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f dual FGFR2-MEK1/2 blockade in patients with iCCA.The evolving microstructure and mechanical properties that promote homeostasis in the aorta are fundamental to age-specific adaptations and disease progression. We combine ex vivo multiphoton microscopy and biaxial biomechanical phenotyping to quantify and correlate layer-specific microstructural parameters, for the primary extracellular matrix components (fibrillar collagen and elastic lamellae) and cells (endothelial, smooth muscle, and adventitial), with mechanical properties of the mouse aorta from weaning through natural aging up to one year. The aging endothelium was characterized by progressive reductions in cell density and altered cellular orientation. The media similarly showed a progressive decrease in smooth muscle cell density and alignment though with inter-lamellar widening from intermediate to older ages, suggesting cell hypertrophy, matrix accumulation, or both. Despite not changing in tissue thickness, the aging adventitia exhibited a marked thickening and straightening of collagen fiber bundles and reduction in cell density, suggestive of age-related remodeling not growth. Multiple microstructural changes correlated with age-related increases in circumferential and axial material stiffness, among other mechanical metrics. Because of the importance of aging as a risk factor for cardiovascular diseases, understanding the normal progression of structural and functional changes is essential when evaluating superimposed disease-related changes as a function of the age of onset.Senescent cells (SCs) accumulate with age and cause various age-related diseases. Clearance of SCs by transgenic or pharmaceutical strategies has been demonstrated to delay aging, treat age-related diseases and extend healthspan. SCs are resistant to various stressors because they are protected from apoptosis by SC anti-apoptotic pathways (SCAPs). Targeting the proteins in the SCAPs with small molecules can selectively kill SCs, the effector proteins are called senolytic targets and the small molecules are called senolytics. Until now, a series of senolytic targets, such as BCL-XL, heat shock protein 90 (HSP90), Na+/K+ ATPase, bromodomain containing 4 (BRD4), and oxidation resistance 1 (OXR1) have been identified. However, current senolytics targeting these proteins still have some limitations in killing SCs in terms of safety, specificity and broad-spectrum activity. To overcome the challenges, some new strategies, such as proteolysis-targeting chimera (PROTAC) technology, chimeric antigen receptor (CAR) T cells, and β-galactosidase-modified prodrugs, were developed to clear SCs and shown to have promising therapeutic potential. Here we review the significance of SCs in aging and age-related diseases, summarize the known senolytic targets and highlight the emerging new strategies for clearing SCs.Romidepsin, a histone deacetylase (HDAC) inhibitor, has been approved for the treatment of relapsed and refractory peripheral T-cell lymphoma. However the use of romidepsin reportedly causes potent EBV (Epstein-Barr virus) reactivation leading to severe adverse events in patients with natural killer (NK)/T-cell lymphoma (NKTL). As inhibition of EBV lytic cycle reactivation may help prevent romidepsin-induced adverse events in NKTL, we herein set out to identify a safe and effective drug for inhibiting EBV reactivation and examine its mechanism of inhibition. EBV reactivation was evaluated by qRT-PCR of BZLF1 and BRLF1 mRNA expression, qPCR of EBV DNA, and immunoblotting of viral EA-D protein. High-throughput screening of FDA-approved drugs was performed to identify safe and effective molecules and test their effect on romidepsin-induced EBV reactivation in the EBV-positive NKTL cell lines, SNK6 and NK92MI. We found that phosphodiesterase 5 (PDE5) inhibitors, including sildenafil (Viagra; Pfizer), appeared to be nontoxic and effective inhibitors of romidepsin-induced EBV reactivation. Clinical relevance was investigated by qPCR of EBV in two primary effusion samples of NKTL patients. We also investigated the molecular consequences downstream of sildenafil-induced PDE5 inhibition in NKTL cells. A negative correlation was established between the cGMP/PKG pathway and EBV reactivation in NKTL cells. On a molecular level, PDE5 inhibition downregulates BZLF1 and BRLF1 through cGMP/PKG signaling-induced ZNF overexpression. Co-treatment with romidepsin and sildenafil (inhibiting HDAC and PDE5, respectively) showed a synergistic inhibitory effect on NKTL cells, highlighting PDE5 as an attractive target for future therapy in NKTL.Avian reovirus (ARV) infection induced apoptosis in vitro and vivo; nevertheless, the intracellular molecular mechanisms have not been sufficiently revealed. In the previous studies, there have been shown that cellular apoptosis caused by ARV were related with GRP78/IRE1/XBP1 pathway. Protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6) are core molecules in unfold protein response (UPR) and play critical role in ER stress related apoptosis, as well as downstream regulation factors, as Caspase-12 and C/EBP homologous protein (CHOP). In this study, we investigated with a focus on the contribution of UPR related signal pathways in the mechanism of ARV mediated apoptosis. Our results showed that the key molecules of UPR pathways proteins, ATF6, PERK and IRE1 as well as Caspase-12 and cleaved-Caspase-3 expression significant increased both in transcript and protein level in ARV infected cultured Vero cells. In the same time, the ARV induces apoptosis was observed by flow cytometric analysis. Further study revealed that when inhibit the UPR effect by 4PBA pretreated or knockdown of ATF6 by lentivirus mediated shRNA abolished the activation effect of UPR, Caspase-12, cleaved-Caspase-3 activation, as well as the apoptosis induction by ARV infection. The present study provides mechanistic insights into that UPR particular ATF6 played critical roles and works upstream of caspase in the process of cellular apoptosis induced by ARV infection.Epidermal