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Macroautophagy decreases with age, and this change is considered a hallmark of the aging process. It remains unknown whether mitophagy, the essential selective autophagic degradation of mitochondria, also decreases with age. In our analysis of mitophagy in multiple organs in the mito-QC reporter mouse, mitophagy is either increased or unchanged in old versus young mice. Transcriptomic analysis shows marked upregulation of the type I interferon response in the retina of old mice, which correlates with increased levels of cytosolic mtDNA and activation of the cGAS/STING pathway. Crucially, these same alterations are replicated in primary human fibroblasts from elderly donors. In old mice, pharmacological induction of mitophagy with urolithin A attenuates cGAS/STING activation and ameliorates deterioration of neurological function. These findings point to mitophagy induction as a strategy to decrease age-associated inflammation and increase healthspan., (© 2024. The Author(s).)

Mitochondrial function is key to support metabolism and homeostasis in the retina, an organ that has one of the highest metabolic rates body-wide and is constantly exposed to photooxidative damage and external stressors. Mitophagy is the selective autophagic degradation of mitochondria within lysosomes, and can be triggered by distinct stimuli such as mitochondrial damage or hypoxia. Here, we review the importance of mitophagy in retinal physiology and pathology. In the developing retina, mitophagy is essential for metabolic reprogramming and differentiation of retina ganglion cells (RGCs). In basal conditions, mitophagy acts as a quality control mechanism, maintaining a healthy mitochondrial pool to meet cellular demands. We summarize the different autophagy- and mitophagy-deficient mouse models described in the literature, and discuss the potential role of mitophagy dysregulation in retinal diseases such as glaucoma, diabetic retinopathy, retinitis pigmentosa, and age-related macular degeneration. Finally, we provide an overview of methods used to monitor mitophagy in vitro, ex vivo, and in vivo. This review highlights the important role of mitophagy in sustaining visual function, and its potential as a putative therapeutic target for retinal and other diseases., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Mitochondria and peroxisomes are closely related metabolic organelles, both in terms of origin and in terms of function. Mitochondria and peroxisomes can also be turned over by autophagy, in processes termed mitophagy and pexophagy, respectively. However, despite their close relationship, it is not known if both organelles are turned over under similar conditions, and if so, how this might be coordinated molecularly. Here, we find that multiple selective autophagy pathways are activated upon iron chelation and show that mitophagy and pexophagy occur in a BNIP3L/NIX-dependent manner. We reveal that the outer mitochondrial membrane-anchored NIX protein, previously described as a mitophagy receptor, also independently localises to peroxisomes and drives pexophagy. We show this process happens in vivo, with mouse tissue that lacks NIX having a higher peroxisomal content. We further show that pexophagy is stimulated under the same physiological conditions that activate mitophagy, including cardiomyocyte and erythrocyte differentiation. Taken together, our work uncovers a dual role for NIX, not only in mitophagy but also in pexophagy, thus illustrating the interconnection between selective autophagy pathways., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Autophagy is a fundamental homeostatic pathway that mediates the degradation and recycling of intracellular components. It serves as a key quality control mechanism, especially in non-dividing cells such as neurons. Proteins, lipids, and even whole organelles are engulfed in autophagosomes and delivered to the lysosome for elimination. The retina is a light-sensitive tissue located in the back of the eye that detects and processes visual images. Vision is a highly demanding process, making the eye one of the most metabolically active tissues in the body and photoreceptors display glycolytic metabolism, even in the presence of oxygen. The retina and eye are also exposed to other stressors that can impair their function, including genetic mutations and age-associated changes. Autophagy, among other pathways, is therefore a key process for the preservation of retinal homeostasis. Here, we review the roles of both canonical and non-canonical autophagy in normal retinal function. We discuss the most recent studies investigating the participation of autophagy in eye diseases such as age-related macular degeneration, glaucoma, and diabetic retinopathy and its role protecting photoreceptors in several forms of retinal degeneration. Finally, we consider the therapeutic potential of strategies that target autophagy pathways to treat prevalent retinal and eye diseases., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Autophagy is a critical cellular process by which biomolecules and cellular organelles are degraded in an orderly manner inside lysosomes. This process is particularly important in neurons: these post-mitotic cells cannot divide or be easily replaced and are therefore especially sensitive to the accumulation of toxic proteins and damaged organelles. Dysregulation of neuronal autophagy is well documented in a range of neurodegenerative diseases. However, growing evidence indicates that autophagy also critically contributes to neurodevelopmental cellular processes, including neurogenesis, maintenance of neural stem cell homeostasis, differentiation, metabolic reprogramming, and synaptic remodelling. These findings implicate autophagy in neurodevelopmental disorders. In this review we discuss the current understanding of the role of autophagy in neurodevelopment and neurodevelopmental disorders, as well as currently available tools and techniques that can be used to further investigate this association., Competing Interests: Conflict of Interest: The author's declare no conflict of interest., (Copyright: © 2021 Zapata-Muñoz et al.)

