Genomic Surveillance for SARS-CoV-2 Variants: Dominance of XBB Replacement - China, January-June 2023.

Introduction: In the first half of 2023, a global shift was observed towards the predominance of XBB variants. China faced a significant epidemic between late 2022 and early 2023 due to Omicron subvariants BA.5.2 and BF.7. This study aims to depict the evolving variant distribution among provincial-level administrative divisions (PLADs) in China and explore the factors driving the predominance of XBB replacement. Methods: Sequences from local and imported coronavirus disease 2019 (COVID-19) cases recorded between January 1 and June 30, 2023, were included. The study analyzed the changing distribution of viral variants and assessed how the prior dominance of specific variants, XBB subvariants, and imported cases influenced the prevalence of the XBB replacement variant. Results: A total of 56,486 sequences were obtained from local cases, and 8,669 sequences were from imported cases. Starting in April, there was a shift in the prevalence of XBB from imported to local cases, with varying dominance among PLADs. In PLADs previously high in BF.7, the rise of XBB was delayed. A positive correlation was found between XBB proportions in imported cases from January to March and local cases in April. The distribution pattern of XBB subvariants differed between local and imported cases within the same PLAD. No significant differences were noted in the replacement rates of XBB subvariants. Conclusions: The timing of XBB dominance differed among various PLADs in China in the first half of 2023, correlating closely with the prevalence of XBB variants among imported cases.

Prevalence and diversity of imported severe acute respiratory syndrome coronavirus 2 variants in China, 2021-2022.

The causative agent of coronavirus disease 2019 (COVID-19), known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread accumulatively to 240 countries and continues to evolve. To gain a comprehensive understanding of the epidemiological characteristics of imported variants in China and their correlation with global circulating variants, genomic surveillance data from 11 139 imported COVID-19 cases submitted by Chinese provincial CDC laboratories between 2021 and 2022 were analyzed. Consensus sequences underwent rigorous quality checks, followed by amino acid mutations analysis using Nextclade. Sequences with satisfactory quality control status were classified according to the Pango nomenclature. The results showed that the dominant variants in imported cases reflected the global epidemic trend. An increase in the number of imported SARS-CoV-2 lineages monitored in China in the second half of 2022, and the circulating Omicron subvariants changed from the ancestral lineages of BA.5 and BA.2 into the lineages containing key amino acid mutations of spike protein. There was significant variation in the detection of Omicron subvariants among continents (χ2 = 321.968, p < 0.001) in the second half of 2022, with four lineages (BA.2.3.7, BA.2.2, BA.5.2.7, and XBB.1.2) identified through imported surveillance mainly prevalent respectively in Taiwan, China, Hong Kong SAR, China, Russian Federation, and Singapore. These findings revealed the alterations in circulating imported variants from 2021 to 2022 in China, reflecting the higher diversity of lineages in the second half of 2022, and revealed the predominant lineages of countries or regions that are in close contacts to China, providing new insights into the global prevalence of SARS-CoV-2.

Aberrant Enhanced NLRP3 Inflammasomes and Cell Pyroptosis in the Brains of Prion-Infected Rodent Models Are Largely Associated with the Proliferative Astrocytes.

Neuroinflammation is a common pathological feature in a number of neurodegenerative diseases, which is mediated primarily by the activated glial cells. Nucleotide-binding oligomerization domain-like receptor pyrin domain-containing-3 (NLRP3) inflammasome-associated neuroinflammatory response is mostly considered. To investigate the situation of the NLRP3-related inflammation in prion disease, we assessed the levels of the main components of NLRP3 inflammasome and its downstream biomarkers in the scrapie-infected rodent brain tissues. The results showed that the transcriptional and expressional levels of NLRP3, caspase-1, and apoptosis-associated speck-like protein (ASC) in the brains of scrapie-infected rodents were significantly increased at terminal stage. The increased NLPR3 overlapped morphologically well with the proliferated GFAP-positive astrocytes, but little with microglia and neurons. Using the brain samples collected at the different time-points after infection, we found the NLRP3 signals increased in a time-dependent manner, which were coincidental with the increase of GFAP. Two main downstream cytokines, IL-1ß and IL-18, were also upregulated in the brains of prion-infected mice. Moreover, the gasdermin D (GSDMD) levels, particularly the levels of GSDMD-NT, in the prion-infected brain tissues were remarkably increased, indicating activation of cell pyroptosis. The GSDMD not only co-localized well with the astrocytes but also with neurons at terminal stage, also showing a time-dependent increase after infection. Those data indicate that NLRP3 inflammasomes were remarkably activated in the infected brains, which is largely mediated by the proliferated astrocytes. Both astrocytes and neurons probably undergo a pyroptosis process, which may help the astrocytes to release inflammatory factors and contribute to neuron death during prion infection.

