Physiology最新文献

Preterm birth remains a worldwide health concern because of ongoing challenges in prediction and prevention. Current predictors are limited by poor performance, need for invasive sampling, and an inability to identify patients in a timely fashion to allow for effective intervention. The multiple etiologies of preterm birth often have an inflammatory component. Thus, a deeper understanding of the inflammatory mechanisms involved in preterm birth may provide opportunities to identify new predictors of preterm birth. This review discusses the multiple etiologies of preterm birth, their links to inflammation, current predictors available, and new directions for the field.

RANKL and its cognate receptor RANK are crucial regulators of bone metabolism in physiological as well as in pathological conditions. Here we go through the works that unveiled the paramount role of this signaling pathway. We focus on the RANKL cytokine, whose alterations are responsible for rare and common bone diseases. We describe recent insights on the regulation of RANKL expression, which provide new hints for the pharmacological regulation of this molecule. Based on the multiple functions exerted by RANKL (within and outside the bone tissue), we advise caution regarding the potential unintended consequences of its inhibition.

Understanding physiological mechanisms of tolerance to heat exposure, and potential ways to improve such tolerance, is increasingly important in the context of ongoing climate change. We discuss the concept of heat tolerance in humans and experimental models (primarily rodents), including intracellular mechanisms and improvements in tolerance with heat acclimation.

Voltage-gated ion channels (VGICs) are pivotal in regulating electrical activity in excitable cells and are critical pharmaceutical targets for treating many diseases including cardiac arrhythmia and neuropathic pain. Despite their significance, challenges such as achieving target selectivity persist in VGIC drug development. Recent progress in deep learning, particularly diffusion models, has enabled the computational design of protein binders for any clinically relevant protein based solely on its structure. These developments coincide with a surge in experimental structural data for VGICs, providing a rich foundation for computational design efforts. This review explores the recent advancements in computational protein design using deep learning and diffusion methods, focusing on their application in designing protein binders to modulate VGIC activity. We discuss the potential use of these methods to computationally design protein binders targeting different regions of VGICs, including the pore domain, voltage-sensing domains, and interface with auxiliary subunits. We provide a comprehensive overview of the different design scenarios, discuss key structural considerations, and address the practical challenges in developing VGIC-targeting protein binders. By exploring these innovative computational methods, we aim to provide a framework for developing novel strategies that could significantly advance VGIC pharmacology and lead to the discovery of effective and safe therapeutics.

Inflammation is an important physiological response of the organism to restore homeostasis upon pathogenic or damaging stimuli. However, the persistence of the harmful trigger or a deficient resolution of the process can evolve into a state of low-grade, chronic inflammation. This condition is strongly associated with the development of several increasingly prevalent and serious chronic conditions, such as obesity, cancer, and cardiovascular diseases, elevating overall morbidity and mortality worldwide. The current pandemic of chronic diseases underscores the need to address chronic inflammation, its pathogenic mechanisms, and potential preventive measures to limit its current widespread impact. The present review discusses the current knowledge and research gaps regarding the association between low-grade chronic inflammation and chronic diseases, focusing on obesity, cardiovascular diseases, digestive diseases, and cancer. We examine the state of the art in selected aspects of the topic and propose future directions and approaches for the field.

Olfactory deficits are increasingly recognized in a variety of neurological, neurodevelopmental, psychiatric and viral diseases. While the pathology underlying olfactory loss is likely to differ across diseases, one shared feature may be an immune response mediated by microglia. Microglia orchestrate the brain's response to environmental insults and maintain neurodevelopmental homeostasis. Here, we explore the potential involvement of microglia in olfactory development and loss in disease. The effects of microglia-mediated immune response during development may be of special relevance to the olfactory system, which is unique in both its vulnerability to environmental insults as well as its extended period of neurogenesis and neuronal migration.

