A revisiting of "the hallmarks of aging" in domestic dogs: current status of the literature.

A progressive decline in biological function and fitness is, generally, how aging is defined. However, in 2013, a description on the "hallmarks of aging" in mammals was published, and within it, it described biological processes that are known to alter the aging phenotype. These include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication (inflammation), and changes within the microbiome. This mini-review provides a detailed account of the progress on each of these hallmarks of aging in the domestic dog within the last 5 years. Additionally, when there are gaps in the literature between other mammalian species and dogs, I highlight the aging biomarkers that may be missing for dogs as aging models. I also argue for the importance of dog aging studies to include several breeds of dogs at differing ages and for age corrections for breeds with differing mean lifespans throughout.

Discovery of a Potent Deubiquitinase (DUB) Small-Molecule Activity-Based Probe Enables Broad Spectrum DUB Activity Profiling in Living Cells.

Deubiquitinases (DUBs) are a family of >100 proteases that hydrolyze isopeptide bonds linking ubiquitin to protein substrates, often leading to reduced substrate degradation through the ubiquitin proteasome system. Deregulation of DUB activity has been implicated in many diseases, including cancer, neurodegeneration and auto-inflammation, and several have been recognized as attractive targets for therapeutic intervention. Ubiquitin-derived covalent activity-based probes (ABPs) provide a powerful tool for DUB activity profiling, but their large recognition element impedes cellular permeability and presents an unmet need for small molecule ABPs which can account for regulation of DUB activity in intact cells or organisms. Here, through comprehensive chemoproteomic warhead profiling, we identify cyanopyrrolidine (CNPy) probe IMP-2373 (12) as a small molecule pan-DUB ABP to monitor DUB activity in physiologically relevant live cells. Through proteomics and targeted assays, we demonstrate that IMP-2373 quantitatively engages more than 35 DUBs across a range of non-toxic concentrations in diverse cell lines. We further demonstrate its application to quantification of changes in intracellular DUB activity during pharmacological inhibition and during MYC deregulation in a model of B cell lymphoma. IMP-2373 thus offers a complementary tool to ubiquitin ABPs to monitor dynamic DUB activity in the context of disease-relevant phenotypes.

Are the integrin binding motifs within SARS CoV-2 spike protein and MHC class II alleles playing the key role in COVID-19?

The previous studies on the RGD motif (aa403-405) within the SARS CoV-2 spike (S) protein receptor binding domain (RBD) suggest that the RGD motif binding integrin(s) may play an important role in infection of the host cells. We also discussed the possible role of two other integrin binding motifs that are present in S protein: LDI (aa585-587) and ECD (661-663), the motifs used by some other viruses in the course of infection. The MultiFOLD models for protein structure analysis have shown that the ECD motif is clearly accessible in the S protein, whereas the RGD and LDI motifs are partially accessible. Furthermore, the amino acids that are present in Epstein-Barr virus protein (EBV) gp42 playing very important role in binding to the HLA-DRB1 molecule and in the subsequent immune response evasion, are also present in the S protein heptad repeat-2. Our MultiFOLD model analyses have shown that these amino acids are clearly accessible on the surface in each S protein chain as monomers and in the homotrimer complex and bind to HLA-DRB1 ß chain. Therefore, they may have the identical role in SARS CoV-2 immune evasion as in EBV infection. The prediction analyses of the MHC class II binding peptides within the S protein have shown that the RGD motif is present in the core 9-mer peptide IRGDEVRQI within the two HLA-DRB1*03:01 and HLA-DRB3*01.01 strong binding 15-mer peptides suggesting that RGD motif may be the potential immune epitope. Accordingly, infected HLA-DRB1*03:01 or HLA-DRB3*01.01 positive individuals may develop high affinity anti-RGD motif antibodies that react with the RGD motif in the host proteins, like fibrinogen, thrombin or von Willebrand factor, affecting haemostasis or participating in autoimmune disorders.