Different reactive profiles of calmodulin in the CSF samples of Chinese patients of four types of genetic prion diseases.

Background and purpose: Calmodulin (CaM) levels exhibit significant elevation in the brain tissue of rodent and cell line models infected with prion, as well as in the cerebrospinal fluid (CSF) samples from patients diagnosed with sporadic Creutzfeldt-Jakob disease (sCJD). However, the status of CSF CaM in patients with genetic prion diseases (gPrDs) remains unclear. This study aims to assess the characteristics of CSF CaM in Chinese patients presenting four subtypes of gPrDs. Methods: A total of 103 CSF samples from patients diagnosed with T188K-gCJD, E200K-gCJD, D178N-FFI, P102L-GSS were included in this study, along with 40 CSF samples from patients with non-prion diseases (non-PrDs). The presence of CSF CaM and 14-3-3 proteins was assessed using Western blots analysis, while levels of CSF 14-3-3 and total tau were measured using enzyme-linked immunosorbent assays (ELISAs). Statistical methods including multivariate logistic regression were employed to evaluate the association between CSF CaM positivity and relevant clinical, laboratory, and genetic factors. Results: The positive rates of CSF CaM were significantly higher in cases of T188K-gCJD (77.1%), E200K-gCJD (86.0%), and P102-GSS (90.9%) compared to non-PrD cases (22.5%). In contrast, CSF CaM positivity was slightly elevated in D178N-FFI (34.3%). CSF CaM positivity was remarkably high in patients who tested positive for CSF 14-3-3 by Western blot and exhibited high levels of total tau (≥1400 pg/ml) as measures by ELISA. Multivariate logistic regression analysis confirmed a significant association between CSF CaM positivity and specific mutations in PRNP, as well as with CSF 14-3-3 positivity. Furthermore, the diagnostic performance of CaM surpassed that of 14-3-3 and tau when analyzing CSF samples from T188K-gCJD and E200K-gCJD patients. Conclusion: Western blot analysis reveals significant variations in the positivity of CSF CaM among the four genotypes of gPrD cases, demonstrating a positive correlation with 14-3-3 positivity and elevated tau levels in CSF.

Optimizing hepatocellular carcinoma disease staging systems by incorporating tumor micronecrosis: A multi-institutional retrospective study.

Tumor micronecrosis is a pathological feature that reflects malignant biological behavior in hepatocellular carcinoma (HCC). However, whether micronecrosis can optimize HCC staging systems remains unilluminated. A total of 1632 HCC patients who underwent curative hepatectomy in four institutions from January 2014 to December 2021 were enrolled in this study. Independent prognostic factors were identified, and optimized staging models were established using a training cohort (n = 934). The performance of optimized staging models was validated using an external cohort consisting of cases from three other institutions (n = 232). In addition, patients from our prospectively collected database (n = 379) tested the application effectiveness of the models. Harrel's c-statistics and the corrected Akaike information criterion (AICc) were used to assess the performance of staging models. In most of Barcelona Clinic Liver Cancer (BCLC) and tumor (T) stages, HCC patients with tumor micronecrosis showed poorer prognosis than those without. Tumor micronecrosis, microvascular invasion, multiple tumors and tumor size >2 cm were independent prognostic-related factors. The BCLC and T staging models incorporating tumor micronecrosis showed better performance than the original systems (c-statistic, 0.712 and 0.711 vs. 0.664 and 0.679; AICc, 2314.8 and 2322.3 vs. 2338.2 and 2338.1; respectively). Furthermore, the external validation cohort confirmed that the optimized staging models had improved efficiency compared with the original ones. Moreover, the prospective cohort demonstrated the applicability of the optimized staging systems. Tumor micronecrosis plays a stage-ascending role in HCC patients. The BCLC and T staging systems incorporating tumor micronecrosis can improve the prognosis stratification efficiency of patients.

The effects of postoperative malrotation alignment on outcomes of Gartland type III/IV paediatric supracondylar humeral fractures treated by close reduction and percutaneous K-wire fixation.

