Physiology最新文献

Imaging is ubiquitous with biomedical research and discovery. This article surveys the role of imaging in our understanding of metabolism, and introduces photoacoustic imaging as a compelling candidate for providing high-resolution, label-free, and real-time insights into metabolic processes. As a rapidly evolving modality, photoacoustics holds promising preclinical and clinical potential in imaging of metabolism as well as metabolism-related changes.

The predatory imminence continuum (PIC) of antipredator defensive behavior has been a helpful strategy for modeling anxiety and fear-related disorders in nonclinical research. The PIC is divided into three different sequential stages that reflect defensive behavioral strategy in response to predatory imminence. However, the PIC was experimentally addressed using a series of shock-based fear conditioning experiments rather than predatory threats. In this study, we will consider the PIC in a more naturalistic behavioral setting, focusing on analyzing the neural systems of animals responding to terrestrial and aerial predators. Of relevance, there is a sequential engagement of the distinct neural circuits along each phase of the PIC. In the preencounter phase, prefrontal cortical networks are particularly involved in planning and organizing behavioral responses to ambiguous threats. As the predatory cues or the real predator is detected, there is an engagement of amygdalar and hippocampal > hypothalamic pathways in conjunction with the periaqueductal gray, which organize fear responses. This dynamic particularly reveals how specific neural circuits are set into action to subserve distinct defensive responses. Moreover, we further explored the neural circuits governing other fearful situations outside the context of the PIC, including agonistic social encounters and interoceptive challenges. This analysis revealed an interesting overlap between the neural systems responding to these threats and those involved in response to predatory threats. The present review clarifies how defensive circuits respond to natural threats and provides a more realistic view of the neural systems underlying anxiety and fear responses.

Sleep has been postulated to play an important role in the removal of potentially neurotoxic molecules, such as amyloid-β, from the brain via the glymphatic system. Disturbed sleep, on the other hand, may contribute to the accumulation of neurotoxins in brain tissue, eventually leading to neuronal death. A bidirectional relationship has been proposed between impaired sleep and neurodegenerative processes, which start years before the onset of clinical symptoms associated with conditions like Alzheimer's and Parkinson's disease. Given the heavy burden these conditions place on society, it is imperative to develop interventions that promote efficient brain clearance, thereby potentially aiding in the prevention or slowing of neurodegeneration. In this review, we explore whether the metabolic clearance function of sleep can be enhanced through sensory (e.g., auditory, vestibular) or transcranial (e.g., magnetic, ultrasound, infra-red light) stimulation, as well as pharmacological (e.g., antiepileptics) and behavioral (e.g., sleeping position, physical exercise, cognitive intervention) modulation of sleep physiology. A particular focus is placed on strategies to enhance slow-wave activity during non-rapid eye movement sleep as a driver of glymphatic brain clearance. Overall, this review provides a comprehensive overview on the potential preventative and therapeutic applications of sleep interventions in combating neurodegeneration, cognitive decline, and dementia.

The spatial organization of chromatin within the eukaryotic nucleus is critical in regulating key cellular functions, such as gene expression, and its disruption can lead to disease. Advances in experimental techniques, such as Hi-C and microscopy, have significantly enhanced our understanding of chromatin's intricate and dynamic architecture, revealing complex patterns of interaction at multiple scales. Along with experimental methods, physics-based computational models, including polymer phase separation and loop-extrusion mechanisms, have been developed to explain chromatin structure in a principled manner. Here, we illustrate genome-wide applications of these models, highlighting their ability to predict chromatin contacts across different scales and to spread light on the underlying molecular determinants. Additionally, we discuss how these models provide a framework for understanding alterations in chromosome folding associated with disease states, such as SARS-CoV-2 infection and pathogenic structural variants, providing valuable insights into the role of chromatin architecture in health and disease.

The autonomic nervous system is critical for regulating cardiovascular physiology. The neurocardiac axis encompasses multiple levels of control, including the motor circuits of the sympathetic and parasympathetic nervous systems, sensory neurons that contribute to cardiac reflexes, and the intrinsic cardiac nervous system that provides localized sensing and regulation of the heart. Disruption of these systems can lead to significant clinical conditions. Recent advances have enhanced our understanding of the autonomic control of the heart, detailing the specific neuronal populations involved and their physiologic roles. In this review, we discuss this research at each level of the neurocardiac axis. We conclude by discussing the clinical field of neurocardiology and attempts to translate this new understanding of neurocardiac physiology to the clinic. We highlight the contributions of autonomic dysfunction in prevalent cardiovascular diseases and assess the current status of novel neuroscience-based treatment approaches.

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.