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Abstract Background Late-onset Alzheimer’s disease (LOAD) is the most common form of dementia; it disproportionally affects women in terms of both incidence rates and severity of progression. The cellular and molecular mechanisms underlying this clinical phenomenon remain elusive and ill-defined. Methods In-depth analyses were performed with multiple human LOAD single-nucleus transcriptome datasets to thoroughly characterize cell populations in the cerebral cortex. ROSMAP bulk human brain tissue transcriptome and DNA methylome datasets were also included for validation. Detailed assessments of microglial cell subpopulations and their relevance to sex-biased changes at the tissue level were performed. Clinical trait associations, cell evolutionary trajectories, and transcription regulon analyses were conducted. Results The relative numbers of functionally defective microglia were aberrantly increased uniquely among affected females. Substratification of the microglia into different subtypes according to their transcriptomic signatures identified a group of female-enriched and disease-associated microglia (FDAMic), the numbers of which were positively associated with disease severity. Phenotypically, these cells exhibit transcriptomic signatures that support active proliferation, MHC class II autoantigen presentation and amyloid-β binding, but they are also likely defective in phagocytosis. FDAMic are likely evolved from female activated response microglia (ARMic) with an APOE4 background and compromised estrogen receptor (ER) signaling that is deemed to be active among most subtypes of microglia. Conclusion This study offered important insights at both the cellular and molecular levels into how ER signaling affects microglial heterogeneity and function. FDAMic are associated with more advanced pathologies and severe trends of cognitive decline. Their emergence could, at least in part, explain the phenomenon of greater penetrance of the APOE4 genotype found in females. The biases of FDAMic emergence toward female sex and APOE4 status may also explain why hormone replacement therapy is more effective in APOE4 carriers. The pathologic nature of FDAMic suggests that selective modulations of these cells may help to regain brain neuroimmune homeostasis, serving as a new target for future drug development.

Background. Growing evidence has revealed that m6A modification of long noncoding RNAs (lncRNAs) dynamically controls tumor stemness and tumorigenesis-related processes. However, the prognostic significance of m6A-related lncRNAs and their associations with stemness in low-grade glioma (LGG) remain to be clarified. Methods. A multicenter transcriptome analysis of lncRNA expression in 1,247 LGG samples was performed in this study. The stemness landscape of LGG tumors was presented and associations with clinical features were revealed. The m6A-related lncRNAs were identified between stemness groups and were further prioritized via least absolute shrinkage and selection operator Cox regression analysis. A risk score model based on m6A-related lncRNAs was constructed and validated in external LGG datasets. Results. Based on the expression of LINC02984, PFKP-DT, and CRNDE, a risk model and nomogram were constructed; they successfully predicted the survival of patients and were extended to external datasets. Significant correlations were observed between the risk score and tumor stemness. Moreover, patients in different risk groups exhibited distinct tumor immune microenvironments and immune signatures. We finally provided several potential compounds suitable for specific risk groups, which may aid in LGG treatment. Conclusions. This novel signature presents noteworthy value in the prediction of prognosis and stemness status for LGG patients and will foster future research on the development of clinical regimens.

Abstract Background Forkhead box (FOX) proteins belong to one of the largest transcription factor families and play crucial roles in the initiation and progression of cancer. Prior research has linked several FOX genes, such as FOXA1 and FOXM1, to the crucial process of carcinogenesis. However, the overall picture of FOX gene family across human cancers is far from clear. Methods To investigate the broad molecular signatures of the FOX gene family, we conducted study on multi‐omics data (including genomics, epigenomics and transcriptomics) from over 11,000 patients with 33 different types of human cancers. Results Pan‐cancer analysis reveals that FOX gene mutations were found in 17.4% of tumor patients with a substantial cancer type‐dependent pattern. Additionally, high expression heterogeneity of FOX genes across cancer types was discovered, which can be partially attributed to the genomic or epigenomic alteration. Co‐expression network analysis reveals that FOX genes may exert functions by regulating the expression of both their own and target genes. For a clinical standpoint, we provided 103 FOX gene‐drug target‐drug predictions and found FOX gene expression have potential survival predictive value. All of the results have been included in the FOX2Cancer database, which is freely accessible at http://hainmu‐biobigdata.com/FOX2Cancer. Conclusion Our findings may provide a better understanding of roles FOX genes played in the development of tumors, and help to offer new avenues for uncovering tumorigenesis and unprecedented therapeutic targets.