PURPOSE: In this study, we aimed to investigate the effects of postoperative malrotation alignment on the outcomes of Gartland type III/IV paediatric supracondylar humeral fracture (SCHF) treated by close reduction and percutaneous K-wire fixation. METHODS: Between January 2014 and December 2021, 295 Gartland type III/IV paediatric SCHFs treated by close reduction and percutaneous K-wire fixation were selected for this retrospective study. The demographic, clinical and radiographic parameters of all cases were collected. The lateral rotation percentage (LRP) was measured on X-rays to evaluate postoperative malrotation alignment of the fracture. All cases were categorized into 4 groups according to LRP: LRP ≤ 10% (210, 71.2%), 10% < LRP ≤ 20% (41, 13.9%), 20% < LRP ≤ 30% (26, 8.8%) and LRP > 30% (18, 6.1%). The carrying angle, ranges of multidirectional motions, Mayo Elbow Performance Score (MEPS) and Flynn's Standard Score (FSS) of the injured elbow were assessed 6 months postoperation and compared among different groups. ROC analysis based on LRP and the excellent/good rate of FSS was performed to determine the acceptable maximum degree of postoperative malrotation alignment. RESULTS: There was no difference in the demographic characteristics (age, sex, injured side and fracture type), postoperative Baumann angle, carrying angle or range of forearm rotation among the 4 groups (P > 0.05). The operation time and time from operation to K-wire removal were longer in the 20% < LRP ≤ 30% and LRP > 30% groups than in the LRP < 10% and 10% < LRP ≤ 20% groups (P < 0.001). The shaft condylar angle, range of elbow flexion, MEPS and FSS of the injured elbow 6 months postoperatively were lower in the 20% < LRP ≤ 30% and LRP > 30% groups than in the LRP < 10% and 10% < LRP ≤ 20% groups (P < 0.001). ROC analysis based on LRP and the excellent/good rate of FSS showed an area under the curve of 0.959 (95% CI 0.936-0.983), with a cutoff value of 26.5%, sensitivity of 95.3% and specificity of 90.1%. CONCLUSION: A certain degree of residual malrotation alignment deformity of the SCHF may reduce the shaft condylar angle and extend the time from operation to removing the K-wire and affect elbow function, especially the range of elbow flexion. The acceptable maximum degree of residual malrotation deformity expressed as the LRP value was 26.5%.

Down-expression of miR-494-3p in senescent osteocyte-derived exosomes inhibits osteogenesis and accelerates age-related bone loss via PTEN/PI3K/AKT pathway.

Aims: To investigate the effects of senescent osteocytes on bone homeostasis in the progress of age-related osteoporosis and explore the underlying mechanism. Methods: In a series of in vitro experiments, we used tert-Butyl hydroperoxide (TBHP) to induce senescence of MLO-Y4 cells successfully, and collected conditioned medium (CM) and senescent MLO-Y4 cell-derived exosomes, which were then applied to MC3T3-E1 cells, separately, to evaluate their effects on osteogenic differentiation. Furthermore, we identified differentially expressed microRNAs (miRNAs) between exosomes from senescent and normal MLO-Y4 cells by high-throughput RNA sequencing. Based on the key miRNAs that were discovered, the underlying mechanism by which senescent osteocytes regulate osteogenic differentiation was explored. Lastly, in the in vivo experiments, the effects of senescent MLO-Y4 cell-derived exosomes on age-related bone loss were evaluated in male SAMP6 mice, which excluded the effects of oestrogen, and the underlying mechanism was confirmed. Results: The CM and exosomes collected from senescent MLO-Y4 cells inhibited osteogenic differentiation of MC3T3-E1 cells. RNA sequencing detected significantly lower expression of miR-494-3p in senescent MLO-Y4 cell-derived exosomes compared with normal exosomes. The upregulation of exosomal miR-494-3p by miRNA mimics attenuated the effects of senescent MLO-Y4 cell-derived exosomes on osteogenic differentiation. Luciferase reporter assay demonstrated that miR-494-3p targeted phosphatase and tensin homolog (PTEN), which is a negative regulator of the phosphoinositide 3-kinase (PI3K)/AKT pathway. Overexpression of PTEN or inhibition of the PI3K/AKT pathway blocked the functions of exosomal miR-494-3p. In SAMP6 mice, senescent MLO-Y4 cell-derived exosomes accelerated bone loss, which was rescued by upregulation of exosomal miR-494-3p. Conclusion: Reduced expression of miR-494-3p in senescent osteocyte-derived exosomes inhibits osteogenic differentiation and accelerates age-related bone loss via PTEN/PI3K/AKT pathway.

