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Reactive oxygen species (ROS) and oxidative stress accelerate cellular aging, but their impact on different tissues varies. The cornea, known for its robust antioxidant defense systems, is relatively resistant to age‐related diseases like cancer. However, the precise mechanisms by which the cornea maintains ROS homeostasis during aging remain unclear. Through comparative single‐cell transcriptomic analysis of the cornea and other tissues in young and old nonhuman primates, we identified that a ZNF281 coding transcriptomic program is specifically activated in cornea during aging. Further investigation revealed that ZNF281 forms a positive feedback loop with FOXO3 to sense elevated levels of ROS and mitigate their effects potentially by regulating the mitochondrial respiratory chain and superoxide dismutase (SOD) expression. Importantly, we observed that overexpression of ZNF281 in MSCs prevented cellular senescence. In summary, these findings open up possibilities for understanding tissue‐specific aging and developing new therapies targeting ROS damage. As cells age, there is an increase in the production of reactive oxygen species (ROS), leading to oxidative stress. ZNF281 and FOXO3 serve as sensors for ROS and mutually enhance their expression levels. Consequently, the elevated expression of ZNF281 and FOXO3 leads to an increase in the expression of antioxidant genes, such as SOD1 and SOD2, while downregulating genes related to oxidative phosphorylation (OXPHOS) in mitochondria and those that govern mitochondrial biogenesis. This coordinated response effectively reduces cellular ROS levels, thereby maintaining cellular homeostasis during the aging process.

Background While human skin aging involves complex transcriptional alterations, the cell‐type‐specific regulatory mechanisms and therapeutic targets remain incompletely defined. The study aims to investigate aging‐associated transcriptional programs and drug‐responsive signatures at single‐cell resolution. Method Here we performed a single‐cell RNA sequencing of young and elder human skin cells and provided a comprehensive analysis of aging‐related genes, a gene regulatory network with immunohistochemistry (IHC) validation, cell–cell interference as well as potential chemical reactions. Result Total 10 distinct cell populations were analyzed based on the scRNA sequencing data. Gene regulatory network analysis showed decreased lactotransferrin gene expression and increased FOSB(+) and DDIT3(+) regulons' regulatory activity. IHC identified the FOSB as an aging‐related transcription factor. Despite uniform MT1 protein distribution across epidermal layers, single‐cell data revealed subcluster‐specific MT1 mRNA dynamics linked to metal ion homeostasis. Drug response prediction experiments revealed possible drug targets and potential antiaging drugs for the skin. Conclusion Our data showed the skin cell clusters presented distinct transcriptional signatures during skin aging. We highlighted the versatile expression profiles of metallothionein family genes and identified the aging‐related signature FOSB in the aged skin. We also provided potential target resources for antiaging therapies.

Differentiation of oligodendrocytes (ODs) presents a challenge in regenerative medicine due to their role in various neurological diseases associated with dysmyelination and demyelination. Here, we designed a peptide derived from vitronectin (VN) using in silico docking simulation and examined its use as a synthetic substrate to support the differentiation of ODs derived from human pluripotent stem cells. The designed peptide, named VNP2, promoted OD differentiation induced by the overexpression of SOX10 in OD precursor cells compared with Matrigel and full-length VN. ODs differentiated on VNP2 exhibited greater contact with axon-mimicking nanofibers than those differentiated on Matrigel. Transcriptomic analysis revealed that the genes associated with morphogenesis, cytoskeleton remodeling, and OD differentiation were upregulated in cells grown on VNP2 compared with cells grown on Matrigel. This new synthetic VN-derived peptide can be used to develop a culture environment for efficient OD differentiation.

