The chronic hypoxia experienced by high-altitude residents profoundly impacts pregnancy, influencing maternal health, placental function, and the growth and development of the fetus. Exposure to chronic hypoxia during pregnancy increases the risk of complications like preeclampsia and fetal growth restriction and has lasting effects on offspring, extending from infancy to adulthood. Understanding how chronic hypoxia alters physiological adaptations to pregnancy and pregnancy outcomes is essential for high-altitude populations and for gaining broader insights into the mechanisms underlying reduced fetoplacental oxygenation in complicated pregnancy at sea level. This review summarizes current knowledge on physiological adaptations during pregnancy under hypoxic conditions. We describe key studies on the effects of high altitude and chronic hypoxia on pregnancy, and examine the maternal, placental, fetal, and long-term physiological consequences. Finally, we review preclinical and clinical studies aimed at identifying interventions that could prevent or alleviate the adverse effects of chronic hypoxia on pregnancy outcomes and beyond.
The chronic hypoxia experienced by high-altitude residents profoundly impacts pregnancy, influencing maternal health, placental function, and the growth and development of the fetus. Exposure to chronic hypoxia during pregnancy increases the risk of complications like preeclampsia and fetal growth restriction and has lasting effects on offspring, extending from infancy to adulthood. Understanding how chronic hypoxia alters physiological adaptations to pregnancy and pregnancy outcomes is essential for high-altitude populations and for gaining broader insights into the mechanisms underlying reduced fetoplacental oxygenation in complicated pregnancy at sea level. This review summarizes current knowledge on physiological adaptations during pregnancy under hypoxic conditions. We describe key studies on the effects of high altitude and chronic hypoxia on pregnancy, and examine the maternal, placental, fetal, and long-term physiological consequences. Finally, we review preclinical and clinical studies aimed at identifying interventions that could prevent or alleviate the adverse effects of chronic hypoxia on pregnancy outcomes and beyond.
Extracellular vesicles (EVs) are lipid-bound nanostructures that play important roles in reproduction as universal mediators of bidirectional cell-to-cell communication. EVs transfer diverse cargoes between reproductive cells, influencing fundamental reproductive processes such as gametogenesis and pregnancy. In the male reproductive tract, specialized EVs such as epididymosomes and prostasomes regulate sperm activation, motility, and capacitation, exerting some of these effects within the female reproductive tract as well. In the female reproductive tract, EVs found in follicular fluid, oviduct, and uterus aid in oocyte maturation, fertilization, and the vital embryo development and embryo-maternal crosstalk necessary for successful implantation, including after in vitro fertilization. With advancing gestation, EVs continue to play crucial roles in mediating communication between maternal, placental and fetal compartments with the ultimate aim of promoting immunotolerance and development of the allogeneic fetus. Focusing on the human reproductive system, development of obstetric conditions such as preeclampsia and gestational diabetes is marked by a significant increase in EV release and systemic impacts, including endothelial dysregulation, perturbation of metabolic homeostasis and disruption to the blood-brain barrier. Disruption of EV-mediated signaling is linked to reproductive pathologies, but detailed etiologies are not yet defined. Importantly, EVs offer an exciting avenue for both biomarker discovery and therapeutic applications. Our advancing understanding of how EVs deliver their molecular cargo and influence gene expression in recipient cells holds promise for manipulating these processes and improving the diagnosis and treatment of infertility and pregnancy complications.
Manganese (Mn) is an essential metal required for many physiological functions, and deficiency or overexposure is associated with neurological dysfunction and neuropathology. Tight homeostatic control of Mn in the body is required to maintain optimal physiological levels and protect against toxicity. Mn homeostasis has been studied for decades, but there has been limited knowledge of the molecular mechanisms until recently, when the first human genetic disorders of Mn metabolism were described. These discoveries led to the identification of the Mn transporters SLC30A10, SLC39A14, and SLC39A8, which spurred a transformation of research into Mn homeostatic mechanisms. This review provides an overview of Mn physiology and homeostasis and the role of the critical Mn transporters and discusses the progress made within recent years toward understanding how these transporters work together to regulate brain Mn biology under both physiological and pathophysiological Mn conditions.
