A radical 1,4-aryl migration enables nickel-catalysed remote cross-electrophile coupling of ß-bromo amino acid esters with vinyl triflates.

A radical 1,4-aryl migration enabling a cross-electrophile coupling reaction toward remote transalkylation of N-benzyl alanine has been developed. In this strategy, with the occurrence of a radical-mediated Turce-Smiles rearrangement, key α-aminoalkyl radicals are generated. The as-formed α-aminoalkyl radical serves as a robust coupling partner for cross-electrophilic coupling with vinyl triflates, affording a series of olefin-tethered amino acid motifs.

Metformin switches cell death modes to soothe the apical periodontitis via ZBP1.

Apical periodontitis (AP) is a disease caused by pathogenic microorganisms and featured with the degradation of periapical hard tissue. Our recent research showed the crucial role of Z-DNA binding protein 1 (ZBP1)-mediated necroptosis and apoptosis in the pathogenesis of AP. However, the specific regulatory mechanisms of ZBP1 in AP are not fully elucidated. It was found that metformin has a regulatory role in cell necroptosis and apoptosis. But whether and how metformin regulates necroptosis and apoptosis through the ZBP1 in the context of AP remains unknown. This study provided evidence that lipopolysaccharide (LPS) promotes the synthesis of left-handed Z-nucleic acids (Z-NA), which in turn activates ZBP1. Knockout of Zbp1 by CRISPR/Cas9 technology significantly reduced LPS-induced necroptosis and apoptosis in vitro. By using Zbp1-knockout mice, periapical bone destruction was alleviated. Moreover, type I interferon induced the expression of interferon-stimulated genes (ISGs), which serve as a major source of Z-NA. In addition, the RNA-editing enzyme Adenosine Deaminase RNA specific 1 (ADAR1) prevented the accumulation of endogenous Z-NA. Meanwhile, metformin suppressed the ZBP1-mediated necroptosis by inhibiting the expression of ZBP1 and the accumulation of ISGs. Metformin also promoted mitochondrial apoptosis, which is critical for the elimination of intracellular bacterial infection. The enhanced apoptosis further promoted the healing of infected apical bone tissues. In summary, these results demonstrated that the recognition of Z-NA by ZBP1 plays an important role in AP pathogenesis. Metformin suppressed ZBP1-mediated necroptosis and promoted apoptosis, thereby contributing to the soothing of inflammation and bone healing in AP.

TRIM21 is a druggable target for the treatment of metastatic colorectal cancer through ubiquitination and activation of MST2.

Metastatic colorectal cancer (mCRC) is characterized by poorer prognosis of patients and limited therapeutic approach, partly due to the lack of effective target. Using mouse models and tumor organoids, this study reported a tripartite motif 21 (TRIM21) protein, exerting potential inhibitory effects on the invasion and metastasis of CRC. Mechanistically, TRIM21 directly interacted with and ubiquitinated MST2 at lysine 473 (K473) via K63-linkage. This ubiquitination enabled the formation of MST2 homodimer and enhanced its kinase activity, ultimately resulting in the functional inactivation of yes-associated protein (YAP) and inhibition of an epithelial-mesenchymal transition (EMT) feature. We identified that vilazodone, an antidepressant, directly bound to TRIM21 to exert effective anti-metastatic action both in vitro and in vivo. Collectively, these findings revealed a previously unrecognized interplay between TRIM21 and the Hippo-YAP signaling. These results suggested that vilazodone could be repositioned as an anti-tumor drug to inhibit CRC metastasis by targeting TRIM21.

The role of tumor-derived extracellular vesicles containing noncoding RNAs in mediating immune cell function and its implications from bench to bedside.