Signatures of Co-Deregulated Genes and Their Transcriptional Regulators in Kidney Cancers.

There are several studies on the deregulated gene expression profiles in kidney cancer, with varying results depending on the tumor histology and other parameters. None of these, however, have identified the networks that the co-deregulated genes (co-DEGs), across different studies, create. Here, we reanalyzed 10 Gene Expression Omnibus (GEO) studies to detect and annotate co-deregulated signatures across different subtypes of kidney cancer or in single-gene perturbation experiments in kidney cancer cells and/or tissue. Using a systems biology approach, we aimed to decipher the networks they form along with their upstream regulators. Differential expression and upstream regulators, including transcription factors [MYC proto-oncogene (MYC), CCAAT enhancer binding protein delta (CEBPD), RELA proto-oncogene, NF-kB subunit (RELA), zinc finger MIZ-type containing 1 (ZMIZ1), negative elongation factor complex member E (NELFE) and Kruppel-like factor 4 (KLF4)] and protein kinases [Casein kinase 2 alpha 1 (CSNK2A1), mitogen-activated protein kinases 1 (MAPK1) and 14 (MAPK14), Sirtuin 1 (SIRT1), Cyclin dependent kinases 1 (CDK1) and 4 (CDK4), Homeodomain interacting protein kinase 2 (HIPK2) and Extracellular signal-regulated kinases 1 and 2 (ERK1/2)], were computed using the Characteristic Direction, as well as GEO2Enrichr and X2K, respectively, and further subjected to GO and KEGG pathways enrichment analyses. Furthermore, using CMap, DrugMatrix and the LINCS L1000 chemical perturbation databases, we highlight putative repurposing drugs, including Etoposide, Haloperidol, BW-B70C, Triamterene, Chlorphenesin, BRD-K79459005 and ß-Estradiol 3-benzoate, among others, that may reverse the expression of the identified co-DEGs in kidney cancers. Of these, the cytotoxic effects of Etoposide, Catecholamine, Cyclosporin A, BW-B70C and Lasalocid sodium were validated in vitro. Overall, we identified critical co-DEGs across different subtypes in kidney cancer, and our results provide an innovative framework for their potential use in the future.

The hypoxia-inducible factor-1α in stemness and resistance to chemotherapy in gastric cancer: Future directions for therapeutic targeting.

Hypoxia-inducible factor-1α (HIF-1α) is a crucial mediator of intra-tumoral heterogeneity, tumor progression, and unresponsiveness to therapy in tumors with hypoxia. Gastric tumors, one of the most aggressive tumors in the clinic, are highly enriched in hypoxic niches, and the degree of hypoxia is strongly correlated with poor survival in gastric cancer patients. Stemness and chemoresistance in gastric cancer are the two root causes of poor patient outcomes. Based on the pivotal role of HIF-1α in stemness and chemoresistance in gastric cancer, the interest in identifying critical molecular targets and strategies for surpassing the action of HIF-1α is expanding. Despite that, the understanding of HIF-1α induced signaling in gastric cancer is far from complete, and the development of efficacious HIF-1α inhibitors bears various challenges. Hence, here we review the molecular mechanisms by which HIF-1α signaling stimulates stemness and chemoresistance in gastric cancer, with the clinical efforts and challenges to translate anti-HIF-1α strategies into the clinic.

Therapeutic strategies of dual-target small molecules to overcome drug resistance in cancer therapy.

Despite some advances in targeted therapeutics of human cancers, curative cancer treatment still remains a tremendous challenge due to the occurrence of drug resistance. A variety of underlying resistance mechanisms to targeted cancer drugs have recently revealed that the dual-target therapeutic strategy would be an attractive avenue. Compared to drug combination strategies, one agent simultaneously modulating two druggable targets generally shows fewer adverse reactions and lower toxicity. As a consequence, the dual-target small molecule has been extensively explored to overcome drug resistance in cancer therapy. Thus, in this review, we focus on summarizing drug resistance mechanisms of cancer cells, such as enhanced drug efflux, deregulated cell death, DNA damage repair, and epigenetic alterations. Based upon the resistance mechanisms, we further discuss the current therapeutic strategies of dual-target small molecules to overcome drug resistance, which will shed new light on exploiting more intricate mechanisms and relevant dual-target drugs for future cancer therapeutics.