Geographic Diversity in the Incidence of Human Prion Diseases - China, 2006-2019.

Introduction: Human prion diseases (PrDs) are rare, fatal encephalopathies requiring comprehensive diagnostic analysis. This study examines hospital referral patterns to the Chinese National Surveillance for Creutzfeldt-Jakob Disease (CNS-CJD) from 2006 to 2019. Methods: We assessed 1,970 PrD cases referred by various hospitals to CNS-CJD. Referral distributions were analyzed based on provincial-level administrative divisions (PLADs). Differences in referral numbers and confirmed cases between monitored and non-monitored PLADs were statistically evaluated. Results: The study included cases from 344 hospitals across 29 Chinese PLADs. Hospital referrals increased over the surveillance years: from 28.2 hospitals annually during 2006-2010, to 64 in 2011-2015, and 107 in 2016-2019. Of these, 12.2% (42/344) of hospitals reported ≥10 PrD cases, accounting for 70.0% (1,379/1,970) of total cases. Referral numbers varied across PLADs, with the top 5 of Beijing (41), Henan (26), Shanghai (21), Guangdong (21), and Jiangsu (21) leading. Additionally, 12 CJD-surveillance PLADs had more referring hospitals and PrD cases than the other 17 non-surveillance PLADs. Conclusions: Geographical variations in PrD recognition exist across Chinese PLADs, with certain regions and major cities reporting notably higher case numbers.

Increased Gal-3 Mediates Microglia Activation and Neuroinflammation via the TREM2 Signaling Pathway in Prion Infection.

Galectin 3 (Gal-3) is one of the major elements for activating microglia and mediating neuroinflammation in some types of neurodegenerative diseases. However, its role in the pathogenesis of prion disease is seldom addressed. In this study, markedly increased brain Gal-3 was identified in three scrapie-infected rodent models at the terminal stage. The increased Gal-3 was mainly colocalized with the activated microglia. Coincidental with the increased brain Gal-3 in prion-infected animals, the expression of brain trigger receptor expressed in myeloid cell 2 (TREM2), one of the Gal-3 receptors, and some components in the downstream pathway also significantly increased, whereas Toll-like receptor 4 (TLR4), another Gal-3 receptor, and the main components in its downstream signaling were less changed. The increased Gal-3 signals were distributed at the areas with PrPSc deposit but looked not to colocalize directly with PrPSc/PrP signals. Similar changing profiles of Gal-3, the receptors TREM2 and TLR4, as well as the proteins in the downstream pathways were also observed in prion-infected cell line SMB-S15. Removal of PrPSc replication in SMB-S15 cells reversed the upregulation of cellular Gal-3, TREM2, and the relevant proteins. Moreover, we presented data for interactions of Gal-3 with TREM2 and with TLR4 morphologically and molecularly in the cultured cells. Stimulation of prion-infected cells or their normal partner cells with recombinant mouse Gal-3 in vitro induced obvious responses for activation of TREM2 signaling and TLR4 signaling. Our data here strongly indicate that prion infection or PrPSc deposit induces remarkably upregulated brain Gal-3, which is actively involved in the microglia activation and neuroinflammation mainly via TREM2 signaling.

Accumulation of Prion Triggers the Enhanced Glycolysis via Activation of AMKP Pathway in Prion-Infected Rodent and Cell Models.

Mitochondrial dysfunction is one of the hallmarks in the pathophysiology of prion disease and other neurodegenerative diseases. Various metabolic dysfunctions are identified and considered to contribute to the progression of some types of neurodegenerative diseases. In this study, we evaluated the status of glycolysis pathway in prion-infected rodent and cell models. The levels of the key enzymes, hexokinase (HK), phosphofructokinase (PFK), and pyruvate kinase (PK) were significantly increased, accompanying with markedly downregulated mitochondrial complexes. Double-stained IFAs revealed that the increased HK2 and PFK distributed widely in GFAP-, Iba1-, and NeuN-positive cells. We also identified increased levels of AMP-activated protein kinase (AMPK) and the downstream signaling. Changes of AMPK activity in prion-infected cells by the AMPK-specific inhibitor or activator induced the corresponding alterations not only in the downstream signaling, but also the expressions of three key kinases in glycolysis pathway and the mitochondrial complexes. Transient removal or complete clearance of prion propagation in the prion-infected cells partially but significantly reversed the increases of the key enzymes in glycolysis, the upregulation of AMPK signaling pathway, and the decreases of the mitochondrial complexes. Measurements of the cellular oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) showed lower OCR and higher ECAR in prion-infected cell line, which were sufficiently reversed by clearance of prion propagation. Those data indicate a metabolic reprogramming from oxidative phosphorylation to glycolysis in the brains during the progression of prion disease. Accumulation of PrPSc is critical for the switch to glycolysis, largely via activating AMPK pathway.