Extracellular vesicles (EVs) are membrane-encapsulated vesicles released by almost all cell types, which participate in intercellular communication by delivering different types of molecular cargoes, such as non-coding RNAs (ncRNAs). Accumulating evidence suggests that tumor-derived EVs act as a bridge for intercellular crosstalk between tumor cells and surrounding cells, including immune cells. Tumor-derived EVs containing ncRNAs (TEV-ncRNAs) mediate intercellular crosstalk to manipulate immune responses and affect the malignant phenotypes of cancer cells. In this review, we summarize the double-edged roles and the underlying mechanisms of TEV-ncRNAs in regulating innate and adaptive immune cells. We also highlight the advantages of using TEV-ncRNAs in liquid biopsies for cancer diagnosis and prognosis. Moreover, we outline the use of engineered EVs to deliver ncRNAs and other therapeutic agents for cancer therapy.

Maxent modeling for predicting the global potential distribution of talaromycosis marneffei / 中国热带医学

@#Abstract: Objective　To predict the potential distribution of talaromycosis marneffei (TSM) and analyze its driving factors, so as to provide evidence for the surveillance and prevention of this disease. Methods　The data of all laboratory-confirmed, non-duplicating TSM published in the English and Chinese literature from the first case in January 1964 to December 2018 was collected. A Maxent ecology model using environmental variables, Rhizomys distribution and HIV/AIDS epidemic was developed to forecast ecological niche of TSM worldwide, as well as identify the driving factors. Results　A total of 705 articles (477 in Chinese and 228 in English) were obtained during the study period. After excluding imported cases, a total of 100 foci information were included in the model. The area under the receiver operating characteristic (ROC) curve (AUC) of the model was 0.997 for the training set and 0.991 for the test set. Maxent model revealed that Rhizomys distribution, mean temperature of warmest quarter, precipitation of wettest month, HIV/AIDS epidemic and mean temperature of driest quarter were the top 5 important variables affecting TSM distribution. In addition to identifying traditional TSM endemic areas (South of the Yangtze River in China, Southeast Asian, North and Northeast India), other potential endemic areas were also identified, including parts of the North of the Yangtze River, Central America, West Coast of Africa, East Coast of South America, the Korean Peninsula and Japan. Conclusion　Our finding has discovered hidden high-risk areas and provided insights about driving factors of TSM distribution, which will help inform surveillance strategies and improve the effectiveness of public health interventions against TM infections.

Non-Coding RNAs of Extracellular Vesicles: Key Players in Organ-Specific Metastasis and Clinical Implications.

Extracellular vesicles (EVs) are heterogeneous membrane-encapsulated vesicles released by most cells. They act as multifunctional regulators of intercellular communication by delivering bioactive molecules, including non-coding RNAs (ncRNAs). Metastasis is a major cause of cancer-related death. Most cancer cells disseminate and colonize a specific target organ via EVs, a process known as "organ-specific metastasis". Mounting evidence has shown that EVs are enriched with ncRNAs, and various EV-ncRNAs derived from tumor cells influence organ-specific metastasis via different mechanisms. Due to the tissue-specific expression of EV-ncRNAs, they could be used as potential biomarkers and therapeutic targets for the treatment of tumor metastasis in various types of cancer. In this review, we have discussed the underlying mechanisms of EV-delivered ncRNAs in the most common organ-specific metastases of liver, bone, lung, brain, and lymph nodes. Moreover, we summarize the potential clinical applications of EV-ncRNAs in organ-specific metastasis to fill the gap between benches and bedsides.

Early memory impairment is accompanied by changes in GluA1/p-GluA1 in APP/PS1 mice.

AIMS: Exploring the neurobiological mechanisms of early AD damage Background: The early diagnosis of Alzheimer's disease (AD) has a very important impact on the prognosis of AD. However, the early symptoms of AD are not obvious and difficult to diagnose. Existing studies have rarely explored the mechanism of early AD. AMPARs are early important learning memory-related receptors. However, it is not clear how the expression levels of AMPARs change in early AD. OBJECTIVE: We explored learning memory abilities and AMPAR expression changes in APP/PS1 mice at 4 months, 8 months, and 12 months. METHOD: We used the classic Morris water maze to explore the learning and memory impairment of APP/PS1 mice and used western blotting to explore the changes in AMPARs in APP/PS1 mice. RESULT: We found that memory impairment occurred in APP/PS1 mice as early as 4 months of age, and the impairment of learning and memory gradually became serious with age. The changes in GluA1 and p-GluA1 were most pronounced in the early stages of AD in APP/PS1 mice. CONCLUSION: Our study found that memory impairment in APP/PS1 mice could be detected as early as 4 months of age, and this early injury may be related to GluA1.

