HFNIHL%) was used to evaluate the effectiveness of CNE-K, using a stratified analysis based on age, sex, industry, or job type. RESULTS: The binary logistic regression analysis showed that in addition to age, sex, exposure duration, and Eight-hour Continuous Equivalent A-weighted Sound Pressure Level (L Aeq,8h ), kurtosis was a key factor influencing HFNIHL% in workers (odds ratio = 1.18, p < 0.05), and its odds ratio increased with an increase in kurtosis value. Multiple linear regression analysis demonstrated that the contribution of kurtosis to NIPTS 346 was second to L Aeq,8h . Complex noise led to a higher risk of NIHL than Gaussian noise at frequencies of 3, 4, 6, and 8 kHz after adjusting for age, sex, and CNE ( p < 0.05). As kurtosis increased, the notch in the audiogram became deeper, and the frequency at which the notch began to deepen shifted from 3 to 1 kHz. The logistic curve between complex noise CNE-K and HFNIHL% nearly overlapped with that between Gaussian noise CNE and HFNIHL%, and the average difference in HFNIHL% between the two curves decreased from 8.1 to 0.4%. Moreover, the decrease of average difference in HFNIHL% between the two logistic curves was evident in several subgroups, such as male workers, aged <30 and 30 to 50 years, furniture and woodworking industries and gunning and nailing job types with relatively high kurtosis values. CONCLUSIONS: Kurtosis, as an indirect metric of noise temporal structure, was an important risk factor for occupational NIHL. Kurtosis-adjusted CNE metric could be more effective than CNE alone in assessing occupational hearing loss risk associated with complex noise.

Quantifying causal effects from observed data using quasi-intervention.

BACKGROUND: Causal inference is a crucial element within medical decision-making. There have been many methods for investigating potential causal relationships between disease and treatment options developed in recent years, which can be categorized into two main types: observational studies and experimental studies. However, due to the nature of experimental studies, financial resources, human resources, and patients' ethical considerations, researchers cannot fully control the exposure of the research participants. Furthermore, most existing observational research designs are limited to determining causal relationships and cannot handle observational data, let alone determine the dosages needed for medical research. RESULTS: This paper presents a new experimental strategy called quasi-intervention for quantifying the causal effect between disease and treatment options in observed data by using a causal inference method, which converts the potential effect of different treatment options on disease into computing differences in the conditional probability. We evaluated the accuracy of the quasi-intervention by quantifying the impact of adjusting Chinese patients' neutrophil-to-lymphocyte ratio (NLR) on their overall survival (OS) (169 lung cancer patients and 79 controls).The results agree with the literature in this study, consisting of nine papers on cohort studies on the NLR and the prognosis of lung cancer patients, proving that our method is correct. CONCLUSION: Taken together, the results imply that quasi-intervention is a promising method for quantifying the causal effect between disease and treatment options without clinical trials, and it could improve confidence about treatment options' efficacy and safety.

Internally inlaid SaCas9 base editors enable window specific base editing.

Rationale: Base editors composed of catalytic defective Cas9 and cytosine or adenosine deaminase are powerful tools to convert bases in a genome. However, the fixed and narrow editing window of current base editors has impeded their utility. To increase the scope and diversify the editing patterns is quite necessary. Methods and Results: We designed a subset of base editors derived from SaCas9 in which deaminase was inlaid into various locations of the SaCas9 protein. The resulting base editors were characterized with multiple genomic sites and were found to have distinct editing features to the N-terminal SaCas9 CBE (Sa-CBE-N). Among them, Sa-CBE-693, in which a cytosine deaminase was inserted between amino acids 693 and 694, showed an increased editing efficiency and a significantly expanded editing window ranging from bases 2-18. This feature enhanced the editing efficiency of BCL11A enhancer that contains multiple consensus bases in a 15-bp fragment. Another variant, Sa-CBE-125, displayed backward-shifted editing window, which we showed was particularly powerful in editing cytosines that were accompanied with unintended bystander cytosines at their 5' side. Additionally, these editors showed reduced Cas9 independent DNA off-target editing compared with Sa-CBE-N. Conclusion: Our inlaid base editors improved the targeting scope and diversified the editing pattern.

