Further, Weighted Gene Correlation Network Analysis revealed a comethylation network module in the pain group that was not preserved in the control group, where the hub gene was the cyclic adenosine monophosphate-dependent transcription factor ATF-2. Our preliminary findings provide new epigenetic insights into the role of aberrant immune signaling in musculoskeletal pain in older adults while further supporting involvement of dysfunctional GABAergic signaling mechanisms in chronic pain. Our findings need to be urgently replicated in larger cohorts as they may serve as a basis for developing and targeting future interventions.The immunodeficiency observed in HIV-1-infected patients is mainly due to uninfected bystander CD4+ T lymphocyte cell death. The viral envelope glycoproteins (Env), expressed at the surface of infected cells, play a key role in this process. Env triggers macroautophagy/autophagy, a process necessary for subsequent apoptosis, and the production of reactive oxygen species (ROS) in bystander CD4+ T cells. Here, we demonstrate that Env-induced oxidative stress is responsible for their death by apoptosis. Y-27632 concentration Moreover, we report that peroxisomes, organelles involved in the control of oxidative stress, are targeted by Env-mediated autophagy. Indeed, we observe a selective autophagy-dependent decrease in the expression of peroxisomal proteins, CAT and PEX14, upon Env exposure; the downregulation of either BECN1 or SQSTM1/p62 restores their expression levels. Fluorescence studies allowed us to conclude that Env-mediated autophagy degrades these entire organelles and specifically the mature ones. Together, our results on Env-induced pexophagy provide new clues on HIV-1-induced immunodeficiency. Abbreviations Ab antibodies; AF auranofin; AP anti-proteases; ART antiretroviral therapy; BafA1 bafilomycin A1; BECN1 beclin 1; CAT catalase; CD4 CD4 molecule; CXCR4 C-X-C motif chemokine receptor 4; DHR123 dihydrorhodamine 123; Env HIV-1 envelope glycoproteins; GAPDH glyceraldehyde-3-phosphate dehydrogenase; GFP green fluorescent protein; GFP-SKL GFP-serine-lysine-leucine; HEK human embryonic kidney; HIV-1 type 1 human immunodeficiency virus; HTRF homogeneous time resolved fluorescence; MAP1LC3/LC3 microtubule associated protein 1 light chain 3; NAC N-acetyl-cysteine; PARP poly(ADP-ribose) polymerase; PEX peroxin; ROS reactive oxygen species; siRNA small interfering ribonucleic acid; SQSTM1/p62 sequestosome 1.Caseinolytic protease (CLPP) is an energy-dependent serine-type protease that plays a role in protein quality control. The CLPP gene is highly conserved across kingdoms and the protein is present in both bacteria and eukaryote organelles like mitochondria across a wide phylogenetic range. This pedigree has all the hallmarks of CLPP being an essential gene. However, in plants, disruption of mitochondrial CLPP has no impact on its growth, reminiscent of its nonessential role in some model fungi. Deletion of mitochondrial CLPP improves health and increased life span in the filamentous fungus, Podospora anserina, while loss of human mitochondrial CLPP leads to infertility and hearing loss. Recently it was revealed that both plant and human CLPP share a similar role in maintenance of the N-module of respiratory complex I. In addition, plant mitochondrial CLPP also coordinates the homeostasis of other mitochondrial protein complexes encoded by genes across mitochondrial and nuclear genomes. Understanding the contextual role of mitochondrial CLPP across kingdoms may help to understand these diverse sets of clpp phenotypes and the widespread conservation of CLPP genes.Glaucoma, cataracts, and cognitive decline are most common in older ages. Although cross-sectional studies showed that these disorders are associated, follow-up studies are lacking. To investigate this issue, baseline and follow-up data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) were employed. We evaluated participants ≥ 55 years-old at follow-up without diagnosis of dementia, stroke, and other eye conditions except for glaucoma and cataracts. Cognition was evaluated using delayed word recall, verbal fluency, and trail making (version B) tests. Regression models were employed to investigate associations between glaucoma and cognition, adjusted by several confounders. Out of 3,867 participants, 379 and 118 presented cataracts and glaucoma, respectively. Only glaucoma was apredictor of lower verbal fluency (B = -0.23, 95% CI -035 to -012, p0.57). Our results suggest that glaucoma may be related to declining cognition.The purpose of this study was to design a polyamidoamine (PAMAM)-based nanovector for the efficient delivery of methotrexate to U87 glioma cells. To this end, 0-100% acetylated PAMAM dendrimers of the fourth generation were synthesized and evaluated using drug encapsulation measurements, molecular dynamics simulations, neurotoxicity assays and neuronal internalization experiments. The best system was tested as a nanovector for methotrexate delivery to U87 glioma cells. The authors found that 25% acetylated PAMAM dendrimers of the fourth-generation combine low intrinsic toxicity, large drug complexation capacity and efficient internalization into hippocampal neurons. Nanovector complexation enhances the cytotoxic response of methotrexate against U87 glioma cells compared with free drug solutions. In conclusion, 25% acetylated PAMAM dendrimers of the fourth-generation increase drug uptake by glioma cells and thereby act as efficient nanovectors for methotrexate delivery.Interoceptive processes emanating from baroreceptor signals support emotional functioning. Previous research suggests a unique link to fear fearful faces, presented in synchrony with systolic baroreceptor firing draw more attention and are rated as more intense than those presented at diastole. This study examines whether this effect is unique to fearful faces or can be observed in other emotional faces. Participants (n = 71) completed an emotional visual search task (VST) in which fearful, happy, disgust and sad faces were presented during systolic and diastolic phases of the cardiac cycle. Visual search accuracy and emotion detection accuracy and latency were recorded, followed by a subjective intensity task. A series of interactions between emotion and cardiac phase were observed. Visual search accuracy for happy and disgust faces was greater at systole than diastole; the opposite was found for fearful faces. Fearful and happy faces were perceived as more intense at systole. Previous research proposed that cardiac signalling has specific effects on the attention and intensity ratings for fearful faces.