We have previously shown that FLSC, a chimeric protein containing HIV-1BAL gp120 and the D1 and D2 domains of human CD4, blocks the binding and entry of HIV-1 into target cells by occluding CCR5, the major HIV-1 coreceptor. In an effort to improve the antiviral potential of FLSC, we fused it with the hinge-CH2-CH3 region of human IgG1. The IgG moiety should increase both the affinity and stability in vivo of FLSC, due to the resultant bivalency and an extended serum half-life, thereby increasing its antiviral potency. We previously showed that (FLSC) IgG1 indeed had greater antiviral activity against T cell infections. Here we extend these results to macrophages, for which (FLSC) IgG1 has a more potent antiviral activity than FLSC alone, due in part to its higher binding affinity for CCR5. We also test both compounds in a relevant humanized mouse model and show that, as anticipated, the IgG1 moiety confers a greatly extended half-life. These data, taken together with previous results, suggest potential clinical utility for (FLSC) IgG1 and support further developmental work toward eventual clinical trials.

Background: Presepsin (PSEP) is released during infectious diseases and can be detected in the blood. PSEP has shown promising results as sepsis marker. We examined the diagnostic and prognostic validity of PSEP in patients suspicious of sepsis on admission in the emergency department (ED)., Methods: One hundred twenty three patients with signs of SIRS and/or sepsis and 123 healthy individuals were enrolled. PSEP was determined on admission, after 8, 24 and 72 h., Results: Mean PSEP concentrations of the control group and the patient group were 130 and 1945 pg/ml. PSEP differed between SIRS, sepsis, severe sepsis and septic shock and showed strong association with 30-day mortality ranging from 10.3% in the 1st to 32.1% in the 4th quartile. The ROC curve analyses revealed an AUC value of 0.743. Combined assessment of PSEP and MEDS score increased the AUC up to 0.878 demonstrating the close relationship with outcome. Based on the PSEP values in the different severity degrees, decision thresholds for risk stratification were established. The course of PSEP during the first 72 h was associated with effectiveness of treatment and outcome., Conclusions: PSEP allowed outcome prediction already on admission to a similar degree as the clinical scores MEDS and APACHE II. Combination of PSEP with MEDS score improved the discriminatory power for outcome prediction., (Copyright © 2015. Published by Elsevier B.V.)

In this article, we show that the dielectric constant of lead-free ferroelectric ceramics based on the solid solution (1-x)(Bi(0.5)Na(0.5))TiO(3)-xBaTiO(3), with compositions at or near the morphotropic phase boundary (MPB), can be tuned by a local applied electric field. Two compositions have been studied, one at the MPB, with x = 0.06 (BNBT6), and another one nearer the BNT side of the phase diagram, with x = 0.04 (BNBT4). The tunability of the dielectric constant is measured at microwave frequencies between 100 MHz and 3 GHz by a nonresonant method and simultaneously applying a dc electric field. As expected, the tunability is higher for the composition at the MPB (BNBT6), reaching a maximum value of 60% for an electric field of 900 V/cm, compared with the composition below this boundary (BNBT4), which saturates at 40% for an electric field of 640 V/cm. The high tunability in both cases is attributed to the fine grain and high density of the samples, which have a submicrometer homogeneous grain structure with grain size of the order of a few hundred nanometers. Such properties make these ceramics attractive for microwave tunable devices. Finally, we have tested these ceramics for their application as infrared pyroelectric detectors and we have found that the pyroelectric figure of merit is comparable to traditional lead-containing pyroelectrics.