Comparing the efficacy and safety of cisplatin and other platinum-based chemotherapies in locally advanced nasopharyngeal carcinoma: a systematic review and meta-analysis.

BACKGROUND: Cisplatin-based concurrent chemoradiotherapy has been identified as the primary and standard treatment for locally advanced nasopharyngeal carcinoma (NPC). However, the side effects of cisplatin affect the compliance to therapy. Thus, the search for a platinum-based substitute for NPC has always been a research focus. However, there is a variability in the efficacy of different platinum-based chemotherapies in the treatment of NPC. We performed a meta-analysis to compare the efficacy and safety of cisplatin-based regimens and other platinum-based derivatives (carboplatin, nedaplatin, and lobaplatin) for locally advanced NPC. METHODS: PubMed, EMBASE, Cochrane Library, Web of Science, and ClinicalTrials.gov were systematically searched for all potentially eligible clinical trials as of February 15, 2022. The pooled hazard ratios, risk ratio, and 95% confidence interval were calculated using Review Manager Software version 5.4. RESULTS: A total of 1,907 patients with locally advanced NPC were eligible from the 1,265 retrieved records. This systematic review included eight articles, six of which were randomized controlled clinical trials. There was no significant difference in the 3- and 5-year overall survival, progression-free survival, distant metastasis-free survival, and locoregional relapse-free survival between cisplatin-based chemotherapy and other platinum-based chemotherapy. Severe acute hematological side effects (≥ grade 3) during treatment, such as neutropenia, leukopenia, and thrombocytopenia, were equivalent in both groups. However, the incidence of anemia was higher in patients receiving other platinum-based chemotherapies. The risk of nausea, vomiting and weight loss was higher in the cisplatin group; however, there was no significant difference in the other non-hematological and late side effects between the two groups. CONCLUSIONS: Other types of platinum-based chemotherapies are as effective as cisplatin-based chemotherapy in the treatment of locally advanced NPC, thus acting as potential alternatives to cisplatin. Further studies providing high-level evidence are needed.

Demographics and Economic Burden of Nasopharyngeal Carcinoma Inpatients.

Objective: Nasopharyngeal carcinoma is particularly prevalent in Guangdong and Guangxi (southern China); the economic burden of nasopharyngeal cancer patients is heavy in China. This study is aimed at retrospectively analyzing the basic features and economic burden of newly diagnosed nasopharyngeal carcinoma patients admitted to the First Affiliated Hospital of Guangxi Medical University and at providing a scientific basis for nasopharyngeal carcinoma prevention and control strategies. Methods: The data of 3,727 nasopharyngeal carcinoma inpatients diagnosed from January 2012 to December 2020 were extracted from the Guangxi Nasopharyngeal Carcinoma Healthcare Big Data Management Information Platform. Basic demographic characteristics, duration of hospital stay, and hospitalization cost of nasopharyngeal carcinoma patients were collected and analyzed statistically. Results: The incidence period of nasopharyngeal carcinoma was primarily from 30 to 69 years of age, with the 40-49-year age group comprising the largest proportion of nasopharyngeal carcinoma patients, accounting for 34.18% of the patients with newly diagnosed nasopharyngeal carcinoma in the hospital. The male-to-female ratio was 2.87 : 1. There were 2,223 cases from rural areas, 2,153 from the Han ethnic group, and 1,460 from the Zhuang ethnic group, accounting for 59.65%, 55.77%, and 39.17% of the total number of cases, respectively. The average duration of hospitalization decreased whereas the average hospitalization cost increased annually. Multivariate analysis of hospitalization cost showed that the duration of hospital stay, rural/urban, and ethnicity was the main influencing factors: the longer the duration of hospital stay, the higher the hospitalization cost; patients from rural incurred lower costs than from urban; ethnic Zhuang patients incurred significantly lower costs than patients from other ethnicities. Conclusion: Early diagnosis and treatment should be actively carried out to reduce the incidence of nasopharyngeal carcinoma, especially for rural, ethnic Zhuang, and males in the 40-49-year age group patients. The future research on nasopharyngeal carcinoma will focus on exploring the pathogenesis of nasopharyngeal carcinoma, improving the screening system, and reducing the burden on patients, in order to further improve the survival rate and quality of life of patients with nasopharyngeal carcinoma.