Spontaneous prion disease in homozygous and heterozygous transgenic mouse models of T188K genetic Creutzfeldt-Jakob disease.

Genetic Creutzfeldt-Jakob disease with T188K mutation (T188K gCJD) is the most frequent genetic prion disease in China. To explore the penetration of T188K mutation and the pathogenesis of T188K gCJD, we constructed 2 lines of transgenic mouse models: homozygous Tg188K+/+ mice containing T188K mutation in 2 alleles of human PRNP background and heterozygous Tg188K+/- mice containing 1 allele of T188K human PRNP and 1 allele of the wild-type mouse PRNP. Spontaneous neurological illnesses were identified in all Tg188K mice at their old ages (750-800 days old). About half of the Tg188K mice died prior to the final observation (930 days old). Extensive spongiosis, PrPSc deposit, and reactive gliosis of astrocytes and microglia are neuropathologically identified, showing time-dependent exacerbation. Proteinase K-resistant PrP was detected in the brain, muscle, and intestine tissues, and positive real-time quaking-induced conversion reactions were elicited by the brain and muscle tissues of Tg188K mice. Those data verify that the constructed Tg188K mice highly mimic the clinicopathology of human T188K gCJD, strongly indicating the pathogenicity of T188K mutated PrP.

Cluster synchronization for controlled nodes via the dynamics of edges in complex dynamical networks.

An appropriate dynamic coupling form between nodes and edges' state can effectively promote the emergence of desired network function (phenomenon), but the existing literatures have not conducted in-depth research on the coupling mechanism. This paper mainly focuses on the coupling auxiliary mechanism of dynamic edges for the emergence of cluster phenomenon of nodes, explores the essential relation between structure and function in complex dynamical networks (CDNs). Firstly, a novel model of CDNs has dynamic systems attached on not only nodes but also edges is proposed from the viewpoint of large-scale system. Secondly, a feedback nodes controller is synthesized associate with the designed linear and adaptive dynamics of edges. Via the appropriate dynamic behaviors of the edges system, the controlled nodes can realize cluster synchronized. Finally, the validity of the proposed approaches is verified by a given numerical example.

Abnormal Changes of IL3/IL3R and Its Downstream Signaling Pathways in the Prion-Infected Cell Line and in the Brains of Scrapie-Infected Rodents.

Interleukin 3 (IL-3) plays an important role in hematopoiesis and immune regulation, brain IL-3/IL-3R signaling has been shown to involve in the physiological and pathological processes of a variety of neurodegenerative diseases, but its role in prion diseases is rarely described. Here, the changes of IL-3/IL-3R and its downstream signaling pathways in a scrapie-infected cell line and in the brains of several scrapie-infected rodent models were evaluated by various methods. Markedly decreased IL-3Rα were observed in the brains of scrapie-infected rodents at terminal stage and in the prion-infected cell model, which showed increased in the brain samples collected at early and middle stage of infection. The IL-3 levels were almost unchanged in the brains of scrapie-infected mice and in the prion-infected cell line. Morphological assays identified close co-localization of the increased IL-3Rα signals with NeuN- and Iba1-positive cells, whereas co-localization of IL-3 signals with NeuN- and GFAP-positive cells in the scrapie-infected brain tissues. Some downstream components of IL-3/IL-3R pathways, including JAK2-STAT5 and PI3K/AKT/mTOR pathways, were downregulated in the brains of scrapie-infected rodents at terminal stage and in the prion-infected cells. Stimulation of recombinant IL-3 on the cultured cells showed prion that the prion-infected cells displayed markedly more reluctant responses of JAK2-STAT5 and PI3K/AKT/mTOR pathways than the normal partner cells. These data suggest that although prion infection or PrPSc accumulation in brain tissues does not affect IL-3 expression, it significantly downregulates IL-3R levels, thereby inhibiting the downstream pathways of IL-3/IL-3R and blocking the neuroregulatory and neuroprotective activities of IL-3.