What can be Expected from Mergers After Deregulation? The Case of the Long-Distance Bus Industry in France.

This study estimates the competitive effects of horizontal mergers in the French long-distance bus industry. We examine the two mergers that followed the 2015 Deregulation Act (the Macron Law); we use an exclusive and exhaustive dataset that covers eight consecutive quarters. We analyze the merger effects by comparing bus links that were affected by mergers with those that were unaffected; we use difference-in-differences estimations. We find that the two mergers are associated with price increases of about 13.5% immediately that then moderate to 5.3%; and with the frequency decreases from - 21.5 to - 25.7%; we observe no effects on load factors. These findings show evidence of short-run anticompetitive effects, while the mergers under study were not scrutinized by the French competition agency, as they were below the notification thresholds.

Targeting oncogenic transcription factors in skin malignancies: An update on cancer stemness and therapeutic outcomes.

The skin is the largest organ of the human body and prone to various diseases, including cancer; thus, provides the first line of defense against exogenous biological and non-biological agents. Skin cancer, a complex and heterogenic process, with steep incidence rate often metastasizes due to poor understanding of the underlying mechanisms of pathogenesis and clinical challenges. Indeed, accumulating evidence indicates that deregulation of transcription factors (TFs) due to genetic, epigenetic and signaling distortions plays essential role in the development of cutaneous malignancies and therapeutic challenges including cancer stemness features and reprogramming. This review highlights the recent developments exploring underlying mechanisms how deregulated TFs (e.g., NF-κB, AP-1, STAT etc.,) orchestrates cutaneous onco-pathogenesis, reprogramming, stemness and poor clinical outcomes. Along this line, bioactive drugs, and their derivatives from natural and or synthetic origin has gained attention due to their multitargeting potential, potentially safer and effective therapeutic outcome for human malignancies. We also discussed therapeutic importance of targeting aberrantly expressed TFs in skin cancers with bioactive natural products and or synthetic agents.

Signatures of Co-Deregulated Genes and Their Transcriptional Regulators in Lung Cancer.

Despite the significant progress made towards comprehending the deregulated signatures in lung cancer, these vary from study to study. We reanalyzed 25 studies from the Gene Expression Omnibus (GEO) to detect and annotate co-deregulated signatures in lung cancer and in single-gene or single-drug perturbation experiments. We aimed to decipher the networks that these co-deregulated genes (co-DEGs) form along with their upstream regulators. Differential expression and upstream regulators were computed using Characteristic Direction and Systems Biology tools, including GEO2Enrichr and X2K. Co-deregulated gene expression profiles were further validated across different molecular and immune subtypes in lung adenocarcinoma (TCGA-LUAD) and lung adenocarcinoma (TCGA-LUSC) datasets, as well as using immunohistochemistry data from the Human Protein Atlas, before being subjected to subsequent GO and KEGG enrichment analysis. The functional alterations of the co-upregulated genes in lung cancer were mostly related to immune response regulating the cell surface signaling pathway, in contrast to the co-downregulated genes, which were related to S-nitrosylation. Networks of hub proteins across the co-DEGs consisted of overlapping TFs (SOX2, MYC, KAT2A) and kinases (MAPK14, CSNK2A1 and CDKs). Furthermore, using Connectivity Map we highlighted putative repurposing drugs, including valproic acid, betonicine and astemizole. Similarly, we analyzed the co-DEG signatures in single-gene and single-drug perturbation experiments in lung cancer cell lines. In summary, we identified critical co-DEGs in lung cancer providing an innovative framework for their potential use in developing personalized therapeutic strategies.