Assessment of Occupational Hearing Loss Associated With Non-Gaussian Noise Using the Kurtosis-Adjusted Cumulative Noise Exposure Metric: A Cross-Sectional Survey.

Objective: There is little literature on the validity of kurtosis-adjusted noise energy metrics in human studies. Therefore, this study aimed to validate the application of cumulative noise exposure (CNE) adjusted by kurtosis in evaluating occupational hearing loss associated with non-Gaussian noise among manufacturing workers. Methods: A cross-sectional survey was conducted on 1,558 manufacturing workers exposed to noise from five industries to collect noise exposure and hearing loss data. Both CNE and kurtosis-adjusted CNE (CNE') were collapsed into 2-dB(A)∙year bins, and the mean noise-induced permanent threshold shifts at 3, 4, and 6 kHz (NIPTS346) in each bin were calculated. The contributions of CNE and CNE' to noise-induced hearing loss (NIHL) were compared using the multiple linear regression. The degree of overlap of two linear regression equations (i.e., between CNE' and NIPTS346 for non-Gaussian noise and between CNE and NIPTS346 for Gaussian noise) was used to evaluate the validity of the CNE' using a stratified analysis based on age and sex. Results: Multiple linear regression models showed that after kurtosis adjustment, the standardized regression coefficient of CNE increased from 0.230 to 0.255, and R 2 increased from 0.147 to 0.153. The linear relationship between NIPTS346 and CNE' or CNE showed that the regression line of non-Gaussian noise was closer to that of Gaussian noise when using CNE' than using CNE. The mean difference in NIPTS346 between the equations of non-Gaussian noise and Gaussian noise was significantly reduced from 4.32 to 1.63 dB HL after kurtosis adjustment (t = 12.00, p < 0.001). Through a stratified analysis, these significant decreases were observed in male and female workers, and workers aged ≥30 years old. Conclusion: As a noise exposure metric combining noise energy and temporal characteristics, the kurtosis-adjusted-CNE metric was more effective than CNE alone in assessing occupational hearing loss among manufacturing workers in non-Gaussian noise environment. However, more studies are needed to verify the validity of the kurtosis-adjusted-CNE metric.

WT-PE: Prime editing with nuclease wild-type Cas9 enables versatile large-scale genome editing.

Large scale genomic aberrations including duplication, deletion, translocation, and other structural changes are the cause of a subtype of hereditary genetic disorders and contribute to onset or progress of cancer. The current prime editor, PE2, consisting of Cas9-nickase and reverse transcriptase enables efficient editing of genomic deletion and insertion, however, at small scale. Here, we designed a novel prime editor by fusing reverse transcriptase (RT) to nuclease wild-type Cas9 (WT-PE) to edit large genomic fragment. WT-PE system simultaneously introduced a double strand break (DSB) and a single 3' extended flap in the target site. Coupled with paired prime editing guide RNAs (pegRNAs) that have complementary sequences in their 3' terminus while target different genomic regions, WT-PE produced bi-directional prime editing, which enabled efficient and versatile large-scale genome editing, including large fragment deletion up to 16.8 megabase (Mb) pairs and chromosomal translocation. Therefore, our WT-PE system has great potential to model or treat diseases related to large-fragment aberrations.

SCAPE: a mixture model revealing single-cell polyadenylation diversity and cellular dynamics during cell differentiation and reprogramming.