Development and Validation of Novel Models Including Tumor Micronecrosis for Predicting the Postoperative Survival of Patients with Hepatocellular Carcinoma.

Background: The heterogeneity of hepatocellular carcinoma (HCC) leads to the unsatisfying predictive performance of current staging systems. HCC patients with pathological tumor micronecrosis have an immunosuppressive microenvironment. We aimed to develop novel prognostic models by integrating micronecrosis to predict the survival of HCC patients after hepatectomy more precisely. Methods: We enrolled 765 HCC patients receiving curative hepatic resection. They were randomly divided into a training cohort (n= 536) and a validation cohort (n = 229). We developed two prognostic models for postoperative recurrence-free survival (RFS) and overall survival (OS) based on independent factors identified through multivariate Cox regression analyses. The predictive performance was assessed using the Harrell concordance index (C-index) and the time-dependent area under the receiver operating characteristic curve, compared with six conventional staging systems. Results: The RFS and OS nomograms were developed based on tumor micronecrosis, tumor size, albumin-bilirubin grade, tumor number and prothrombin time. The C-indexes for the RFS nomogram and OS nomogram were respectively 0.66 (95% CI, 0.62-0.69) and 0.74 (95% CI, 0.69-0.79) in the training cohort, which was significantly better than those of the six common staging systems (0.52-0.61 for RFS and 0.53-0.63 for OS). The results were further confirmed in the validation group, with the C-indexes being 0.66 and 0.77 for the RFS and OS nomograms, respectively. Conclusion: The two nomograms could more accurately predict RFS and OS in HCC patients receiving curative hepatic resection, thereby aiding in formulating personalized postoperative follow-up plans.

Low-Pass Genomic Sequencing Reveals Novel Subtypes of Pancreatic Cystic Neoplasms.

BACKGROUND: Over the years, the detection rate of pancreatic cystic neoplasms (PCNs) has significantly increased; however, the differential diagnosis and identification of high-risk PCNs remain challenging. We sought to investigate whether chromosomal instability (CIN) features in cell-free DNA in the cystic fluid of PCNs could help to identify high-risk PCNs. METHODS: Pancreatic cystic fluid samples from 102 patients with PCNs were intraoperatively collected for detection of CIN using an ultrasensitive chromosomal aneuploidy detector. Clinical and imaging data were retrospectively collected, and statistical analysis was performed to assess the potential role of CIN in clinical practice. RESULTS: CIN was investigated in a total of 100 patients. Sixteen of 26 serous cystic cystadenomas (SCAs) harbored deletions of chr3p and/or chr6p, whereas low rates of CIN were detected in mucinous cystic neoplasms. Most malignant PCNs presented with more than one type of CIN; amplification of chr1q and chr8q found in nine and seven of 11 malignant PCNs (81.8% and 63.6%), respectively, could aid in distinguishing high-risk IPMNs from low-risk ones, with a higher sensitivity than imaging. A combination of the mural nodule imaging feature and amplification of chr1q and chr8q achieved a sensitivity of 70.0% and a specificity of 82.4% in identifying high-risk IPMNs. CONCLUSIONS: Our work revealed the distinct CIN signature of different types of PCNs. Deletions of chr3p and chr6p defined a subtype of SCAs. Gains of chr1q and chr8q were associated with insidious malignant PCNs and helped identify high-risk IPMNs.

Genomic Surveillance for SARS-CoV-2 - China, September 26, 2022 to January 29, 2023.