Triple‐negative breast cancer (TNBC) liver metastasis is associated with poor prognosis and low patient survival. It occurs when tumor cells disseminate from primary tumors, circulate in blood/lymph [circulating tumor cells (CTCs)], and acquire distinct characteristics during disease progression toward the metastatic phenotype. The purpose of this study was to decipher the genomic/transcriptomic properties of TNBC liver metastasis and its recurrence for potential therapeutic targeting. We employed a negative depletion strategy to isolate and interrogate CTCs from the blood of patients with TNBC, and to establish sequential generations of CTC‐derived xenografts (CDXs) through injection of patient CTCs in immunodeficient mice. The isolation and validation of CDX‐derived cell populations [analyses of CTCs were paired with bone marrow‐resident cells (BMRTCs) and liver tissue cells obtained from the same animal] were performed by multiparametric flow cytometry, immune phenotyping, and genomic sequencing of putative CTCs. Comprehensive characterization of gene expression arrays from sequentially generated CDX‐derived cell populations, online gene expression arrays, and TCGA databases were employed to discover a CTC‐driven, liver metastasis‐associated TNBC signature. We discovered a distinct transcriptomic signature of TNBC patient‐isolated CTCs from primary TNBCs, which was consistent throughout sequential CDX modeling. We established a novel TNBC liver metastasis‐specific CDX model that selectively recapitulates CTC biology for four sequential generations of mice. The evaluation of online databases and CDX‐derived populations revealed 597 genes specific to the TNBC liver metastasis signatures. Further investigation of the TNBC liver metastasis signature predicted 16 hub genes, 6 biomarkers with clinically available drugs, and 22 survival genes. The sequential interrogation of CDX‐CTCs is an innovative liquid biopsy‐based approach for the discovery of organ metastasis‐specific signatures of CTCs. This represents the first step for mechanistic and analytical validation in their application as prognostic indicators and therapeutic targets. Targeting CTC drug candidate biomarkers along with combination therapy can improve the clinical outcome of TNBC patients in general and recurrence of liver metastasis in particular. This study provides the first evidence proving that sequential generation of circulating tumor cell xenografts (CDXs) and CTC interrogation in triple‐negative breast cancer (TNBC) patients can identify CTC signatures and biomarkers to predict TNBC liver metastasis. Extrapolation of CDX modeling to other cancer types and its mechanistic and analytical validation will have prognostic and therapeutic relevance for discovery of biomarkers to treat target organ‐specific metastasis.

Nearly 3 million people worldwide are coinfected with HIV and HCV. Affordable strategies for prevention are needed. We developed a novel vaccination regimen involving replication-defective and serologically distinct chimpanzee adenovirus (ChAd3, ChAd63) vector priming followed by modified vaccinia Ankara (MVA) boosts, for simultaneous delivery of HCV non-structural (NSmut) and HIV-1 conserved (HIVconsv) region immunogens. We conducted a phase I trial in which 33 healthy volunteers were sequentially enrolled and vaccinated via the intramuscular route as follows: 9 received ChAd3-NSmut [2.5 × 10 vp] and MVA-NSmut [2 × 10 pfu] at weeks 0 and 8, respectively; 8 received ChAdV63.HIVconsv [5 × 10 vp] and MVA.HIVconsv [2 × 10 pfu] at the same interval; 16 were co-primed with ChAd3-NSmut [2.5 × 10 vp] and ChAdV63.HIVconsv [5 × 10 vp] followed at week 8 by MVA-NSmut and MVA.HIVconsv [both 1 × 10 pfu]. Immunogenicity was assessed using peptide pools in ELISpot and intracellular cytokine assays. Vaccine-induced whole blood transcriptome changes were assessed by microarray analysis. All vaccines were well tolerated and no vaccine-related serious adverse events occurred. Co-administration of the prime-boost vaccine regimens induced high magnitude and broad T cell responses that were similar to those observed following immunization with either regimen alone. Median (interquartile range, IQR) peak responses to NSmut were 3,480 (2,728-4,464) and 3,405 (2,307-7,804) spot-forming cells (SFC)/10 PBMC for single and combined HCV vaccinations, respectively ( = 0.8). Median (IQR) peak responses to HIVconsv were 1,305 (1,095-4,967) and 1,005 (169-2,482) SFC/10 PBMC for single and combined HIV-1 vaccinations, respectively ( = 0.5). Responses were maintained above baseline to 34 weeks post-vaccination. Intracellular cytokine analysis indicated that the responding populations comprised polyfunctional CD4 and CD8 T cells. Canonical pathway analysis showed that in the single and combined vaccination groups, pathways associated with antiviral and innate immune responses were enriched for upregulated interferon-stimulated genes 24 h after priming and boosting vaccinations. Serologically distinct adenoviral vectors encoding HCV and HIV-1 immunogens can be safely co-administered without reducing the immunogenicity of either vaccine. This provides a novel strategy for targeting these viruses simultaneously and for other pathogens that affect the same populations. https://clinicaltrials.gov, identifier: NCT02362217.