Community Assembly of Fungi and Bacteria along Soil-Plant Continuum Differs in a Zoige Wetland.

Distinct plant associated microbiomes live in rhizosphere soil, roots, and leaves. However, the differences in community assembly of fungi and bacteria along soil-plant continuum are less documented in ecosystems. We examined fungal and bacterial communities associated with leaves, roots, and rhizosphere soil of the dominant arbuscular mycorrhizal (AM) plants Taraxacum mongolicum and Elymus nutans and non-AM plant Carex enervis in the Zoige Wetland by using high throughput sequencing techniques. The operational taxonomic unit (OTU) richness of fungi and bacteria was significantly higher in rhizosphere soil than in roots and leaves, and their community compositions were significantly different in the rhizosphere soil, roots, and leaves in each plant species. The co-occurrence network analysis revealed that the sensitive fungal and bacterial OTUs with various taxonomic positions were mainly clustered into different modules according to rhizosphere soil, roots, and leaves in each plant species. Along the soil-plant continuum, the rhizosphere soil pool contributed more source on bacterial than on fungal communities in roots and leaves of the three plant species, and more source on bacterial and fungal communities in leaves of T. mongolicum and E. nutans compared with C. enervis. Furthermore, the root pool contributed more source on bacterial than on fungal communities in leaves of T. mongolicum and E. nutans but not that of C. enervis. This study highlights that the host plant selection intensity is higher in fungal than in bacterial communities in roots and leaves from rhizosphere soil in each plant species, and differs in fungal and bacterial communities along the soil-plant continuum in AM plants T. mongolicum and E. nutans and non-AM plant C. enervis in the Zoige Wetland. IMPORTANCE Elucidating the community microbiome assemblage alone the soil-plant continuum will help to better understand the biodiversity maintenance and ecosystem functioning. Here, we examined the fungal and bacterial communities in rhizosphere soil, roots, and leaves of two dominant AM plants and a non-AM plant in Zoige Wetland. We found that along the soil - plant continuum, host plant selection intensity is higher in fungal than in bacterial communities in roots and leaves from rhizosphere soil in each plant species, and differs in fungal and bacterial communities in the AM- and non-AM plants. This is the first report provides evidence of different assembly patterns of fungal and bacterial communities along the soil-plant continuum in the AM- and non-AM plants in the Zoige Wetland.

Investigation and influencing factors about well-being level of elderly chronic patients during COVID-19 postpandemic period in Beijing.

ABSTRACT: The Corona Virus Disease 2019 (COVID-19) pandemic has huge impacts on the world, including human health and economic decline. The COVID-19 has severe infectivity, especially the elderly with chronic diseases will cause various complications after infection and accelerate the disease process. In addition, COVID-19 will also affect their mental health. Therefore, the mental health of elderly patients with chronic diseases cannot be ignored. The aim of this study was to investigate the well-being level of elderly people with chronic disease during COVID-19 postpandemic period in Beijing and analysis related influencing factors, so as to provide a basis for improving the well-being level of elderly chronic patients during the postpandemic period.Elderly patients with chronic diseases who met the inclusion criteria in 5 different administrative regions in Beijing were selected to carry out a questionnaire survey. The contents of the questionnaire included general data, the Memorial University of Newfoundland Happiness scale and the awareness situation of the COVID-19 pandemic. A total of 500 questionnaires were distributed by WeChat and 486 valid questionnaires were collected. The t test and one-way analysis of variance were used to compare Memorial University of Newfoundland Happiness scores between 2 or more groups, multiple linear regression analysis was used to conduct multiple factor analysis to explore the related factors about well-being level of elderly chronic patients.A total of 109 cases (22.43%) were evaluated high well-being level, 319 cases (65.64%) were evaluated moderate well-being level and 58 cases (11.93%) were evaluated low well-being according to the Memorial University of Newfoundland Happiness (MUNSH) scores rating. The multiple linear regression indicated that the education level, number of chronic diseases, medical expenses, frequency of children's visits, taking care of grandchildren or not, and group activity frequency significantly affected the well-being of patients with chronic diseases during COVID-19 postpandemic period in Beijing (P < .05).Most elderly patients with chronic diseases had moderate or above sense of well-being during postpandemic period, but we should still pay attention to the mental health of those elderly chronic patients with low education level, much comorbidity, more medical expenses, less visits by children, not take care of grandchildren and never participate in group activities.