Introduction: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has generated 2,431 variants over the course of its global transmission over the past 3 years. To better evaluate the genomic variation of SARS-CoV-2 before and after the optimization of coronavirus disease 2019 (COVID-19) prevention and control strategies, we analyzed the genetic evolution branch composition and genomic variation of SARS-CoV-2 in both domestic and imported cases in China (the data from Hong Kong and Macau Special Administrative Regions and Taiwan, China were not included) from September 26, 2022 to January 29, 2023. Methods: Analysis of the number of genome sequences, sampling time, dynamic changes of evolutionary branches, origin, and clinical typing of SARS-CoV-2 variants submitted by 31 provincial-level administrative divisions (PLADs) and Xinjiang Production and Construction Corps (XPCC) was conducted to assess the accuracy and timeliness of SARS-CoV-2 variant surveillance. Results: From September 26, 2022 to January 29, 2023, 20,013 valid genome sequences of domestic cases were reported in China, with 72 evolutionary branches. Additionally, 1,978 valid genome sequences of imported cases were reported, with 169 evolutionary branches. The prevalence of the Omicron variants of SARS-CoV-2 in both domestic and imported cases was consistent with that of international epidemic variants. Conclusions: This study provides an overview of the prevalence of Omicron variants of SARS-CoV-2 in China. After optimizing COVID-19 prevention and control strategies, no novel Omicron variants of SARS-CoV-2 with altered biological characteristics or public health significance have been identified since December 1, 2022.

Aberrant SENP1-SUMO-Sirt3 Signaling Causes the Disturbances of Mitochondrial Deacetylation and Oxidative Phosphorylation in Prion-Infected Animal and Cell Models.

Post-translational modifications of proteins, such as acetylation and SUMOylation, play important roles in regulation of protein functions and pathophysiology of different diseases including neurodegenerative diseases. Our previous studies have identified aberrant acetylation profiles and reduced deacetylases Sirt3 and Sirt1 in the brains of prion-infected mouse models. In this study, we have found that the levels of acetylated forms of AceCS2 and LCAD, the key enzymes regulating lipid metabolism, CS and IHD2, the key enzymes regulating complete oxidative metabolism, GDH, the key enzyme regulating the oxidative decomposition of glutamate into the tricarboxylic acid (TCA) cycle, and NDUFA9, the essential component in the complex I of respiratory chain activity, were significantly upregulated in the prion-infected animal and cell models, along with the decrease of Sirt3 activity and mitochondrial cytochrome c oxidase activity. Meanwhile, the increases of SUMO1 modifications and SUMO1-Sirt3 and decrease of SENP1 were identified in the brains and the cultured cells with prion infections. Removal of prion propagation in the cultured cells partially, but significantly, reversed the aberrant situations. Moreover, similar abnormal phenomena were also observed in the cultured 293 T cells transiently expressing cytosolic form PrP (Cyto-PrP), including decreased SENP1, increased SUMO1, decreased Sirt3 activity, increased acetylated forms of the key enzymes, and decreased cytochrome c oxidase activity. Attenuation of the accumulation of Cyto-PrP by co-expression of the p62 protein sufficiently diminished those abnormalities. The data here strongly indicate that deposits of prions in brains or accumulations of Cyto-PrP in cells trigger dysregulation of the SENP1-SUMO1-Sirt pathway and subsequently induce aberrant mitochondrial deacetylation and the mitochondrial respiratory chain.

Corrigendum: Single-cell RNA-seq analysis reveals cellular functional heterogeneity in dermis between fibrotic and regenerative wound healing fates.

[This corrects the article DOI: 10.3389/fimmu.2022.875407.].

Isolation and characterization of the new isolated bacteriophage YZU-L1 against Citrobacter freundii from a package-swelling of meat product.

Citrobacter freundii is an important foodborne pathogen that can cause urethritis, bacteremia, necrotizing abscess, and meningitis in infants. In this study, a gas-producing isolate from vacuum-packed meat products was identified as C. freundii by 16S rDNA. In addition, a new virulent phage YZU-L1, which could specifically lyse C. freundii, was isolated from sewage samples in Yangzhou. Transmission electron microscopy showed that phage YZU-L1 had a polyhedral head of 73.51 nm in diameter and a long tail of 161.15 nm in length. According to phylogenetic analysis employing the terminase large subunit, phage YZU-L1 belonged to the Demerecviridae family and the Markadamsvirinae subfamily. The burst size was 96 PFU/cell after 30 min of latent period and 90 min of rising period. Phage YZU-L1 could maintain high activity at pH of 4-13, and resist 50 °C for up to 60 min. The complete genome of YZU-L1 was 115,014 bp double-stranded DNA with 39.94% G + C content, encoding 164 open reading frames (ORFs), without genes encoding for virulence, antibiotic resistance, or lysogenicity. Phage YZU-L1 treatment significantly reduced the viable bacterial count of C. freundii in a sterile fish juice model, which is expected to be a natural agent for the biocontrol of C. freundii in foods.