Background Skeletal muscle atrophy manifests across numerous diseases; however, the extent of similarities/differences in causal mechanisms between atrophying conditions in unclear. Ageing and disuse represent two of the most prevalent and costly atrophic conditions, with resistance exercise training (RET) being the most effective lifestyle countermeasure. We employed gene‐level and network‐level meta‐analyses to contrast transcriptomic signatures of disuse and RET, plus young and older RET to establish a consensus on the molecular features of, and therapeutic targets against, muscle atrophy in conditions of high socio‐economic relevance. Methods Integrated gene‐level and network‐level meta‐analysis was performed on publicly available microarray data sets generated from young (18–35 years) m. vastus lateralis muscle subjected to disuse (unilateral limb immobilization or bed rest) lasting ≥7 days or RET lasting ≥3 weeks, and resistance‐trained older (≥60 years) muscle. Results Disuse and RET displayed predominantly separate transcriptional responses, and transcripts altered across conditions were mostly unidirectional. However, disuse and RET induced directly inverted expression profiles for mitochondrial function and translation regulation genes, with COX4I1, ENDOG, GOT2, MRPL12, and NDUFV2, the central hub components of altered mitochondrial networks, and ZMYND11, a hub gene of altered translation regulation. A substantial number of genes (n = 140) up‐regulated post‐RET in younger muscle were not similarly up‐regulated in older muscle, with young muscle displaying a more pronounced extracellular matrix (ECM) and immune/inflammatory gene expression response. Both young and older muscle exhibited similar RET‐induced ubiquitination/RNA processing gene signatures with associated PWP1, PSMB1, and RAF1 hub genes. Conclusions Despite limited opposing gene profiles, transcriptional signatures of disuse are not simply the converse of RET. Thus, the mechanisms of unloading cannot be derived from studying muscle loading alone and provides a molecular basis for understanding why RET fails to target all transcriptional features of disuse. Loss of RET‐induced ECM mechanotransduction and inflammatory profiles might also contribute to suboptimal ageing muscle adaptations to RET. Disuse and age‐dependent molecular candidates further establish a framework for understanding and treating disuse/ageing atrophy.

Background High-throughput transcriptomic datasets are often examined to discover new actors and regulators of a biological response. To this end, graphical interfaces have been developed and allow a broad range of users to conduct standard analyses from RNA-seq data, even with little programming experience. Although existing solutions usually provide adequate procedures for normalization, exploration or differential expression, more advanced features, such as gene clustering or regulatory network inference, often miss or do not reflect current state of the art methodologies. Results We developed here a user interface called DIANE (Dashboard for the Inference and Analysis of Networks from Expression data) designed to harness the potential of multi-factorial expression datasets from any organisms through a precise set of methods. DIANE interactive workflow provides normalization, dimensionality reduction, differential expression and ontology enrichment. Gene clustering can be performed and explored via configurable Mixture Models, and Random Forests are used to infer gene regulatory networks. DIANE also includes a novel procedure to assess the statistical significance of regulator-target influence measures based on permutations for Random Forest importance metrics. All along the pipeline, session reports and results can be downloaded to ensure clear and reproducible analyses. Conclusions We demonstrate the value and the benefits of DIANE using a recently published data set describing the transcriptional response of Arabidopsis thaliana under the combination of temperature, drought and salinity perturbations. We show that DIANE can intuitively carry out informative exploration and statistical procedures with RNA-Seq data, perform model based gene expression profiles clustering and go further into gene network reconstruction, providing relevant candidate genes or signalling pathways to explore. DIANE is available as a web service ( https://diane.bpmp.inrae.fr ), or can be installed and locally launched as a complete R package.