TRIP6 promotes inflammatory damage via the activation of TRAF6 signaling in a murine model of DSS-induced colitis.

BACKGROUND: TRIP6 is a zyxin family member that serves as an adaptor protein to regulate diverse biological processes. In prior reports, TRIP6 was shown to play a role in regulating inflammation. However, its in vivo roles and mechanistic importance in colitis remain largely elusive. Herein, we therefore employed TRIP6-deficient (TRIP6-/-) mice in order to explore the mechanistic importance of TRIP6 in a dextran sodium sulfate (DSS)-induced model of murine colitis. FINDINGS: Wild-type (TRIP6+/+) mice developed more severe colitis following DSS-mediated disease induction relative to TRIP6-/- mice, as evidenced by more severe colonic inflammation and associated crypt damage. TRIP6 expression in wild-type mice was significantly elevated following DSS treatment. Mechanistically, TRIP6 binds to TRAF6 and enhances oligomerization and autoubiquitination of TRAF6. This leads to the activation of NF-κB signaling and the expression of pro-inflammatory cytokines such as TNFα and IL-6, in the in vivo mouse model of colitis. CONCLUSIONS: These in vivo data demonstrate that TRIP6 serves as a positive regulator of DSS-induced colitis through interactions with TRAF6 resulting in the activation of inflammatory TRAF6 signaling, highlighting its therapeutic promise as a protein that theoretically can be targeted to prevent or treat colitis.

Binding specificity of type three secretion system effector NleH2 to multi-cargo chaperone CesT and their phosphorylation.

Gram-negative pathogens like Enteropathogenic Escherichia coli (EPEC) utilize the type three secretion system (T3SS) to translocate various effector proteins that are needed to "hijack" the host system for pathogenic survival. Specialized T3SS chaperones inside bacterial cells stabilize these effector proteins and facilitate their translocation. CesT is a unique multi-cargo chaperone that interacts with and translocates ~10 different effector proteins. Here, we report the specific interaction between CesT and its key effector, NleH2, and explore the potential role of NleH2 as a kinase for CesT phosphorylation. First, we identified the chaperone-binding domain (CBD; 19-97aa) of NleH2, and mapped the specific interaction sites for both CesT and NleH2. The N- and C-terminal residues of the CBD interact with the dimeric interface of CesT. Further, we compared the CesT binding to NleH2, to that of another key effector Tir and with the global carbon regulator CsrA. Notably, the effectors have the binding regions at the ß-sheet core and dimer interface of CesT, whereas the CsrA regulator interacts predominantly through the C-terminal region, which is found ~17 Å away from the effectors-binding sites. Next, we showed that NleH2 remains an active kinase even as a complex with CesT and is responsible for its autophosphorylation as well as phosphorylation of CesT at Tyr153. Collectively, our findings enhance the understanding of the role of multi-cargo chaperone CesT in orchestrating effector translocation through T3SS.

The Role of TGF-ß Signaling Pathways in Cancer and Its Potential as a Therapeutic Target.

The transforming growth factor-ß (TGF-ß) signaling pathway mediates various biological functions, and its dysregulation is closely related to the occurrence of malignant tumors. However, the role of TGF-ß signaling in tumorigenesis and development is complex and contradictory. On the one hand, TGF-ß signaling can exert antitumor effects by inhibiting proliferation or inducing apoptosis of cancer cells. On the other hand, TGF-ß signaling may mediate oncogene effects by promoting metastasis, angiogenesis, and immune escape. This review summarizes the recent findings on molecular mechanisms of TGF-ß signaling. Specifically, this review evaluates TGF-ß's therapeutic potential as a target by the following perspectives: ligands, receptors, and downstream signaling. We hope this review can trigger new ideas to improve the current clinical strategies to treat tumors related to the TGF-ß signaling pathway.