Enhancing the performance of a deregulated nonlinear integrated power system utilizing a redox flow battery with a self-tuning fractional-order fuzzy controller.

Load frequency regulation is one of the most vital and complex ancillary services in a deregulated power system. Increasing penetration from renewable energy sources in an integrated power system (IPS) further escalates the related control complexity due to a considerable decrement in IPS's effective inertia. This may incur additional costs and can even lead to the destabilization of IPS. To overcome these problems in frequency regulation, this work proposes and investigates the use of an intelligent, direct adaptive control scheme, i.e., self-tuning fractional order fuzzy PID (STFOFPID) controller with and without the presence of a recently devised energy storage unit, i.e., the redox flow battery. The IPS' efficacy with the STFOFPID controller is validated for various contracts in a deregulated operation mode for considered three area IPS. Extensive simulation studies are carried out, and detailed comparative studies have been drawn with conventional PID and fractional order PID controllers for load frequency regulation in Poolco, bilateral, and contract-violation mode of operation. Robustness analysis in terms of parametric variations in different nonlinearities present in a reheated thermal power plant is also carried out, and the efficacy of the STFOFPID controller is established using a thorough quantitative comparative analysis. The real-time digital simulation validation of the investigated control structure has been carried out on OPAL-RT 4150 based on Xilinx Kintex-7 FPGA board with INTEL multi-core processor.

RNA-seq dataset of subcutaneous adipose tissue: Transcriptional differences between obesity and healthy women.

In this data article, we present the dataset from the RNA-Seq analysis of subcutaneous adipose tissue collected from 5 healthy normal weight women (NW, age 37 ± 6.7 years, BMI 24.3 ± 0.9 kg/m2) and 5 obese women (OBF, age 41 ± 12.5 years, BMI 38.2 ± 4.6 kg/m2). Raw data obtained from Illumina NextSeq 500 sequencer were processed through BlueBee® Genomics Platform while differential expression analysis was performed with the DESeq2 R package and deposited in the GEO public repository with GSE166047 as accession number. Specifically, 20 samples divided between NW (control), OBF (obese women), OBM (obese male) and OBT2D (obese women with diabetes) are deposited in the GSE166047. We hereby describe only 10 samples (5 healthy normal weight women reported as NW and 5 obese women reported as OBF) because we refer to the data published in the article "Transcriptional characterization of Subcutaneous Adipose Tissue in obesity affected women highlights metabolic dysfunction and implications for lncRNAs" (DOI: 10.1016/j.ygeno.2021.09.014). Pathways analyses were performed on g:Profiler, Enrichr, ClueGO and GSEA to gain biological insights on gene expression. Raw data reported in GEO database along with detailed methods description reported in this data article could be reused for comparisons with other datasets on the topic to obtain transcriptional differences in a wider co-hort. Moreover, detailed pathways analysis along with cross-referenced data with other datasets will allow to identify novel dysregulated pathways and genes responsible for this regulation. The biological interpretation of this dataset, along with related in vitro experiments, is reported by Rey et al., in Genomics (DOI: 10.1016/j.ygeno.2021.09.014).

Patient-matched analysis identifies deregulated networks in prostate cancer to guide personalized therapeutic intervention.

Prostate cancer (PrCa) is the second most common malignancy in men. More than 50% of advanced prostate cancers display the TMPRSS2-ERG fusion. Despite extensive cancer genome/transcriptome data, little is known about the impact of mutations and altered transcription on regulatory networks in the PrCa of individual patients. Using patient-matched normal and tumor samples, we established somatic variations and differential transcriptome profiles of primary ERG-positive prostate cancers. Integration of protein-protein interaction and gene-regulatory network databases defined highly diverse patient-specific network alterations. Different components of a given regulatory pathway were altered by novel and known mutations and/or aberrant gene expression, including deregulated ERG targets, and were validated by using a novel in silico methodology. Consequently, different sets of pathways were altered in each individual PrCa. In a given PrCa, several deregulated pathways share common factors, predicting synergistic effects on cancer progression. Our integrated analysis provides a paradigm to identify druggable key deregulated factors within regulatory networks to guide personalized therapies.

