An unprecedented catalytic asymmetric inverse‐electron‐demand aza‐Diels–Alder reaction of indoles with in situ formed azoalkenes is reported. A diverse set of 2,3‐fused indoline heterocycles were ...achieved in generally good yields (up to 97 %) with high regioselectivity and diastereoselectivity (>20:1 d.r.), and with excellent enantioselectivity (up to 99 % ee).
In(verse) demand: The unprecedented catalytic asymmetric inverse‐electron‐demand aza‐Diels–Alder reaction of indoles with in situ formed azoalkenes is reported. A diverse set of 2,3‐fused indoline heterocycles were produced in generally good yields with high regioselectivity and diastereoselectivity, and with excellent enantioselectivity.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Ylides at a crossing: An unprecedented 1,3‐dipolar cycloaddition (cross‐cycloaddition) between two different ylides (see scheme) was realized by using the chiral CuI/tBu‐Phosferrox complex as the ...catalyst under mild reaction conditions. This catalytic system provides an expeditious approach to the construction of highly functionalized 1,2,4‐triazinane derivatives in good yields with excellent diastereoselectivities and enantioselectivities.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Genetic variation has an important role in the development of non-small-cell lung cancer (NSCLC). However, genetic factors for lung cancer have not been fully identified, especially in Chinese ...populations, which limits the use of existing polygenic risk scores (PRS) to identify subpopulations at high risk of lung cancer for prevention. We therefore aimed to identify novel loci associated with NSCLC risk, and generate a PRS and evaluate its utility and effectiveness in the prediction of lung cancer risk in Chinese populations.
To systematically identify genetic variants for NSCLC risk, we newly genotyped 19 546 samples from Chinese NSCLC cases and controls from the Nanjing Medical University Global Screening Array Project and did a meta-analysis of genome-wide association studies (GWASs) of 27 120 individuals with NSCLC and 27 355 without NSCLC (13 327 cases and 13 328 controls of Chinese descent as well as 13 793 cases and 14 027 controls of European descent). We then built a PRS for Chinese populations from all reported single-nucleotide polymorphisms that have been reported to be associated with lung cancer risk at genome-wide significance level. We evaluated the utility and effectiveness of the generated PRS in predicting subpopulations at high-risk of lung cancer in an independent prospective cohort of 95 408 individuals from the China Kadoorie Biobank (CKB) with more than 10 years' follow-up.
We identified 19 susceptibility loci to be significantly associated with NSCLC risk at p≤5·0 × 10
, including six novel loci. When applied to the CKB cohort, the PRS of the risk loci successfully predicted lung cancer incident cases in a dose-response manner in participants at a high genetic risk (top 10%) than those at a low genetic risk (bottom 10%; adjusted hazard ratio 1·96, 95% CI 1·53-2·51; p
=2·02 × 10
). Specially, we observed consistently separated curves of lung cancer events in individuals at low, intermediate, and high genetic risk, respectively, and PRS was an independent effective risk stratification indicator beyond age and smoking pack-years.
We have shown for the first time that GWAS-derived PRS can be effectively used in discriminating subpopulations at high risk of lung cancer, who might benefit from a practically feasible PRS-based lung cancer screening programme for precision prevention in Chinese populations.
National Natural Science Foundation of China, the Priority Academic Program for the Development of Jiangsu Higher Education Institutions, National Key R&D Program of China, Science Foundation for Distinguished Young Scholars of Jiangsu, and China's Thousand Talents Program.
Silent hypoxia has emerged as a unique feature of coronavirus disease 2019 (COVID-19). In this study, we show that mucins are accumulated in the bronchoalveolar lavage fluid (BALF) of COVID-19 ...patients and are upregulated in the lungs of severe respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected mice and macaques. We find that induction of either interferon (IFN)-β or IFN-γ upon SARS-CoV-2 infection results in activation of aryl hydrocarbon receptor (AhR) signaling through an IDO-Kyn-dependent pathway, leading to transcriptional upregulation of the expression of mucins, both the secreted and membrane-bound, in alveolar epithelial cells. Consequently, accumulated alveolar mucus affects the blood-gas barrier, thus inducing hypoxia and diminishing lung capacity, which can be reversed by blocking AhR activity. These findings potentially explain the silent hypoxia formation in COVID-19 patients, and suggest a possible intervention strategy by targeting the AhR pathway.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Strontium titanite (SrTiO3), which is an experimentally-friendly thermoelectric material, could be a promising candidate for thermoelectric power generation applications. The theorectical study ...indicates the co-doping of La and Nb could enhance the thermoelectric performance, however, the thermoelectric figure of merits (ZTs) of SrTiO3 are still low because the co-doping process at nano-scale is experimentally difficult to control. Here we report a high performance SrTiO3 with La-Nb co-doping, which are prepared by a combination of hydrothermal method and high-efficiency sintering. Nano-scale co-doping is successfully modulated by hydrothermal method, and nano-inclusions precipitate during sintering process, to form complex microstructures. In this case, the electrical and thermal transport properties are optimized simultaneously by doping concentration and dopants type, resulting in a record-high ZT >0.6 at 1000−1100K in the 10mol% La and 10mol% Nb doped SrTiO3 bulk materials. The nano-scale modulation doping and microstructure controlling approach validated in the present study should be also applicable for other thermoelectric materials.