One of the most remarkable properties of the mammalian brain is its ability to change in response to experience, a phenomenon referred to as neural plasticity. Synaptic plasticity specifically refers to activity-dependent changes in synaptic strength or efficacy of synaptic transmission. Synaptic plasticity enables us to acquire and perform different sensory, motor, and cognitive tasks, such as playing a musical instrument or learning a language. Synaptic plasticity is involved in the creation of memories and is a phenomenon that varies and evolves over an individual's lifetime. The most extensively studied forms of synaptic plasticity in the mammalian brain are long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission. Sixty years ago, an abstract by Terje Lømo first described a long-lasting synaptic potentiation induced by high-frequency afferent stimulation (Lømo T. Acta Physiol Scand 68: 128, 1966), and 7 years later the first full paper on LTP was published by Tim Bliss and Terje Lømo in the Journal of Physiology (Bliss TV, Lomo T. J Physiol 232: 331-356, 1973). Since then, "neuroplasticity" or "brain plasticity" has emerged as a central theme of research in neuroscience. Increasing evidence supports the supposition that LTP is a natural phenomenon that is directly involved in neurodevelopment and learning and memory processes. Additionally, different brain disorders seem to be due to alterations in brain plasticity. Since its discovery, thousands of papers have appeared describing the underlying mechanisms and demonstrating that LTP is a robust and general brain mechanism that exists in vivo in animals including humans. Currently, the field is dedicated to defining more precisely the functions in which LTP (and LTD) is involved, including development, learning, and memory, as well as their roles in brain disorders. Here, we describe the present state of the field. We foresee that important discoveries remain to be made with implications for the understanding of, and treatment of, brain disorders.
After a previous overview published more than 20 years ago, key aspects of catecholamine metabolism remain incompletely understood by physiologists. Meanwhile, the repertoire of assayable catecholamine-related compounds has expanded. Moreover, alterations in catecholamine metabolic patterns associated with physiological changes, drug effects, and pathophysiological states were not covered, and biochemical phenotyping via kinetic models now makes it possible to elucidate physiology and pathophysiology in individuals. Accordingly, this review starts with the inventory of catecholamine-related compounds and the three main peripheral catecholamine systems (sympathoneuronal, adrenomedullary, and autocrine/paracrine). Catecholamine systems contribute to virtually every organ function, behavior, and emotional state, and we describe situations where alterations in those systems exert syndromic pathophysiological effects. We then describe the relationships of catecholamine metabolic patterns to synthesis, storage, release, reuptake, and intraneuronal and extraneuronal metabolism of catecholamines; effects of physiological processes and drugs on those patterns; and catecholamine biochemical patterns associated with pathophysiological states. We provide examples of how detailed, comprehensive knowledge acquired over the past half century has led to computational models for estimating the rates of processes that characterize specific physiological changes and some clinical disorders. The integrative physiological approach presented here has the potential to pinpoint specific functional abnormalities within catecholaminergic cells and thereby rationalize novel, testable treatment and prevention strategies.
Transcranial magnetic stimulation (TMS) noninvasively activates the human cortex through the intact skull and is now employed worldwide to interrogate physiological and pathological functions of the human brain and to treat a variety of neurological and psychiatric brain disorders. Yet the precise routes from the induced electric field to neuronal excitation including network effects remain not fully resolved, limiting the mechanistic basis of all TMS applications. This review deeply surveys how TMS activates the human cortex. We integrate evidence from physics, biophysics, computational modeling, neurophysiological studies in humans using electromyography, electroencephalography, and epidural spinal recordings, and converging nonhuman primate, rodent, and cortical slice studies. Collectively, the data suggest that TMS preferentially depolarizes superficial large-diameter myelinated axons, likely at bends, thereby triggering near-instantaneous synaptic activation of local cortical circuits and the emergence of long-range corticocortical and cortico-subcortical network activity. Through this cascade, axonal excitation, cell and circuit recruitment, and network propagation, TMS provides a versatile probe of excitability, function, and dysfunction across spatial scales, from single axons to distributed human brain networks.