Hybrid-architectured promoter design to deregulate expression in yeast.

Hybrid-architectured promoter design to deregulate expression in yeast under modulating power of carbon sources involves replacing native cis-acting DNA sequence(s) with de novo synthetic tools in coordination with master regulator transcription factor (TF) to alter crosstalk between signaling pathways, and consequently, transcriptionally rewire the expression. Hybrid-promoter architectures can be designed to mimic native promoter architectures in yeast's preferred carbon source utilization pathway. The method aims to generate engineered promoter variants (EPVs) that combine the advantages of being an exceptionally stronger EPV(s) than the naturally occurring promoters and permit "green-and-clean" production on a non-toxic carbon source. To implement the method, a predetermined essential part of the general transcription machinery is targeted. This targeting involves cis-acting DNA sequences to be replaced with synthetic cis-acting DNA sites in coordination with the targeted TF that must bind for transcription machinery activation. The method needs genomic and functional information that can lead to the discovery of the master TF(s) and synthetic cis-acting DNA elements, which enable the engineering of binding of master regulator TF(s). By introducing our recent work on the engineering of Pichia pastoris (syn. Komagataella phaffii) alcohol oxidase 1 (AOX1) hybrid-promoter architectures, we provide the method and protocol for the hybrid-architectured EPV design to deregulate expression in yeast. The method can be adapted to other promoters in different substrate utilization pathways in P. pastoris, as well as in other yeasts.

Pathway-Based Personalized Analysis of Pan-Cancer Transcriptomic Data.

The occurrence of cancer is closely related to the deregulation of certain pathways. Based on pathway deregulation scores (PDS) inferred by the Pathifier algorithm, we analyzed transcriptomic data of 13 different cancer types in The Cancer Genome Atlas database to identify cancer-specific deregulated pathways and prognostic pathways. The results showed that the individual-specific pathway deregulation scores can clearly distinguish different cancer types and their tumor-adjacent tissues. In addition, the cancer-specific deregulated pathways and prognostic pathways of different cancer types had high heterogeneity, and the identified cancer prognostic pathways have been reported to be closely related to the corresponding cancers. Furthermore, we also found that cancers with more deregulation pathways tend to be malignant and have worse prognoses. Finally, a Cox proportional Hazards model was constructed based on the prognostic pathways; this model successfully predicted survival and prognosis based on data from cancer samples. In addition, the performance of the breast cancer prognostic model was validated with an independent data set in the METABRIC database. Therefore, the prognostic pathways we identified have the potential to become targets for the treatment of cancer.

The deregulated immune reaction and cytokines release storm (CRS) in COVID-19 disease.

COVID-19 caused by the SARS-CoV-2 virus, accompanies an unprecedented spike in cytokines levels termed cytokines release syndrome (CRS), in critically ill patients. Clinicians claim that the surge demonstrates a deregulated immune defence in host, as infected cell expression analysis depicts a delay in type-I (interferon-I) and type-III IFNs expression, along with a limited Interferon-Stimulated Gene (ISG) response, which later resume and culminates in elicitation of several cytokines including- IL-6, IL-8, IL-12, TNFα, IL-17, MCP-1, IP-10 and IL-10 etc. Although cytokines are messenger molecules of the immune system, but their increased concentration results in inflammation, infiltration of macrophages, neutrophils and lung injury in patients. This inflammatory response results in the precarious pathogenesis of COVID-19; thus, a complete estimation of the immune response against SARS-CoV-2 is vital in designing a harmless and effective vaccine. In pathogenesis analysis, it emerges that a timely forceful type-I IFN production (18-24hrs post infection) promotes innate and acquired immune responses, while a delay in IFNs production (3-4 days post infection) actually renders both innate and acquired responses ineffective in fighting infection. Further, underlying conditions including hypertension, obesity, cardio-vascular disease etc may increase the chances of putting people in risk groups, which end up having critical form of infection. This review summarizes the events starting from viral entry, its struggle with the immune system and failure of host immunological parameters to obliterate the infections, which finally culminate into massive release of CRS and inflammation in gravely ill patients.