Alternative polyadenylation increases transcript diversities at the 3' end, regulating biological processes including cell differentiation, embryonic development and cancer progression. Here, we present a Bayesian method SCAPE, which enables de novo identification and quantification of polyadenylation (pA) sites at single-cell level by utilizing insert size information. We demonstrated its accuracy and robustness and identified 31 558 sites from 36 mouse organs, 43.8% (13 807) of which were novel. We illustrated that APA isoforms were associated with miRNAs binding and regulated in tissue-, cell type-and tumor-specific manners where no difference was found at gene expression level, providing an extra layer of information for cell clustering. Furthermore, we found genome-wide dynamic changes of APA usage during erythropoiesis and induced pluripotent stem cell (iPSC) differentiation, suggesting APA contributes to the functional flexibility and diversity of single cells. We expect SCAPE to aid the analyses of cellular dynamics and diversities in health and disease.

A universal strategy for AAV delivery of base editors to correct genetic point mutations in neonatal PKU mice.

Base editing tools enabled efficient conversion of C:G or A:T base pairs to T:A or G:C, which are especially powerful for targeting monogenic lesions. However, in vivo correction of disease-causing mutations is still less efficient because of the large size of base editors. Here, we designed a dual adeno-associated virus (AAV) strategy for in vivo delivery of base editors, in which deaminases were linked to Cas9 through the interaction of GCN4 peptide and its single chain variable fragment (scFv) antibody. We found that one or two copies of GCN4 peptide were enough for the assembly of base editors and produced robust targeted editing. By optimization of single-guide RNAs (sgRNAs) that target phenylketonuria (PKU) mutation, we were able to achieve up to 27.7% correction in vitro. In vivo delivery of this dual AAV base editing system resulted in efficient correction of PKU-related mutation in neonatal mice and subsequent rescue of hyperphenylalaninemia-associated syndromes. Considering the similarity between Cas9 proteins from different organisms, our delivery strategy will be compatible with other Cas9-derived base editors.

Industry Distribution Characteristics of Benzene-Exposed Workers with Cytopenia - Four Provinces, China, 2020.

What is already known about this topic?: Benzene is harmful to the hematopoietic system and can cause leukemia. However, benzene is still being used in various industries including furniture, rubber, plastic products, and metal product manufacturing. What is added by this report?: The white blood cell count of workers in general equipment, special equipment, chemical raw materials, and chemical products manufacturing decreased significantly. The enterprises in which benzene concentration exceeded the occupational exposure limit were small enterprises and private enterprises. What are the implications for public health practice?: Regular health examinations are necessary for benzene-exposed workers. In addition, the monitoring of benzene concentration in small enterprises and private enterprises should be strengthened.

[Effect of electroacupuncture on expression of NF-κB and TNF-α in renal tissue of rats with acute cerebral infarction].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on motor function, serum Cystatin C (Cys C) content, and expressions of tumour necrosis factor-α (TNF-α) and nuclear factor-kappa B (NF-κB) in renal tissue of rats with acute cerebral infarction (ACI), so as to explore its underlying mechanisms in protecting renal tissue after ACI. METHODS: Seventy-two male SD rats were randomly divided into three groups: sham operation, model and EA groups which were further randomly allocated to 1 d, 3 d, 7 d and 14 d subgroups (n=6 per subgroup). The ACI model was established by occlusion of the middle cerebral artery (MCAO). Rats of the EA group received EA of "Neiguan" (PC6) and "Zusanli" (ST36) for 30 min, once daily for 1, 3, 7 and 14 days, respectively. The motor function and content of Cys C were determined on the 1st, 3rd, 7th and 14th day after ACI. The expressions of TNF-α and NF-κB were detected by immunohistochemistry. RESULTS: Compared with the sham operation group, the motor function scores and the content of Cys C increased significantly on the 1st, 3rd, 7th and 14th d (P<0.01), while the numbers of TNF-α and NF-κB positive cells of the model group increased significantly on the 3rd, 7th and 14th d (P<0.01). After EA treatment, the motor function scores and the content of Cys C on the 7th, and 14th d, and the numbers of TNF-α and NF-κB positive cells on the 3rd, 7th and 14th d obviously decreased (P<0.05). CONCLUSION: EA at PC6 and ST36 can improve motor function and alleviate renal injury in ACI rats, possibly by regulating the expression of TNF-α, NF-κB in renal tissue and Cys C in serum.