Accidental falls of our elderly, and physical injuries resulting, represent a major health and economic. Falls are the most common causes of serious injuries and a major health threats in the stratum of older population. Early detection of a fall is a key factor when trying to provide adequate care to the elderly person who has suffered an accident at home. In this paper, we present a support system for detecting falls of an elder person by a static wireless nonintrusive sensorial infrastructure based on heterogenous sensor nodes. This previous infrastructure, named AID (Alarm Intelligent Device), is an AAL (Ambient Assisted Living) system that allows to infer a potential fall. We have developed, different to other contributions, a specific low-power multi-hop network consists of nodes (Motes) that wirelessly communicate to each other and are capable of hopping radio messages to a base station where they are passed to a PC (or other possible client). The goal of this project is 1) to provide alerts to caregivers in the event of an accident, acute illness or strange (possibly dangerous) activities, and 2) to enable that authorized and authenticated caregivers by means of a itinerant wearable mote can be inserted into mesh and interact with it. In this paper, we describe an ubiquitous assistential monitoring system at home.

A single injection of ML29 reassortant vaccine for Lassa fever induces low, transient viremia, and low or moderate levels of ML29 replication in tissues of common marmosets depending on the dose of the vaccination. The vaccination elicits specific immune responses and completely protects marmosets against fatal disease by induction of sterilizing cell-mediated immunity. DNA array analysis of human peripheral blood mononuclear cells from healthy donors exposed to ML29 revealed that gene expression patterns in ML29-exposed PBMC and control, media-exposed PBMC, clustered together confirming safety profile of the ML29 in non-human primates. The ML29 reassortant is a promising vaccine candidate for Lassa fever.

Lassa virus (LASV) is responsible for the deaths of thousands of people in West Africa annually. Genetic diversity among LASV strains is the highest among the Arenaviridae and represents a great challenge for vaccine development. Guinea pigs vaccinated with a ML29 reassortant vaccine experienced sterilizing immunity and complete protection when challenged on day 30 either with homologous virus or with the distantly related Nigerian isolate. Simultaneous vaccination-challenge or challenge on day 2 after vaccination also protected 60-100% of the animals against both strains, but without sterilizing immunity. These results indicate that simultaneous replication of ML29 and LASV attenuates the virulence of LASV infection.

The Yellow Fever Vaccine 17D (YFV17D) has been used as a vector for the Lassa virus glycoprotein precursor (LASV-GPC) resulting in construction of YFV17D/LASV-GPC recombinant virus. The virus was replication-competent and processed the LASV-GPC in cell cultures. The recombinant replicated poorly in guinea pigs but still elicited specific antibodies against LASV and YFV17D antigens. A single subcutaneous injection of the recombinant vaccine protected strain 13 guinea pigs against fatal Lassa Fever. This study demonstrates the potential to develop an YFV17D-based bivalent vaccine against two viruses that are endemic in the same area of Africa.

Lassa virus (LASV) and Mopeia virus (MOPV) are closely related Old World arenaviruses that can exchange genomic segments (reassort) during coinfection. Clone ML29, selected from a library of MOPV/LASV (MOP/LAS) reassortants, encodes the major antigens (nucleocapsid and glycoprotein) of LASV and the RNA polymerase and zinc-binding protein of MOPV. Replication of ML29 was attenuated in guinea pigs and nonhuman primates. In murine adoptive-transfer experiments, as little as 150 PFU of ML29 induced protective cell-mediated immunity. All strain 13 guinea pigs vaccinated with clone ML29 survived at least 70 days after LASV challenge without either disease signs or histological lesions. Rhesus macaques inoculated with clone ML29 developed primary virus-specific T cells capable of secreting gamma interferon in response to homologous MOP/LAS and heterologous MOPV and lymphocytic choriomeningitis virus. Detailed examination of two rhesus macaques infected with this MOPV/LAS reassortant revealed no histological lesions or disease signs. Thus, ML29 is a promising attenuated vaccine candidate for Lassa fever.