The Genomics of Myelodysplastic Syndromes: Origins of Disease Evolution, Biological Pathways, and Prognostic Implications.

The molecular pathogenesis of myelodysplastic syndrome (MDS) is complex due to the high rate of genomic heterogeneity. Significant advances have been made in the last decade which elucidated the landscape of molecular alterations (cytogenetic abnormalities, gene mutations) in MDS. Seminal experimental studies have clarified the role of diverse gene mutations in the context of disease phenotypes, but the lack of faithful murine models and/or cell lines spontaneously carrying certain gene mutations have hampered the knowledge on how and why specific pathways are associated with MDS pathogenesis. Here, we summarize the genomics of MDS and provide an overview on the deregulation of pathways and the latest molecular targeted therapeutics.

Identification of Parkinson's disease-related pathways and potential risk factors.

OBJECTIVE: To identify Parkinson's disease (PD)-associated deregulated pathways and genes, to further elucidate the pathogenesis of PD. METHODS: Dataset GSE100054 was downloaded from the Gene Expression Omnibus, and differentially expressed genes (DEGs) in PD samples were identified. Functional enrichment analyses were conducted for the DEGs. The top 10 hub genes in the protein-protein interaction (PPI) network were screened out and used to construct a support vector machine (SVM) model. The expression of the top 10 genes was then validated in another dataset, GSE46129, and a clinical patient cohort. RESULTS: A total of 333 DEGs were identified. The DEGs were clustered into two gene sets that were significantly enriched in 12 pathways, of which 8 were significantly deregulated in PD, including cytokine-cytokine receptor interaction, gap junction, and actin cytoskeleton regulation. The signature of the top 10 hub genes in the PPI network was used to construct the SVM model, which had high performance for predicting PD. Of the 10 genes, GP1BA, GP6, ITGB5, and P2RY12 were independent risk factors of PD. CONCLUSION: Genes such as GP1BA, GP6, P2RY12, and ITGB5 play critical roles in PD pathology through pathways including cytokine-cytokine receptor interaction, gap junctions, and actin cytoskeleton regulation.

Hybrid-architectured double-promoter expression systems enhance and upregulate-deregulated gene expressions in Pichia pastoris in methanol-free media.

Double-promoter expression system (DPES) design as de novo metabolic engineering strategy enables fine-tuned and enhanced gene expression. We constructed a collection of monodirectional hybrid-architectured DPESs with engineered promoter variants PADH2-Cat8-L2 and PmAOX1 and with the naturally occurring promoter PGAP to enhance and upregulate-deregulated gene expressions in Pichia pastoris in methanol-free media. Reporter red fluorescent protein (mApple) and enhanced green fluorescent protein (eGFP) were expressed under PADH2-Cat8-L2 and PmAOX1 or PGAP, respectively, enabling the determination of the transcription period and strength of each constituent in the DPESs. We determined fluorescent protein expressions in batch cultivations on 2% (v/v) ethanol, excess glucose, and excess glycerol, and compared them with single-promoter expression systems constructed with PADH2-Cat8-L2, PmAOX1, and PGAP. The transcription- and expression-upregulation power of bifunctional DPESs was higher than that of twin DPESs (two-copy expression systems). Our findings answer long-standing questions regarding the high- (or multi-) copy clone results in the literature. Our first conclusion is that increasing identical components in the DPES architectures linearly increases the concentrations of cis-acting DNA sites and increases the demand for key transcription factors (TFs) that perturb their good coupling of supply and demand. The next is that the synthesis of some amino acids may create bottleneck(s) as rate-limiting amino acid(s) in recombinant protein synthesis. With bifunctional DPESs, each constituent upregulated the transcription and increased the expression and reduced the demand for the same TF(s) in the generation of novel regulatory circuits, due to the increased number of nonidentical cis-acting DNA sites. We tested superior DPES performances in extracellular human growth hormone (rhGH) production. Thereby, the indications related to the rate-limiting amino acids were verified. Compared with its constituents PADH2-Cat8-L2 and PmAOX1, the bifunctional DPES4 enhanced rhGH production by 1.44- and 2.02-fold, respectively. The DPES design method, with its constraint and parameters, enables the generation of promising r-protein production platforms with high impact on industrial-scale production processes and opens up new avenues for research in yeasts. KEY POINTS: • Design method with the constraint and parameters for the construction of the DPESs is presented. • Hybrid-architectured de novo DPESs are designed to enhance and fine-tune gene expression. • Bifunctional DPESs demonstrate enhanced transcription and expression. • Twin DPESs linearly increase cis-acting DNA sites and consequently increase the demand for the same TFs. • Bifunctional DPESs enable good coupling of supply and demand to bind with TFs. • Ethanol-controlled Snf1 pathway and crosstalk enable fine-tuned transcription and enhanced expression.