Abstract Background N6‐methyladenosine (m6A) plays an essential role in tumorigenesis and cancer progression. Long noncoding RNAs (lncRNAs) are discovered to be important targets of m6A modification, and they play fundamental roles in diverse biological processes. However, there is still a lack of knowledge with regards to the association between m6A and lncRNAs in human tumors. Methods The relationship between lncRNAs and 21 m6A regulators was comprehensively explored, through the integration of multi‐omics data from M6A2Target, m6A‐Atlas, and TCGA (The Cancer Genome Atlas). In order to explore the potential roles of m6A‐related lncRNAs in human tumors, three applicable methods were introduced, which include the construction of ceRNA networks, drug sensitivity estimation, and survival analysis. Results A substantial number of positive correlation events across 33 cancer types were found. Moreover, cancer‐specific lncRNAs were associated with tissue specificity, and cancer‐common lncRNAs were conserved in cancer‐related biological function. In particular, the m6A‐related lncRNA FGD5‐AS1 was found to be associated with cancer treatment, through its influence on cisplatin resistance in breast cancer patients. Finally, a user‐friendly interface Lnc2m6A, which is enriched with various browsing sections resource for the exhibition of relationships and putative biogenesis between lncRNAs and m6A modifications, is offered in http://hainmu‐biobigdata.com/Lnc2m6A. Conclusions In summary, the results from this paper will provide a valuable resource that guides both mechanistic and therapeutic roles of m6A‐related lncRNAs in human tumors.

Background: Myopia is a good model for understanding the interaction between genetics and environmental stimuli. Here we dissect the biological processes affecting myopia progression. Methods: Human Genetic Analyses: (1) gene set analysis (GSA) of new genome wide association study (GWAS) data for 593 individuals with high myopia (refraction ≤ -6 diopters [D]); (2) over-representation analysis (ORA) of 196 genes with de novo mutations, identified by whole genome sequencing of 45 high-myopia trio families, and (3) ORA of 284 previously reported myopia risk genes. Contributions of the enriched signaling pathways in mediating the genetic and environmental interactions during myopia development were investigated in vivo and in vitro. Results: All three genetic analyses showed significant enrichment of four KEGG signaling pathways, including amphetamine addiction, extracellular matrix (ECM) receptor interaction, neuroactive ligand-receptor interaction, and regulation of actin cytoskeleton pathways. In individuals with extremely high myopia (refraction ≤ -10 D), the GSA of GWAS data revealed significant enrichment of the HIF-1α signaling pathway. Using human scleral fibroblasts, silencing the key nodal genes within protein-protein interaction networks for the enriched pathways antagonized the hypoxia-induced increase in myofibroblast transdifferentiation. In mice, scleral HIF-1α downregulation led to hyperopia, whereas upregulation resulted in myopia. In human subjects, near work, a risk factor for myopia, significantly decreased choroidal blood perfusion, which might cause scleral hypoxia. Interpretation: Our study implicated the HIF-1α signaling pathway in promoting human myopia through mediating interactions between genetic and environmental factors. Funding: National Natural Science Foundation of China grants; Natural Science Foundation of Zhejiang Province.

Ethanol is the most extensively used oxygenate for spark ignition (SI) engines. In comparison with ethanol, n-butanol exhibits a number of desirable properties for use in SI engines, which has proved to be a very promising oxygenated alternative fuel in recent years. However, the dehydration and recovery of bio-n-butanol consume extra money and energy in the acetone-n-butanol-ethanol (ABE) fermentation process. Hence, we focus on the research of ABE as a potential oxygenated alternative fuel in SI engines. The combustion, performance, and emission characteristics of B30, E30, ABE30 (i.e., 30 vol.% n-butanol, ethanol, and ABE blended with 70 vol.% gasoline), and G100 (pure gasoline) were compared in this study. The comparison results between B30, E30, and ABE30 at stoichiometric conditions show that ABE30 presents retarded combustion phasing, higher brake thermal efficiency, lower CO emissions, higher UHC emissions, and similar NOx emissions. In comparison with G100 under various engine loads and equivalence ratios, for the most part, ABE30 exhibits 1.4% higher brake thermal efficiency, 14% lower carbon monoxide, 9.7% lower unburned hydrocarbons, and 23.4% lower nitrogen oxides. It is indicated that ABE could be served as the oxygenate in spark ignition engine due to its capability to improve energy efficiency and reduce pollutant emissions.