A-kinase anchoring proteins (AKAPs) received their name based on their ability to bind protein kinase A (PKA). Now, AKAPs have grown to a diverse family of more than 50 proteins, coordinating molecules far beyond PKA and the PKA signaling pathway. AKAPs are scaffolding proteins spanning in size between 15 and several hundred kilodaltons and can directly engage in protein interactions with other signaling proteins, their upstream regulators, and their downstream effectors. AKAPs possess unique targeting domains directing them to defined cellular compartments to coordinate cellular signaling spatially and temporally. A few AKAPs possess their own catalytic activity. AKAPs are crucial in directing cAMP signaling locally and in mediating cross talk with other second messenger systems. This review introduces individual AKAPs and their physiological functions in their respective cellular compartments and illustrates how they organize local signal transduction. The crucial role of AKAPs in coordinating cAMP responses to extracellular cues and how they facilitate specific responses to each stimulus will be exemplified. Dysregulation of AKAPs is associated with or causes disease. We will examine the pathophysiological roles of AKAPs in inherited and noninherited noncommunicable diseases, such as cardiovascular diseases and cancer. Due to the lack of understanding of molecular mechanisms underlying most of these diseases, the available therapeutic approaches often only slow progression and cause side effects. This review will discuss the unique opportunities AKAPs provide to address the medical need for novel therapeutic concepts. Finally, gaps in our knowledge about AKAPs will be outlined, and future directions in AKAP research will be suggested.
Cells undergoing transitional states have been broadly referred to as plastic intermediates emerging between stable identities in multiple biological contexts. Once regarded as indistinct midpoints on lineage trajectories, these states are now recognized as discrete, biologically meaningful epigenetically permissive states, exquisitely responsive to environmental and stress signals at critical junctures of biological events that confer competence to proceed along their trajectories. These high-plasticity nodes have emerged as central regulators of developmental progression and determinants of disease outcomes, serving as functional bottlenecks in which resolution or persistence dictates normal or maladaptive pathological responses. Recent single-cell and multiomics technologies enabled their detection with unprecedented resolution, revealing conserved regulatory themes, including stress-response activation and striking context dependence shaped by niche cues and tissue architecture. Yet challenges remain in capturing their rapid heterogeneous dynamic in the multiple contexts, and defining their function, in vivo. Here we summarize current concepts on the identification, diversity, role, and regulation of these cell states in events from early development to adult homeostasis, repair, and disease. The increasing recognition that transitional states can be productive conduits or pathological traps underscores their relevance in these processes and potential for the identification of therapeutic targets for intervention in disease, cancer, and regenerative medicine.
Cholangiocytes are specialized epithelial cells that line the intrahepatic and extrahepatic biliary tree and play a critical role in bile modification, liver homeostasis, and response to injury. Cholangiocytes exhibit notable heterogeneity and plasticity, and their dysfunction is central to a spectrum of diseases targeting the bile ducts, collectively called cholangiopathies. These disorders include genetic, infectious, immune-mediated, and malignant diseases, with primary sclerosing cholangitis (PSC) representing one of the most complex and enigmatic of these disorders. PSC is a progressive, fibro-inflammatory disease of the bile ducts that is closely linked to inflammatory bowel disease, carries a heightened risk of cancer, and lacks any approved therapies. This review explores the biology of cholangiocytes, including their development, functional plasticity, and roles in secretion, absorption, and cellular signaling. We provide a detailed examination of cholangiopathies, particularly PSC, a complex cholangiopathy characterized by a paradoxical state of cholangiocyte senescence and hyperproliferation. We describe how immune cell dysfunction, the gut microbiome, genetic predispositions, and environmental factors converge to mediate PSC pathogenesis. We revisit the foundational technologies that empowered early discoveries and shaped the field as we know it today. We also explore how newer techniques such as organoid cultures, single-cell transcriptomics, epigenomics, and spatialomics have transformed our modern understanding of biliary pathophysiology. Finally, we provide an overview of existing rodent models of cholangiopathies and discuss their relevance to human disease. PSC remains therapeutically unaddressed, and thus ongoing multidisciplinary efforts are essential to developing targeted interventions. This review serves as a comprehensive resource for researchers and clinicians navigating the rapidly evolving landscape of cholangiocyte-centered liver disease research.