SP1-induced long non-coding RNA SNHG6 facilitates the carcinogenesis of chondrosarcoma through inhibiting KLF6 by recruiting EZH2.

Small nucleolar RNA host gene 6 (SNHG6) is a newly discovered long non-coding RNA (lncRNA), while the regulatory mechanism of SNHG6 in chondrosarcoma is largely unknown. Here we found that SNHG6 expression was upregulated and showed positive correlation with the progression of chondrosarcoma. Functional assays demonstrated that SNHG6 was required for the proliferation, migration, and invasion of chondrosarcoma cells. Mechanistic study revealed that SNHG6 could recruit EZH2 and maintain high level of H3K27me3 to repress the transcription of tumor-suppressor genes, including KLF6. KLF6 was found to bind to the promoter region of SP1 and restrained its transcription, while SP1 could be recruited to the promoter region of SNHG6 and promoted its transcription to form a positive loop. In summary, this study reveals that SP1-induced SNHG6 forms a positive loop to facilitate the carcinogenesis of chondrosarcoma through the suppression of KLF6 by recruiting EZH2, which manifests the oncogenic function of SNHG6 in chondrosarcoma.

[Three-dimensional finite element analysis of cuspal-coverage thickness influence on the stress distribution of all-ceramic onlay-restored premolars].

OBJECTIVE: To investigate the influence of cuspal-coverage thickness on the stress distribution of all-ceramic onlay-restored premolars by using 3D finite element (FE) analysis and to provide references for the design of all-ceramic onlays for clinical application. METHODS: 3D FE models of all-ceramic onlays with three cuspal-coverage thicknesses (2, 3, and 4 mm) of endodontically treated maxillary premolar were constructed based on micro-CT images. Stress distributions in the onlay, adhesive resin cement layer, and dentin of models were analyzed under vertical load (600 N) and oblique load (200 N). RESULTS: When the cuspal-coverage thickness increased, the peak maximum principal stress value decreased inside the onlay but increased in the margin of the adhesive resin cement layer. In addition, stress concentration areas increased in the coronal residual dentin on the palatal side under oblique load. CONCLUSIONS: An increase in the cuspal-coverage thickness of all-ceramic onlays may reduce the risk of rupture of the restoration but may deteriorate the restoration and cause palatal dentin fracture.

Development of a 9-locus X-STR multiplex PCR system for genetic analysis of three ethnic populations in China.

X-chromosome short tandem repeats (X-STR) analysis has been confirmed to be effective for kinship testing such as in deficiency paternity cases. The aim of this study was to develop a new multiplex polymerase chain reaction (PCR) system that can simultaneously amplify 9 X-STR loci (GATA172D05, DXS10159, DXS6797, HPRTB, DXS10079, DXS6789, DXS9895, DXS10146 and GATA31E08) in the same PCR reaction, and to obtain the database of the 9 X-STR loci in three ethnic populations in China. The genetic data of 815 (404 females and 411 males) unrelated Han Chinese from Hubei province, and Yi and Zhuang Chinese from Yunnan province were analyzed by using this multiplex system. The results showed that a total of 93 alleles for all these loci were found, and 7 to 20 alleles for each locus were observed. All of the analyzed loci were in agreement with Hardy-Weinberg equilibrium after Bonferroni correction in the three studied populations. The polymorphism information content (PIC) and power of discrimination (PD) in females were 0.6566-0.8531 and 0.8639-0.9684, respectively. Pairwise comparisons of allele frequency distribution showed significant differences in the most of these loci between different populations. The results indicate that this multiplex system is very useful for forensic analysis of different ethnic populations in China.

Multistep microsatellite mutation in a case of non-exclusion parentage.

