Neuronal inputs and outputs of aging and longevity.

An animal's survival strongly depends on its ability to maintain homeostasis in response to the changing quality of its external and internal environment. This is achieved through intracellular and intercellular communication within and among different tissues. One of the organ systems that plays a major role in this communication and the maintenance of homeostasis is the nervous system. Here we highlight different aspects of the neuronal inputs and outputs of pathways that affect aging and longevity. Accordingly, we discuss how sensory inputs influence homeostasis and lifespan through the modulation of different types of neuronal signals, which reflects the complexity of the environmental cues that affect physiology. We also describe feedback, compensatory, and feed-forward mechanisms in these longevity-modulating pathways that are necessary for homeostasis. Finally, we consider the temporal requirements for these neuronal processes and the potential role of natural genetic variation in shaping the neurobiology of aging

Adenovirus flow in host cell networks

Viruses are obligatory parasites that take advantage of intracellular niches to replicate. During infection, their genomes are carried in capsids across the membranes of host cells to sites of virion production by exploiting cellular behaviour and resources to guide and achieve all aspects of delivery and the downstream virus manufacturing process. Successful entry hinges on execution of a precisely tuned viral uncoating program where incoming capsids disassemble in consecutive steps to ensure that genomes are released at the right time, and in the right place for replication to occur. Each step of disassembly is cell-assisted, involving individual pathways that transmit signals to regulate discrete functions, but at the same time, these signalling pathways are organized into larger networks, which communicate back and forth in complex ways in response to the presence of virus. In this review, we consider the elegant strategy by which adenoviruses (AdVs) target and navigate cellular networks to initiate the production of progeny virions. There are many remarkable aspects about the AdV entry program; for example, the virus gains targeted control of a large well-defined local network neighbourhood by coupling several interacting processes (including endocytosis, autophagy and microtubule trafficking) around a collective reference state centred on the interactional topology and multifunctional nature of protein VI. Understanding the network targeting activity of protein VI, as well as other built-in mechanisms that allow AdV particles to be efficient at navigating the subsystems of the cell, can be used to improve viral vectors, but also has potential to be incorporated for use in entirely novel delivery systems.Peer reviewe

A microfabricated sensor for thin dielectric layers

We describe a sensor for the measurement of thin dielectric layers capable of operation in a variety of environments. The sensor is obtained by microfabricating a capacitor with interleaved aluminum fingers, exposed to the dielectric to be measured. In particular, the device can measure thin layers of solid frozen from a liquid or gaseous medium. Sensitivity to single atomic layers is achievable in many configurations and, by utilizing fast, high sensitivity capacitance read out in a feedback system onto environmental parameters, coatings of few layers can be dynamically maintained. We discuss the design, read out and calibration of several versions of the device optimized in different ways. We specifically dwell on the case in which atomically thin solid xenon layers are grown and stabilized, in cryogenic conditions, from a liquid xenon bath

An update on peptide-based therapies for type 2 diabetes and obesity

Long-acting analogues of the naturally occurring incretin, glucagon-like peptide-1 (GLP-1) and those modified to interact also with receptors for glucose-dependent insulinotropic polypeptide (GIP) have shown high glucose-lowering and weight-lowering efficacy when administered by once-weekly subcutaneous injection. These analogues herald an exciting new era in peptide-based therapy for type 2 diabetes (T2D) and obesity. Of note is the GLP-1R agonist semaglutide, available in oral and injectable formulations and in clinical trials combined with the long-acting amylin analogue, cagrilintide. Particularly high efficacy in both glucose- and weight lowering capacities has also been observed with the GLP-1R/GIP-R unimolecular dual agonist, tirzepatide. In addition, a number of long-acting unimolecular GLP-1R/GCGR dual agonist peptides and GLP-1R/GCGR/GIPR triagonist peptides have entered clinical trials. Other pharmacological approaches to chronic weight management include the human monoclonal antibody, bimagrumab which blocks activin type II receptors and is associated with growth of skeletal muscle, an antibody blocking activation of GIPR to which are conjugated GLP-1R peptide agonists (AMG-133), and the melanocortin-4 receptor agonist, setmelanotide for use in certain inherited obesity conditions. The high global demand for the GLP-1R agonists liraglutide and semaglutide as anti-obesity agents has led to shortage so that their use in T2D therapy is currently being prioritized. [Abstract copyright: Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Relatively Complete Counterexamples for Higher-Order Programs

In this paper, we study the problem of generating inputs to a higher-order program causing it to error. We first study the problem in the setting of PCF, a typed, core functional language and contribute the first relatively complete method for constructing counterexamples for PCF programs. The method is relatively complete in the sense of Hoare logic; completeness is reduced to the completeness of a first-order solver over the base types of PCF. In practice, this means an SMT solver can be used for the effective, automated generation of higher-order counterexamples for a large class of programs. We achieve this result by employing a novel form of symbolic execution for higher-order programs. The remarkable aspect of this symbolic execution is that even though symbolic higher-order inputs and values are considered, the path condition remains a first-order formula. Our handling of symbolic function application enables the reconstruction of higher-order counterexamples from this first-order formula. After establishing our main theoretical results, we sketch how to apply the approach to untyped, higher-order, stateful languages with first-class contracts and show how counterexample generation can be used to detect contract violations in this setting. To validate our approach, we implement a tool generating counterexamples for erroneous modules written in Racket.Comment: In Proceedings of the 36th annual ACM SIGPLAN conference on Programming Language Design and Implementation, Portland, Oregon, June 201

Exploring the Relationship Between Cognitive Health and the Social Environment of Older Adults

Cognitive health is an important aspect of successful aging, and includes maintaining several cognitive functions such as memory, decision-making, and executive function. Various aspects of older adults’ social environment may play a role in cognitive health. Three studies were conducted, aimed at testing the relationships between memory performance and two socio-environmental factors (social networks and social activities) in a community-based sample of older adults. Study 1 examined the associations between memory performance and several structural characteristics of social networks using linear regression models. Better memory performance was associated with having larger networks, more connected ties, and greater potential access to social capital (less network constraint). Study 2, a qualitative in-depth interview study, explored the types and purposes of social activities in late life, as well as their potential implications for cognitive health, using a grounded theory approach. From this study, we found that older adults tended to participate in four social activity types—Altruism, Creativity, Game and Motion. Building off our findings from the qualitative study, Study 3 examined the associations between four social activity types and memory performance via logistic regression models. We found that those who participated in Altruism and/or in two or more of these social activity types in a typical week were more likely to have better memory performance. These findings raise a number of questions related to the importance of emotional closeness, social capital, enjoyment, creativity, and volunteering in late life, and how these factors could be important for memory and preserving cognitive health. Maintaining cognitive health in late life is an emerging public health issue with important implications for the well-being of older adults and families in an aging society.Future research is needed to confirm whether these aspects of the social environment are important for memory and overall cognitive functioning in late life. Public health practitioners should consider interventions that enhance older adults’ social network structure or encourage participation in different types of social activities as they may play an important role in cognitive health and well-being in late life