Burn injuries are among the most devastating disruptors of human physiology, provoking systemic disturbances unmatched by nearly any other form of pathology, yet they remain critically underappreciated. Each year, approximately 8.4 million people sustain burn injuries worldwide, leading to 110,000 deaths and countless cases of long-term disability. Beyond the immediate tissue damage, burns trigger a uniquely severe and persistent hypermetabolic response that, if not effectively managed, cascades into widespread dysfunction across multiple organ systems, driving morbidity and, in many cases, mortality. Among the many affected organ systems is the endocrine system, which, when disrupted, leads to compromised fluid and mineral balance, cachexia, insulin resistance, immunosuppression, and various other health issues. In this narrative literature review, we highlight the various endocrine axes and how they are dysregulated by thermal injury and the current pharmacological strategies that are used to treat these burn-induced hormone disruptions and hypermetabolism. Taking into account the widespread effects of the endocrine system, we also delve into the intricate interplay between the endocrine and immune systems of each axis, highlighting the substantial challenge of immunosuppression often observed in severe burn patients. Additionally, we underline the current gaps that exist in the literature and the urgent need for long-term longitudinal trials that take factors such as age and sex into consideration. A better understanding of the implications of burns on the endocrine system will help with the development of effective treatments that could improve the long-term health of severe burn patients.
Alveolar macrophages (AMs) are pivotal immune sentinels, essential for maintaining tissue homeostasis and mediating immune responses to inhaled particles and pathogens. They demonstrate remarkable plasticity by transitioning from proinflammatory (M1) and anti-inflammatory/reparative (M2) phenotypes in response to local signals. Upon exposure to environmental agents, such as particulate matter, atypical respiratory pathogens, opportunistic Gram-negative bacteria, or respiratory viruses, they undergo dynamic activation that profoundly influences their functional repertoire. Acute or chronic environmental/biological insults disrupt normal AM activities such as phagocytosis, efferocytosis, and cytokine production, inciting oxidative stress, inflammasome activation, and in some cases forms of programmed cell death such as pyroptosis. Although these responses are indispensable for eliminating noxious particles and pathogens, such as Mycoplasma pneumoniae or Klebsiella pneumoniae, influenza A, or SARS-CoV-2, they can also derail the resolution phase by perpetuating inflammation, driving tissue remodeling and fibrosis, and thereby fueling chronic lung disorders such as chronic obstructive pulmonary disease (COPD), pneumoconiosis, and post-COVID interstitial lung disease. Moreover, environmental and microbial exposures modify AMs by altering receptor repertoires, intracellular phenotype by signaling cascades, and cross talk with epithelial and mesenchymal cells that collectively determine the disease trajectory. Elucidating how diverse environmental agents, together with pathogens such as M. pneumoniae, K. pneumoniae, influenza A, and SARS-CoV-2, shape AM biology is therefore pivotal for understanding the pathogenesis of COPD, pneumoconiosis, progressive fibrotic lung disease, and COVID-19-related pulmonary sequelae. This review brings together the current insights into exposure-driven modulation of AM functions, highlighting recent advances and identifying knowledge gaps relevant for therapeutic targeting of exposure-induced and pathogen-mediated lung pathology.
Magnetosensation, or the magnetic sense, is the ability of organisms to detect the Earth’s magnetic field. Behavioral evidence supporting magnetosensation emerged in the latter half of the twentieth century, and it is now recognized as widespread across the animal kingdom. Yet the mechanisms underlying this sense remain poorly understood, with three main hypotheses proposed: magnetite-based detection, radical pair reactions in photosensitive molecules, and electromagnetic induction. This review provides a concise overview of current knowledge on magnetosensation, emphasizing behavioral evidence, sensory mechanisms, and the neural processing of magnetic information. We also discuss findings on magnetosensitivity in humans, highlighting evidence that suggests humans may retain a residual unconscious magnetic sense. We argue that understanding the mystery of magnetosensation has broad implications: it can yield insight into poorly understood biological and health effects of magnetic fields, inform the emerging field of magnetogenetics for remote control of cellular activity, and guide the protection of ecosystems dependent on magnetosensitive species.
