Physiology最新文献

Long regarded as an accessory sense, olfaction is now emerging as a metabolic architect, an active agent in energy homeostasis, appetite regulation, and systemic physiology. This review explores the converging lines of evidence positioning the olfactory system not as a passive enhancer of flavor but as a dynamic mediator between environment, behavior, and internal metabolic state. Food odors engage specific olfactory receptors (ORs), which are embedded in neural circuits that project to hypothalamic, limbic, and reward regions. These circuits modulate insulin release, lipid metabolism, thermogenesis, and feeding behavior, often before a single bite is taken. This sensory-metabolic dialogue is continuously tuned by hormonal signals (e.g., leptin, ghrelin, insulin) and deeply shaped by genetic variation across the ∼400 human OR genes, where individual differences in perception carry metabolic consequences. Yet this ancient sensory system now operates in a radically altered chemical landscape. Synthetic volatiles, industrial food aromas, and urban pollutants desensitize olfactory pathways, potentially contributing to overeating and metabolic disease. In parallel, a new therapeutic frontier is emerging: targeted modulation of olfactory pathways, via intranasal hormones, neuromodulation, sensory retraining, and personalized interventions informed by OR genotypes, offers a compelling strategy for precision metabolic care. Revisiting Sydney Whiting's 1853 satire, in which "Smell" was cast as a meddling underling at the digestive gates, we now find this once-overlooked sentinel wielding remarkable authority. The nose, it turns out, knows and may yet hold the key to rebalancing metabolism in a world that smells very different from the one we evolved to navigate.

In recent years, the introduction of mRNA vaccines for SARS-CoV2 and respiratory syncytial virus (RSV) has highlighted the success of the mRNA technology platform. Designing mRNA sequences involves multiple components and requires balancing several parameters, including enhancing transcriptional efficiency, boosting antigenicity, and minimizing immunogenicity. Moreover, changes in the composition and properties of delivery vehicles can also affect vaccine performance. Traditional methods of experimentally testing these conditions are time-consuming, labor-intensive, and costly, necessitating advanced optimization strategies. Recently, the rapid development of computational tools has significantly accelerated the optimization process for mRNA vaccines. In this review, we systematically examine computation-aided approaches for optimizing mRNA components, including coding and noncoding regions, and for improving the efficiency of lipid nanoparticle (LNP) delivery systems by focusing on their composition, ratios, and characterization. The use of computational tools can significantly accelerate mRNA vaccine development, enabling rapid responses to emerging infectious diseases and supporting the development of precise, personalized therapies. These approaches may guide the future direction of mRNA vaccine development. Our review aims to provide integrated constructive support for computer-aided mRNA vaccine design.

Ischemic heart disease, which affects more than 200 million people worldwide, is caused by reduced blood flow to the heart and leads to widespread cardiomyocyte death. Due to the limited regenerative potential of cardiomyocytes, the lost tissue is replaced by a fibrotic scar, resulting in reduced cardiac function and progression to heart failure. Current therapeutic interventions aim to improve blood flow but cannot address the inability of cardiomyocytes to renew after injury. However, multiple studies have shown that modulating the Hippo signaling pathway to activate Yes-associated protein (YAP), a transcription coactivator, in adult murine and porcine cardiomyocytes induces robust cardiomyocyte proliferation. Here, we discuss the therapeutic potential of YAP activation in the context of cardiac renewal, with a focus on both cardiomyocyte intrinsic mechanisms and the role of the microenvironment. These findings provide important insights into cardiac regeneration and strategies for developing therapies for human patients.

Endocytosis in nonneuronal cells requires gradual recruitment of proteins to endocytic sites for inducing membrane curvature and forming scaffolds around the neck of endocytic pits. This recruitment process is thought to be rate-limiting, requiring tens of seconds. In contrast, a form of endocytosis in neurons called ultrafast endocytosis is much faster, requiring only 100 ms. In this review, we compare the mechanisms of protein recruitment during clathrin-mediated endocytosis in nonneuronal cells and ultrafast endocytosis in neurons and discuss how endocytosis can complete within 100 ms. We then discuss the potential clinical relevance of this endocytic pathway.

Omega-3 fatty acids, such as docosahexaenoic acid (DHA), are essential nutrients required to support the growth, maintenance, and function of the central nervous system (CNS). While the brain has a high demand for DHA, it cannot synthesize it de novo and thus relies on its uptake from the bloodstream. Circulating DHA is primarily obtained from dietary sources and is transported across the blood-brain barrier (BBB) in the form of lysophosphatidylcholine (LPC-DHA) by the transmembrane transporter major facilitator superfamily domain containing 2A (MFSD2A) in a sodium-dependent manner. Here we provide a comprehensive analysis of recent insights gained from structural, functional, and computational studies of MFSD2A. We focus on the mechanism by which this transporter mediates sodium-dependent uptake of LPC-DHA, and lysolipids more broadly, highlighting different conformational states, substrate entry and release pathways, and the ligand binding sites. This review presents a detailed overview of the molecular mechanism that enables MFSD2A to supply the brain with this essential nutrient, while simultaneously providing biophysical insights into how lysolipids are transported across biological membranes.

