Although clinical studies have shown promise for targeting programmed cell death protein-1 (PD-1) and ligand (PD-L1) signaling in non-small cell lung cancer (NSCLC), the factors that predict which subtype patients will be responsive to checkpoint blockade are not fully understood. We performed an integrated analysis on the multiple-dimensional data types including genomic, transcriptomic, proteomic, and clinical data from cohorts of lung adenocarcinoma public (discovery set) and internal (validation set) database and immunotherapeutic patients. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups. We observed that mutation significantly increased expression of immune checkpoints and activated T-effector and interferon-γ signature. More importantly, the comutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of Meanwhile, or -mutated tumors showed prominently increased mutation burden and specifically enriched in the transversion-high (TH) cohort. Further analysis focused on the potential molecular mechanism revealed that or mutation altered a group of genes involved in cell-cycle regulating, DNA replication and damage repair. Finally, immunotherapeutic analysis from public clinical trial and prospective observation in our center were further confirmed that or mutation patients, especially those with co-occurring mutations, showed remarkable clinical benefit to PD-1 inhibitors. This work provides evidence that and mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding anti-PD-1/PD-L1 immunotherapy. .

In this paper, we report a facile ultrasonic method to synthesize well-dispersed CoO quantum dots (3-8 nm) on graphene nanosheets at room temperature by employing Co(4)(CO)(12) as cobalt precursor. The prepared CoO/graphene composites displayed high performance as an anode material for lithium-ion battery, such as high reversible lithium storage capacity (1592 mAh g(-1) after 50 cycles), high Coulombic efficiency (over 95%), excellent cycling stability, and high rate capability (1008 mAh g(-1) with a total retention of 77.6% after 50 cycles at a current density of 1000 mA g(-1), dramatically increased from the initial 50 mA g(-1)). The extraordinary performance arises from the structure advantages of the composites: the nanosized CoO quantum dots with high dispersity on conductive graphene substrates supply not only large quantity of accessible active sites for lithium-ion insertion but also good conductivity and short diffusion length for lithium ions, which are beneficial for high capacity and rate capability. Meanwhile, the isolated CoO quantum dots anchored tightly on the graphene nanosheets can effectively circumvent the volume expansion/contraction associated with lithium insertion/extraction during discharge/charge processes, which is good for high capacity as well as cycling stability. Moreover, regarding the anomalous behavior of capacity increase with cycles (activation effect) observed, we proposed a tentative hypothesis stressing the competition between the conductivity increase and the amorphorization of the composite electrodes during cycling in determining the trends of the capacity, in the hope to gain a fuller understanding of the inner working of the novel nanostructured electrode-based lithium-ion batteries.

Patients with mutations showed unfavorable response to programmed cell death-1 (PD-1) blockade immunotherapy in non-small cell lung cancer (NSCLC). Yet the underlying association between mutation and immune resistance remains largely unclear. We performed an integrated analysis of PD-ligand 1(PD-L1)/CD8 expression and mutation profile based on the repository database and resected early-stage NSCLC in Guangdong Lung Cancer Institute (GLCI). Meanwhile, 2 pool-analyses were set to clarify the correlation between mutation and PD-L1 expression, and the association of status with response to anti-PD-1/L1 therapy. Pool-analysis of 15 public studies suggested that patients with mutations had decreased PD-L1 expression (odds ratio: 1.79, 95% CI: 1.10-2.93; P = 0.02). Analysis of The Cancer Genome Atlas (TCGA) and the GCLI cohort confirmed the inverse correlation between mutation and PD-L1 expression. Furthermore, patients with mutation showed a lack of T-cell infiltration and shrinking proportion of PD-L1/CD8 TIL (P = 0.034). Importantly, patients with mutations, especially the sensitive subtype, showed a significantly decreased mutation burden, based on analysis of the discovery and validation sets. Finally, a pool-analysis of 4 randomized control trials confirmed that patients with mutation did not benefit from PD-1/L1 inhibitors (Hazard ratio [HR] = 1.09, P = 0.51) while patients with wild-type did (HR = 0.73, P< 0.00001). This study provided evidence of a correlation between mutations and an uninflamed tumor microenvironment with immunological tolerance and weak immunogenicity, which caused an inferior response to PD-1 blockade in NSCLCs.