The Small Ubiquitin-like Modifier (SUMO) protein pathway governs a panoply of vital biological processes ranging from cell death, proliferation, differentiation, metabolism, and signal transduction by diversifying the functions, half-lives, and partnerships of target proteins in situ. More recently, SUMOylation has emerged as a key regulator of ion homeostasis and excitability across multiple tissues due to regulation of a plethora of ion channels expressed in a range of tissues subtypes. Altogether, the balance of SUMOylation states amongst relevant ion channels can result in graded biophysical effects that tune excitability and contribute to a range of disease states including cardiac arrythmia, epilepsy, pain transmission, and inflammation. Here, we consolidate these concepts by focusing on the role of ion channel SUMOylation in the central nervous system, peripheral nervous system and the cardiovascular system. In addition, we review what is known about the enigmatic factors that regulate the SUMO pathway and consider the emerging role of small molecule SUMO-modulators as potential therapeutics in a range of diseases.

The mammalian target of Rapamycin complex 1 (mTORC1) is a serine/threonine kinase that couples nutrient and growth factor signaling to the cellular control of metabolism and plays a fundamental role in aberrant proliferation in cancer. mTORC1 has previously been considered an "on/off" switch, capable of phosphorylating the entire pool of its substrates when activated. However, recent studies have indicated that mTORC1 may be active toward its canonical substrates, eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) and S6 kinase (S6K), involved in mRNA translation and protein synthesis, and inactive toward TFEB and TFE3, transcription factors involved in the regulation of lysosome biogenesis, in several pathological contexts. Among these conditions are Birt-Hogg-Dubé syndrome (BHD) and, recently, tuberous sclerosis complex (TSC). Furthermore, increased TFEB and TFE3 nuclear localization in these syndromes, and in translocation renal cell carcinomas (tRCC), drives mTORC1 activity toward the canonical substrates, through the transcriptional activation of the Rag GTPases, thereby positioning TFEB and TFE3 upstream of mTORC1 activity toward 4EBP1 and S6K. The expanding importance of TFEB and TFE3 in the pathogenesis of these renal diseases warrants a novel clinical grouping that we term "TFEopathies." Currently, there are no therapeutic options directly targeting TFEB and TFE3, which represents a challenging and critically required avenue for cancer research.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as pivotal medications for heart failure, demonstrating remarkable cardiovascular benefits extending beyond their glucose-lowering effects. The unexpected cardiovascular advantages have intrigued and prompted the scientific community to delve into the mechanistic underpinnings of these novel actions. Preclinical studies have generated many mechanistic theories, ranging from their renal and extrarenal effects to potential direct actions on cardiac muscle cells, to elucidate the mechanisms linking these drugs to clinical cardiovascular outcomes. Despite the strengths and limitations of each theory, many await validation in human studies. Furthermore, whether SGLT2 inhibitors confer therapeutic benefits in specific subsets of cardiomyopathies akin to their efficacy in other heart failure populations remains unclear. By examining the shared pathological features between heart failure resulting from vascular diseases and other causes of cardiomyopathy, certain specific molecular actions of SGLT2 inhibitors (particularly those targeting cardiomyocytes) would support the concept that these medications will yield therapeutic benefits across a broad range of cardiomyopathies. This article aims to discuss the important mechanisms of SGLT2 inhibitors and their implications in hypertrophic and dilated cardiomyopathies. Furthermore, we offer insights into future research directions for SGLT2 inhibitor studies, which hold the potential to further elucidate the proposed biological mechanisms in greater detail.

Most studies in comparative immunology involve investigations into the detailed mechanisms of the immune system of a nonmodel organism. Although this approach has been insightful, it has promoted a deep understanding of only a handful of species, thus inhibiting the recognition of broad taxonomic patterns. Here, we call for investigating the immune defenses of numerous species within a pointillist framework, that is, the meticulous, targeted collection of data from dozens of species and investigation of broad patterns of organismal, ecological, and evolutionary forces shaping those patterns. Without understanding basic immunological patterns across species, we are limited in our ability to extrapolate and/or translate our findings to other organisms, including humans. We illustrate this point by focusing predominantly on the biological scaling literature with some integrations of the pace of life literature, as these perspectives have been the most developed within this framework. We also highlight how the more traditional approach in comparative immunology works synergistically with a pointillist approach, with each approach feeding back into the other. We conclude that the pointillist approach promises to illuminate comprehensive theories about the immune system and enhance predictions in a wide variety of domains, including host-parasite dynamics and disease ecology.