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•Nb-La-doped SrTiO3 nano powders were successfully synthesized by the hydrothermal method.•The nano-inclusions and second phases precipitated from matrix to form a complex micro and electron structure.•Record-high ZTs >0.6 at 1000–1100K were obtained in La-Nb-doped SrTiO3 bulks.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Saliva sampling is a non‐invasive method, and could be performed by donors themselves. However, there are few studies reporting biomarkers in saliva in the diagnosis of NPC. A total of 987 salivary ...samples were used in this study. First, EBV DNA methylation was profiled by capture sequencing in the discovery cohort (n = 36). Second, a q‐PCR based method was developed and five representative EBV DNA CpG sites (11 029 bp, 45 849 bp, 57 945 bp, 66 226 bp and 128 102 bp) were selected and quantified to obtain the methylated density in the validation cohort1 (n = 801). Third, a validation cohort2 (n = 108) was used to further verify the differences of EBV methylation in saliva. A significant increase of EBV methylation was found in NPC patients compared with controls. The methylated score of EBV genome obtained by capture sequencing could distinguish NPC from controls (sensitivity 90%, specificity 100%). Further, the methylated density of EBV DNA CpG sites revealed by q‐PCR showed a good diagnostic performance. The sensitivity and specificity of detecting a single CpG site (11 029 bp) could reach 75.4% and 99.7% in the validation cohort1, and 78.2% and 100% in the validation cohort2. Besides, the methylated density of the CpG site was found to decrease below the COV in NPC patients after therapy, and increase above the COV after recurrence. Our study provides an appealing alternative for the non‐invasive detection of NPC without clinical setting. It paves the way for conducting a home‐based large‐scale screening in the future.
What's new?
While various Epstein‐Barr virus (EBV)‐related biomarkers have been established as potential screening biomarkers for nasopharyngeal carcinoma, most of them rely on blood or nasopharyngeal swab samples. Using saliva samples, this study found a significant increase in EBV DNA methylation in nasopharyngeal carcinoma patients compared to controls. Detection at a single CpG site could reach a sensitivity of 75.8% and specificity of 99.7%. The methylated density of the CpG site was found to decrease below the cut‐off value after therapy and increase above the cut‐off value after recurrence. This study potentially provides a non‐invasive alternative for the detection of nasopharyngeal carcinoma.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Detecting EBV DNA load in nasopharyngeal (NP) brushing samples for the diagnosis of nasopharyngeal carcinoma (NPC) has attracted widespread attentions. Currently, NP brush sampling mostly relies on ...endoscopic guidance, and there are few reports on diagnostic markers suitable for nonguided conditions (blind brush sampling), which is of great significance for extending its application. One hundred seventy nasopharyngeal brushing samples were taken from 98 NPC patients and 72 non‐NPC controls under the guidance of endoscope, and 305 blind brushing samples were taken without endoscopic guidance from 164 NPC patients and 141 non‐NPC controls (divided into discovery and validation sets). Among these, 38 cases of NPC underwent both endoscopy‐guided NP brushing and blind brushing. EBV DNA load targeting BamHI‐W region and EBV DNA methylation targeting 11029 bp CpG site located at Cp‐promoter region were detected by quantitative polymerase chain reaction (q‐PCR). EBV DNA load showed good classification accuracy for NPC in endoscopy‐guided brushing samples (AUC = 0.984). However, in blind bushing samples, the diagnostic performance was greatly reduced (AUC = 0.865). Unlike EBV DNA load, the accuracy of EBV DNA methylation was less affected by brush sampling methods, whether in endoscopy‐guided brushing (AUC = 0.923) or blind brushing (AUC = 0.928 in discovery set and AUC = 0.902 in validation set). Importantly, EBV DNA methylation achieved a better diagnostic accuracy than EBV DNA load in blind brushing samples. Overall, detection of EBV DNA methylation with blind brush sampling shows great potential in the diagnosis of NPC and may facilitate its use in nonclinical screening of NPC.
What's new?