Over the past several decades, physiological research has undergone a progressive shift toward greater and greater reductionism, culminating in the rise of "molecular physiology." The introduction of omic techniques, chiefly protein mass spectrometry and next-generation DNA sequencing (NGS), has further accelerated this trend, adding massive amounts of information about individual genes, mRNA transcripts, and proteins. However, the long-term goal of understanding physiological and pathophysiological processes at a whole organism level has not been fully realized. This review summarizes the major protein mass spectrometry and NGS techniques relevant to physiology and explores the challenges of merging data from omic methodologies with data from traditional hypothesis-driven research to broaden the understanding of physiological mechanisms. It summarizes recent progress in large-scale data integration through 1) creation of online user-friendly omic data resources with cross-indexing across datasets to democratize access to omic data; 2) application of Bayesian methods to combine data from multiple omic datasets with knowledge from hypothesis-driven studies to address specific physiological and pathophysiological questions; and 3) application of concepts from natural language processing to probe the literature and to create user-friendly causal graphs representing physiological mechanisms. Progress in development of so-called large language models, e.g. ChatGPT, for knowledge integration is also described, along with a discussion of the shortcomings of large language models with regard to management and integration of physiological data.

Early-life undernutrition is known to be a potentially important risk factor for the development of diabetes mellitus in adult life. Additionally, some literature suggests that undernutrition during later life or adulthood may lead to metabolic consequences, including diabetes, despite an individual's normal nutritional status earlier in life. Notably, individuals with diabetes and undernutrition show some unique features that do not fit the usual phenotype of type 2 diabetes mellitus, such as a low body mass index of <18.5 kg/m², resistance to ketosis, and low serum C-peptide levels. Many global descriptions of this unique phenotype have led to a controversy that "undernutrition-associated diabetes mellitus" is a distinct form of diabetes, deserving a separate diabetes category in the WHO classification of diabetes. However, a few investigators argue that undernutrition-associated diabetes mellitus is one of the variants of the classical forms of diabetes. The second controversy is whether adult undernutrition is independently associated with metabolic abnormalities. Its pathophysiology has been difficult to determine, given confounding factors such as infections that can complicate the direct effects of malnutrition. Studies have shown that insulin deficiency due to pancreatic β-cell impairment is likely to contribute to the development of undernutrition-associated diabetes. To examine these controversies, further research is warranted to understand the role of undernutrition in the pathogenesis of undernutrition-associated diabetes. This review aims to shed more light on these controversies, focusing on whether diabetes in malnourished individuals represents a distinct diabetes category and the association between malnutrition and diabetes in adults.

More than 100 years after the original descriptions of altitude adaptation, it is now clear that many of these responses are mediated by a specific isoform of the transcription factor hypoxia-inducible factor (HIF)-2α. Here, we review this work, including connectivity with the oxygen chemosensitive response itself and with paraganglioma, a tumor often affecting chemosensitive tissues.

Genomic rearrangements play an important role in shaping genetic diversity, as they enable the generation of novel structural variations through specific genome manipulation tools. These variations contribute to phenotypic differences among individuals within a population, thereby serving as the foundation for natural selection and driving evolutionary processes. In recent years, synthetic chromosome rearrangement and modification by LoxP-mediated evolution (SCRaMbLE) has emerged as a promising tool for studying genomic rearrangements. SCRaMbLE utilizes site-specific recombination mediated by loxPsym sites to induce targeted chromosomal rearrangements in yeast cells. In this review, we provide a comprehensive overview of recent advancements in optimization strategies of the SCRaMbLE system and discuss influential factors that affect its performance based on recent research findings. We demonstrate how the SCRaMbLE system can be employed for pathway engineering, phenotype improvement, genome minimization, and dissection of genotype-to-phenotype relationships. We highlight both the advantages and challenges associated with SCRaMbLE and envision its potential applications beyond yeast genetics.

There is a fundamental need to consider plant physiology in relation to human health as it encompasses a number of often overlooked issues, from plant-based medicines to nutrition. The goal here is to provide a historical narrative of plant physiological and biological responses to rising CO₂ and climate variability while addressing current controversies and finally a "next steps" overview of current links between plants and human health and crucial, unmet research needs.