Molecular Connections Between Circadian Clocks and Aging.

The mammalian circadian clockwork has evolved as a timing system that allows the daily environmental changes to be anticipated so that behavior and tissue physiology can be adjusted accordingly. The circadian clock synchronizes the function of all cells within tissues in order to temporally separate preclusive and potentially harmful physiologic processes and to establish a coherent temporal organismal physiology. Thus, the proper functioning of the circadian clockwork is essential for maintaining cellular and tissue homeostasis. Importantly, aging reduces the robustness of the circadian clock, resulting in disturbed sleep-wake cycles, a lowered capacity to synchronize circadian rhythms in peripheral tissues, and reprogramming of the circadian clock output at the molecular function levels. These circadian clock-dependent behavioral and molecular changes in turn further accelerate the process of aging. Here we review the current knowledge about how aging affects the circadian clock, how the functional decline of the circadian clock affects aging, and how the circadian clock machinery and the molecular processes that underlie aging are intertwined.

BCL2 and hsa-miR-181a-5p are potential biomarkers associated with papillary thyroid cancer based on bioinformatics analysis.

BACKGROUND: The morbidity of thyroid carcinoma has been rising worldwide and increasing faster than any other cancer type. The most common subtype with the best prognosis is papillary thyroid cancer (PTC); however, the exact molecular pathogenesis of PTC is still not completely understood. METHODS: In the current study, 3 gene expression datasets (GSE3678, GSE3467, and GSE33630) and 2 miRNA expression datasets (GSE113629 and GSE73182) of PTC were selected from the Gene Expression Omnibus (GEO) database and were further used to identify differentially expressed genes (DEGs) and deregulated miRNAs between normal thyroid tissue samples and PTC samples. Then, Gene Ontology (GO) and pathway enrichment analyses were conducted, and a protein-protein interaction (PPI) network was constructed to explore the potential mechanism of PTC carcinogenesis. The hub gene detection was performed using the CentiScaPe v2.0 plugin, and significant modules were discovered using the MCODE plugin for Cytoscape. In addition, a miRNA-gene regulatory network in PTC was constructed using common deregulated miRNAs and DEGs. RESULTS: A total of 263 common DEGs and 12 common deregulated miRNAs were identified. Then, 6 significant KEGG pathways (P < 0.05) and 82 significant GO terms were found to be enriched, indicating that PTC was closely related to amino acid metabolism, development, immune system, and endocrine system. In addition, by constructing a PPI network and miRNA-gene regulatory network, we found that hsa-miR-181a-5p regulated the most DEGs, while BCL2 was targeted by the most miRNAs. CONCLUSIONS: The results of this study suggested that hsa-miR-181a-5p and BCL2 and their regulatory networks may play important roles in the pathogenesis of PTC.