A non-exclusion paternity with multistep mutation in the locus D5S818 was reported. Examination of 39 autosomal short tandem repeats (STR) loci revealed a mismatch of the maternally or paternally transmitted allele in the locus D5S818 in the questioned child. The composition of the alleles of this locus in the mother, the questioned child and the alleged father are 11/13, 7/13 and 13, respectively. The sequence analysis of the regions flanking the locus D5S818 of the mother, the questioned child and the alleged father excluded the possibility of null allele as a cause of the allelic mismatch in the child. The combined paternity index of 39 autosomal STRs is up to 2.461×10(9). Genotyping of sixteen Y-STR loci in the questioned child matched completely with the alleged father. The results prove that the alleged father is the biological father of the questioned child with four-step or six-step microsatellite mutation in the locus D5S818.

[Research progress on the phenotype informative SNP in forensic science].

Single nucleotide polymorphism (SNP) refers to the single base sequence variation in specific location of the human genome. Phenotype informative SNP has gradually become one of the research hot spots in forensic science. In this paper, the forensic research situation and application prospect of phenotype informative SNP in the characteristics of hair, eye and skin color, height, and facial feature are reviewed.

Safety and immunogenicity from a phase I trial of inactivated severe acute respiratory syndrome coronavirus vaccine.

BACKGROUND: Emergence of severe acute respiratory syndrome (SARS) from the winter of 2002 to the spring of 2003 has caused a serious threat to public health. METHODS: To evaluate the safety and immunogenicity of the inactivated SARS coronavirus (SARS-CoV) vaccine, 36 subjects received two doses of 16 SARS-CoV units (SU) or 32 SU inactivated SARS-CoV vaccine, or placebo control. RESULTS: On day 42, the seroconversion reached 100% for both vaccine groups. On day 56, 100% of participants in the group receiving 16 SU and 91.1% in the group receiving 32 SU had seroconverted. The geometric mean titre of neutralizing antibody peaked 2 weeks after the second vaccination, but decreased 4 weeks later. CONCLUSION: The inactivated vaccine was safe and well tolerated and can elicit SARS-CoV-specific neutralizing antibodies.

A serological survey on neutralizing antibody titer of SARS convalescent sera.

A seroepidemiologic study was conducted in North China in 2003 to determine the neutralizing antibody titer of severe acute respiratory syndrome (SARS) convalescent sera. A total of 99 SARS convalescent serum samples were collected from patients from the Inner Mongolia Autonomous Region, Hebei Province, and Beijing 35-180 days after the onset of symptoms. The anti-SARS antibodies were detected by enzyme-linked immunosorbent assay (ELISA), neutralization assay, and Western blot. Eighty-seven serum samples were confirmed to be positive for SARS antibodies. The neutralizing antibody titer of the 87 positive sera was analyzed quantitatively by neutralization assay. The geometric mean titer (GMT) of the 87 convalescent sera was 1:61. The Kolmogorov-Smirnov test showed that the neutralizing antibody titers conform to normal distribution, which suggests that the average anti-SARS antibody level in this study was representative of the convalescent antibody level of the SARS population. This result could be useful for the development and quality control of SARS vaccines.

[Serological investigation on close contacts to patients with severe acute respiratory syndrome in an SARS outbreak].

OBJECTIVE: To study the evidence of severe acute respiratory syndrome (SARS) infection among close contacts to SARS patients and the level of sera IgG antibody in SARS cases. METHODS: Specific IgG antibody against SARS-CoV in serum samples from contacts to patients, five months before an SARS outbreak in Beijing. Neutralized test, ELISA and immunity adherence test were studied. Samples were collected after clinical onset of patients or close contacts to patients, for 22 - 24 weeks. 19 close contacts and 13 cases were included in the study. RESULTS: In close contacts, all tests were negative on three methods. All SARS cases were positive except one by immunity adherence test. The neutralized antibody levels were from 1:16 to 1:203, with medium level of 1:43. CONCLUSION: According to our survey, there was no latent infection among close contacts. IgG antibody in sera continued to be at higher levels among SARS cases 22 - 24 weeks after onset.