keratinocytes (KCs) rapidly proliferate to repair the skin barrier, and a strict control of division is necessary for healthy tissue homeostasis. However, the pathways that restrain proliferation after epidermal stress are not known. AMPK is an important signaling mediator of energy metabolism previously associated with skin stress and cancer; yet, its explicit impact on KC growth is not known. To examine the requirement of epidermal AMPK in physiologic skin repair, we genetically deleted AMPK within all adult, keratin 14‒expressing KCs of mice. AMPK loss resulted in hyperproliferation and hyperactive mTOR signaling after acute wounding, UVB exposure, and phorbol ester application. This excessive division could be completely blocked by the mTORC1 inhibitor rapamycin. Moreover, we establish that the diabetes drug metformin depends on AMPK to suppress stress-induced KC proliferation. Collectively, these findings show that KC AMPK restrains mTORC1 to control epidermal proliferation after tissue injury.In skin lesions caused by pemphigus, a group of life-threatening autoimmune bullous diseases, an over-representation of CD4+ tissue-resident memory T (TRM) cells was found. We sought to investigate the contributions of CD4+ TRM cells to the severity and refractoriness of pemphigus and their role in local immunological pathogenesis. Our data showed that CD4+ TRM cells accumulated significantly in pemphigus skin lesions. These CD4+ TRM cells expressed a specific set of T follicular helper cell‒related costimulatory molecules. We also found that CD4+ TRM cells remaining in the lesions produced IL-17A and IL-21. In vitro, CD4+ TRM cells exhibited strong support and assistance to autoantibody production. Through transcriptomic sequencing and bioinformatics analysis, we identified that the transcription factor IRF4 was responsible for IL-21 overexpression and autoantibody production. Our results showed that T follicular helper-like CD4+ TRM cells in pemphigus lesions promoted local autoantibody production, resulting in the formation and recurrence of lesions, which supports targeting this cell subset in pemphigus treatment. IRF4 might serve as a potential therapeutic target.Fertility drugs have not definitively been linked to malignant melanoma. By the use of data from a large nationwide cohort of women aged 20.0-45.0 years and living in Denmark between January 1, 1995 and December 31, 2011, we assessed the association between the use of fertility drugs and the risk of malignant melanoma. Information on fertility status and the use of fertility drugs was obtained from the population-based Danish Infertility Cohort. Cox proportional hazard regression models were applied to estimate hazard ratios and 95% confidence intervals with adjustment for potential confounders. The study population comprised 1,330,954 women, of whom 86,231 (6.5%) were treated with fertility drugs. Cerdulatinib manufacturer During a median follow-up of 21.0 years, 6,139 women were diagnosed with malignant melanoma. Compared with fertile women, women with fertility challenges who had used any fertility drugs had an increased risk of malignant melanoma (hazard ratio = 1.14; 95% confidence interval = 1.02-1.27). Furthermore, the use of specific types of fertility drugs (clomiphene, gonadotropins, human chorionic gonadotropin, gonadotropin-releasing hormone preparations, and progesterone) was also associated with an increased risk of malignant melanoma, with hazard ratios ranging between 1.09 and 1.13; however, the association did not reach statistical significance. Our findings indicate that the use of fertility drugs was associated with a modestly increased risk of malignant melanoma.Mal de Meleda is an autosomal recessive palmoplantar keratoderma associated with mutations in a gene encoding SLURP-1. SLURP-1 controls growth, differentiation, and apoptosis of keratinocytes by interaction with α7-type nicotinic acetylcholine receptors. SLURP-1 has a three-finger structure with a β-structural core (head) and three prolonged loops (fingers). To determine the role of SLURP-1 mutations, we produced 22 mutant variants of the protein, including those involved in Mal de Meleda pathogenesis. All mutants except R71H, R71P, T52A, R96P, and L98P were produced in the folded form. SLURP-1 reduces the growth of Het-1A keratinocytes; thus, we studied the influence of the mutations on its antiproliferative activity. Mutations in loops I and III led to the protein inactivation, whereas most mutations in loop II increased SLURP-1 antiproliferative activity. Alanine substitutions of R96 and L98 residues located in the protein head resulted in the appearance of additional pro-apoptotic activity. Our results agree with the diversity of Mal de Meleda phenotypes. Using obtained functional data, the SLURP-1/α7 type nicotinic acetylcholine receptor complex was modeled in silico. Our study provides functional and structural information about the role of the SLURP-1 mutations in Mal de Meleda pathogenesis and predicts SLURP-1 variants, which could drive the disease.Background Quantitative detection of allergens is of great significance for clarifying the cause, treatment, and prevention of allergy disease. Birch pollen is one of the most common inhalational allergens and Bet v1 is the major component allergen of birch allergen. This study aims to develop a stable and sensitive chemiluminescence immunoassay (CLIA) for the detection of birch pollen allergic specific IgE (sIgE) based on recombinant Bet v1 (rBet v1) protein. Methods rBet v1 protein was expressed in Escherichia coli and purified. Then rBet v1 was applied to detect sIgE in human serum. The performance of the established CLIA was evaluated and compared with Phadia rBet v1 fluorescence enzyme immunoassay (FEIA) system. Results The developed CLIA for sIgE to rBet v1 detection shows excellent performance. The assay showed a linear range from 0.1 to 100 IU/mL, with a low detection limit of 0.06 IU/mL. A total of 164 samples were evaluated by CLIA and compared with the results of FEIA. The positive, negative, and total coincidence rate was 90.