Graphical Abstract Highlights d Genome sequencing from low-pass noninvasive prenatal testing samples d GWAS of 141,431 low-pass genomes reveals 16 unknown genetic associations d Patterns of clinically relevant viral infection in maternal plasma d Insights into the genetic structure and history of the Chinese population SUMMARYWe analyze whole-genome sequencing data from 141,431 Chinese women generated for non-invasive prenatal testing (NIPT). We use these data to characterize the population genetic structure and to investigate genetic associations with maternal and infectious traits. We show that the present day distribution of alleles is a function of both ancient migration and very recent population movements. We reveal novel phenotype-genotype associations, including several replicated associations with height and BMI, an association between maternal age and EMB, and between twin pregnancy and NRG1. Finally, we identify a unique pattern of circulating viral DNA in plasma with high prevalence of hepatitis B and other clinically relevant maternal infections. A GWAS for viral infections identifies an exceptionally strong association between integrated herpesvirus 6 and MOV10L1, which affects piwi-interacting RNA (piRNA) processing and PIWI protein function. These findings demonstrate the great value and potential of accumulating NIPT data for worldwide medical and genetic analyses. BLAST Sayers et al., 2009 https://blast.ncbi.nlm.nih.gov/Blast.cgi

Building a population-specific catalogue of single nucleotide variants (SNVs), indels and structural variants (SVs) with frequencies, termed a national pan-genome, is critical for further advancing clinical and public health genetics in large cohorts. Here we report a Danish pan-genome obtained from sequencing 10 trios to high depth (50 × ). We report 536k novel SNVs and 283k novel short indels from mapping approaches and develop a population-wide de novo assembly approach to identify 132k novel indels larger than 10 nucleotides with low false discovery rates. We identify a higher proportion of indels and SVs than previous efforts showing the merits of high coverage and de novo assembly approaches. In addition, we use trio information to identify de novo mutations and use a probabilistic method to provide direct estimates of 1.27e−8 and 1.5e−9 per nucleotide per generation for SNVs and indels, respectively.

The COVID-19 pandemic has accounted for millions of infections and hundreds of thousand deaths worldwide in a short-time period. The patients demonstrate a great diversity in clinical and laboratory manifestations and disease severity. Nonetheless, little is known about the host genetic contribution to the observed interindividual phenotypic variability. Here, we report the first host genetic study in the Chinese population by deeply sequencing and analyzing 332 COVID-19 patients categorized by varying levels of severity from the Shenzhen Third People’s Hospital. Upon a total of 22.2 million genetic variants, we conducted both single-variant and gene-based association tests among five severity groups including asymptomatic, mild, moderate, severe, and critical ill patients after the correction of potential confounding factors. Pedigree analysis suggested a potential monogenic effect of loss of function variants in GOLGA3 and DPP7 for critically ill and asymptomatic disease demonstration. Genome-wide association study suggests the most significant gene locus associated with severity were located in TMEM189–UBE2V1 that involved in the IL-1 signaling pathway. The p.Val197Met missense variant that affects the stability of the TMPRSS2 protein displays a decreasing allele frequency among the severe patients compared to the mild and the general population. We identified that the HLA-A*11:01, B*51:01, and C*14:02 alleles significantly predispose the worst outcome of the patients. This initial genomic study of Chinese patients provides genetic insights into the phenotypic difference among the COVID-19 patient groups and highlighted genes and variants that may help guide targeted efforts in containing the outbreak. Limitations and advantages of the study were also reviewed to guide future international efforts on elucidating the genetic architecture of host–pathogen interaction for COVID-19 and other infectious and complex diseases.

The pathogenesis of osteoarthritis (OA) is poorly understood, and therapeutic approaches are limited to preventing progression of the disease. Recent studies have shown that exosomes play a vital role in cell-to-cell communication, and pathogenesis of many age-related diseases. Molecular profiling of synovial fluid derived exosomal miRNAs may increase our understanding of OA progression and may lead to the discovery of novel biomarkers and therapeutic targets. In this article we report the first characterization of exosomes miRNAs from human synovial fluid. The synovial fluid exosomes share similar characteristics (size, surface marker, miRNA content) with previously described exosomes in other body fluids. MiRNA microarray analysis showed OA specific exosomal miRNA of male and female OA. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis identified gender-specific target genes/signaling pathways. These pathway analyses showed that female OA specific miRNAs are estrogen responsive and target TLR (toll-like receptor) signaling pathways. Furthermore, articular chondrocytes treated with OA derived extracellular vesicles had decreased expression of anabolic genes and elevated expression of catabolic and inflammatory genes. In conclusion, synovial fluid exosomal miRNA content is altered in patients with OA and these changes are gender specific.

Two-dimensional (2D) materials and ultrathin nanosheets are advantageous for elevating the catalysis performance and elucidating the catalysis mechanism of heterogeneous catalysts, but they are mostly restricted to inorganic or organic materials based on covalent bonds. We report an electrochemical/chemical exfoliation strategy for synthesizing metal-organic 2D materials based on coordination bonds. A catechol functionalized ligand is used as the redox active pillar to construct a pillared-layer framework. When the 3D pillared-layer MOF serves as an electrocatalyst for water oxidation (pH 13), the pillar ligands can be oxidized in situ and removed. The remaining ultrathin (2 nm) nanosheets of the metal-organic layers are an efficient catalyst with overpotentials as low as 211 mV at 10 mA cm and a turnover frequency as high as 30 s at an overpotential of 300 mV.