Background： Chronic intermittent hypoxia is the most remarkable feature of obstructive sleep apnea/hypopnea syndrome and it can induce the change of hypoxia-inducible factor-1α （H IF-1α） expression and contractile properties in the genioglossus. To clarify the role of HIF-lot in contractile properties of the genioglossus, this study generated and compared high-throughput RNA-sequencing data from genioglossus between HIF-1α conditional knockout （KO） mice and littermate wild-type （WT） mice. Methods： KO mice were generated with cre-loxP strategy. Gene expression profile analysis was performed using gene enrichment analysis. Gene ontology （GO） and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway analyses of differently expressed messenger RNAs were performed to identify the related pathways and biological lhnctions. Six differentially expressed genes （DEGs） were validated by qualitative reverse transcription polymerase chain reaction. Results： A total of 142 （77 upregulated and 65 downregulated） transcripts were found to exhibit statistically significant difference between the HIF-la-KO and WT mice. GO and KEGG analyses indicated that DEGs included genes involved in ＂skeletal muscle cell differentiation,＂ ＂muscle organ development,＂ ＂glucose metabolic process,＂ ＂glycogen biosynthetic and metabolic process,＂ etc. Conclusion： This study might provide evidence that H IF-lot affects the expression of multiple genes involved in the myogenesis, muscle developrnent, and carbohydrate metabolism through transcriptome analysis in conditional HIE-1α-KO mice.

Glioblastoma (GBM), with its high recurrence and mortality rates, makes it the deadliest neurological malignancy. Oxidative phosphorylation is a highly active cellular pathway in GBM, and NFYB is a tumor-associated transcription factor. Both are related to mitochondrial function, but studies on their relationship with GBM at the single-cell level are still scarce. We re-analyzed the single-cell profiles of GBM from patients with different subtypes by single-cell transcriptomic analysis and further subdivided the large population of Glioma cells into different subpopulations, explored the interrelationships and active pathways among cell stages and clinical subtypes of the populations, and investigated the relationship between the transcription factor NFYB of the key subpopulations and GBM, searching for the prognostic genes of GBM related to NFYB, and verified by experiments. Glioma cells and their C5 subpopulation had the highest percentage of G2M staging and rGBM, which we hypothesized might be related to the higher dividing and proliferating ability of both Glioma and C5 subpopulations. Oxidative phosphorylation pathway activity is elevated in both the Glioma and C5 subgroup, and NFYB is a key transcription factor for the C5 subgroup, suggesting its possible involvement in GBM proliferation and recurrence, and its close association with mitochondrial function. We also identified 13 prognostic genes associated with NFYB, of which MEM60 may cause GBM patients to have a poor prognosis by promoting GBM proliferation and drug resistance. Knockdown of the NFYB was found to contribute to the inhibition of proliferation, invasion, and migration of GBM cells. These findings help to elucidate the key mechanisms of mitochondrial function in GBM progression and recurrence, and to establish a new prognostic model and therapeutic target based on NFYB.

Neighbor detection and allelochemical response are important mediators in plant–plant interactions. Although there is increasing knowledge about plant allelochemicals released in response to the presence of competitors and involved in neighbor-derived signaling, less is known about which signaling chemicals are responsible for the neighborinduced allelochemical response. Here, we experimentally demonstrate that (−)-loliolide, a carotenoid metabolite, acts as a signaling chemical in barnyardgrass–rice allelopathic interactions. The production of the rice allelochemicals momilactone B and tricin was increased in the presence of five biotypes of barnyardgrass. (−)-Loliolide was found in all the biotypes of barnyardgrass and their root exudates and rhizosphere soils. There were significant positive relationships between rice allelochemicals and (−)-loliolide concentrations across the biotypes of barnyardgrass. Furthermore, (−)-loliolide elicited the production of momilactone B and tricin. Comparative transcriptomic analysis revealed regulatory activity of (−)-loliolide on the diterpenoid and flavonoid biosynthesis pathway. The expression of key genes involved in the biosynthesis of momilactone B (CPS4, KSL4, and MAS) and tricin (CYP75B3 and CYP75B4) was up-regulated by (−)-loliolide. These findings suggest that (−)-loliolide acts as a signaling chemical and participates in barnyardgrass-rice allelopathic interactions. Allelopathic rice plants can detect competing barnyardgrass through the presence of this signaling chemical and respond by increasing levels of their allelochemicals to achieve an advantage for their own growth.