Detection of Epstein‐Barr virus (EBV) DNA load in nasopharyngeal (NP) brush samples is a promising diagnostic tool for nasopharyngeal carcinoma (NPC). Brush sampling, however, typically requires endoscopic guidance, whereas blind brushing, without endoscopy, could facilitate the use of brush sampling for NPC detection. Here, the authors compared methylation markers against EBV DNA load for NPC diagnosis in endoscopy‐guided and nonguided brush samples. Under blind brushing conditions, a qPCR‐based method for detecting EBV DNA methylation outperformed EBV DNA load detection for NPC diagnosis. Blind brushing, combined with EBV DNA methylation detection, could have significant advantages for NPC diagnosis in nonclinical settings.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invades the alveoli, where abundant alveolar macrophages (AMs) reside. How AMs respond to SARS-CoV-2 invasion remains elusive. Here, we ...show that classically activated M1 AMs facilitate viral spread; however, alternatively activated M2 AMs limit the spread. M1 AMs utilize cellular softness to efficiently take up SARS-CoV-2. Subsequently, the invaded viruses take over the endo-lysosomal system to escape. M1 AMs have a lower endosomal pH, favoring membrane fusion and allowing the entry of viral RNA from the endosomes into the cytoplasm, where the virus achieves replication and is packaged to be released. In contrast, M2 AMs have a higher endosomal pH but a lower lysosomal pH, thus delivering the virus to lysosomes for degradation. In hACE2 transgenic mouse model, M1 AMs are found to facilitate SARS-CoV-2 infection of the lungs. These findings provide insights into the complex roles of AMs during SARS-CoV-2 infection, along with potential therapeutic targets.
Background Colorectal cancer (CRC) is the leading cause of cancer death worldwide. Screening is a confirmed way to reduce the incidence and mortality rates of CRC. This study aimed to identify a ...fecal-based, noninvasive, and accurate method for detection of colorectal cancer (CRC) and advanced adenoma (AA). Methods Through detection in tissue (n = 96) and fecal samples (n = 88) and tested in an independent group of fecal samples (n = 294), the methylated DNA marker ITGA4 and bacterial markers Fusobacterium nucleatum (Fn) and Pepetostreptococcusanaerobius (Pa) were identified from the candidate biomarkers for CRC and AA detection. A prediction score (pd-score) was constructed using the selected markers and fecal immunochemical test (FIT) for distinguishing AA and CRC from healthy subjects by logistic regression method. The diagnostic performance of the pd-score was compared with FIT and validated in the external validation cohort (n = 117) and in a large CRC screening cohort. Results The pd-score accurately identified AA and CRC from healthy subjects with an area under the curve (AUC) of 0.958, at a specificity of 91.37%; the pd-score showed sensitivities of 95.38% for CRC and 70.83% for AA, respectively. In the external validation cohort, the sensitivities of the pd-score for CRC and AA detection were 94.03% and 80.00%, respectively. When applied in screening, the pd-score identified 100% (11/11) of CRC and 70.83% (17/24) of AA in participants with both colonoscopy results and qualified fecal samples, showing an improvement by 41.19% compared to FIT. Conclusions The current study developed a noninvasive and well-validated approach for AA and CRC detection, which could be applied widely as a diagnostic and screening test. Keywords: Colorectal cancer, Advanced adenoma, Noninvasive test, Fecal biomarkers, Screening
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Human leukocyte antigen (HLA) molecules are essential for presenting Epstein−Barr virus (EBV) antigens and are closely related to nasopharyngeal carcinoma (NPC). This study aims to systematically ...investigate the association between HLA‐bound EBV peptides and NPC risk through in silico HLA‐peptide binding prediction. A total of 455 NPC patients and 463 healthy individuals in NPC endemic areas were recruited, and HLA‐target sequencing was performed. HLA‐peptide binding prediction for EBV, followed by peptidome‐wide logistic regression and motif analysis, was applied. Binding affinity changes for EBV peptides carrying high‐risk mutations were analyzed. We found that NPC‐associated EBV peptides were significantly enriched in immunogenic proteins and core linkage disequilibrium (LD) proteins related to evolution, especially those binding HLA‐A alleles (p = 3.10 × 10−4 for immunogenic proteins and p = 8.10 × 10−5 for core LD proteins related to evolution). These peptides were clustered and showed binding motifs of HLA supertypes, among which supertype A02 presented an NPC‐risk effect (padj = 3.77 × 10−4) and supertype A03 presented an NPC‐protective effect (padj = 4.89 × 10−4). Moreover, a decreased binding affinity toward risk HLA supertype A02 was observed for the peptide carrying the NPC‐risk mutation BNRF1 V1222I (p = 0.0078), and an increased binding affinity toward protective HLA supertype A03 was observed for the peptide carrying the NPC‐risk mutation BALF2 I613V (p = 0.022). This study revealed the distinct preference of EBV peptides for binding HLA supertypes, which may contribute to shaping EBV population structure and be involved in NPC development.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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