Smooth muscle is vital to hollow organs such as vessels, airways, bladder, prostate, uterus, and gastrointestinal tract. Its ability to contract and relax is essential for organ function. In vessels, vascular smooth muscle cells or arterial myocytes help regulate blood pressure and ensure proper blood flow to tissues. However, during diseases such as atherosclerosis, hypertension, and restenosis, these myocytes undergo a major transformation. They shift from a quiescent, contractile state to an active, synthetic one. In this synthetic state, they behave like inflammatory cells: secreting cytokines and signaling molecules, remodeling the surrounding matrix, and becoming migratory and proliferative. This shift is tied to a remodeling of their ion transport repertoire. Here, we build and refine a cohesive model whereby synthetic myocytes adopt a phenotype resembling nonexcitable cells. We propose that their ion transport toolkit changes as a coordinated unit, creating a distinct calcium signaling signature that supports their new roles in growth, movement, inflammation, and secretion, while sacrificing their contractile features. Focusing mainly on arterial myocytes, we examine how disease-driven changes in ion transport reshape the calcium signaling landscape. This shift moves away from classical excitation-contraction, mediated by L-type calcium channels and ryanodine receptors, and toward channels such as store-operated stromal interaction molecule (STIM)/Orai and transient receptor potential (TRP) channels, which are activated by growth and vasoactive factors and operate best at hyperpolarized membrane potentials. We also explore the remodeling of ion channels, transporters, and pumps within internal organelles and emphasize how understanding these changes could reveal new therapeutic targets for treating disease.
Antibody-drug conjugates (ADCs) are a leading area of targeted cancer therapeutics, typically combining a tumor-associated antigen-specific antibody conjugated to a toxic payload that targets key cellular mechanisms, such as mitosis and survival. The global ADC clinical trial landscape has been expanding significantly, with over 430 ADCs reaching early to late clinical studies in the past two decades, up from just 90 between 2004 and 2014. The US Food and Drug Administration (FDA) has so far approved 14 ADCs for use in clinical oncology. This growth is likely driven by significant advances in antibody technology and conjugation methods enabling more effective and precise delivery to cancer cells and more effective payloads that target vital cancer biology. Here, we review the ADCs that have reached clinical approval as well as current and emerging trends in ADC development, and we discuss these from multiple perspectives, including ADC mechanisms of action, emerging antigen targets, linker and conjugation chemistry, payloads, combination of ADC with checkpoint inhibitor immunotherapy, and antibody fragment crystallizable (Fc) engineering. We also consider how the field is evolving through the application of artificial intelligence (AI) and pathology-based biomarker discovery. Combined, innovative and emerging ADC design coupled with precision medicine and patient stratification strategies hold great promise to develop diverse and personalized cancer treatments with improved therapeutic indices and to enhance tolerability compared to traditional chemotherapy and current established ADCs. This review aims to assist researchers in exploring the evolution, characteristics, and development trends in ADC design and to provide new directions for future research.
Small-molecule discovery and drug development are increasingly being pursued in academic settings, expanding beyond their traditional confinement to the pharmaceutical industry. The initial steps in drug discovery typically include identification and validation of a target, screening of chemical libraries to identify modulators of target activity, and subsequent prioritization and optimization of lead compounds using in vitro systems and animal models, with emphasis on compound potency, selectivity, and pharmacological properties. This review focuses on early-stage discovery of small molecules that target plasma membrane transporters on epithelial cells, including absorptive and secretory epithelia in kidney, gastrointestinal tract, lung, and eye. Of the estimated 500 distinct epithelial plasma membrane transporters, fewer than a dozen are the targets of approved drugs, most of which have been in clinical use for decades. We discuss the logistics and challenges associated with small-molecule discovery in an academic setting. Specific epithelial cell targets are considered, including chloride channels, solute-coupled transporters, urea transporters, and aquaporins, with therapeutic implications spanning constipation and secretory diarrheas, cystic fibrosis, dry eye disease, edema, hypertension, and kidney stones. We conclude by identifying unmet needs and outlining opportunities to enable next-generation pharmacological modulation of epithelial transport processes.
The stomach is home to numerous nuclear receptor transcription factors (NRs) that can respond to food, toxins, and other ingested agents. Conversely, signals secreted from other organs (e.g., hormones) can engage gastric NRs to modulate gastric physiology. Thus, there is a rich potential interface between external and internal signals that gastric NRs might respond to and interpret. Here, we seek to comprehensively review the role of NRs in gastric homeostasis and disease pathogenesis. NRs are evolutionarily conserved proteins that regulate gene transcription by interpreting hormonal and environmental signals. We explore NR roles in normal stomach development, cell fate determination, and responses to dietary compounds and xenobiotics. The last topic is of particular recent importance 1) because NRs stimulated by ingested agents might directly regulate gastric physiology like the relative activity of acid-secreting and stem cells and 2) because the stomach is one of the first organs to encounter dietary compounds and pollutants. Additionally, we review the emerging yet understudied field of gastro-endocrinology, exploring how systemic endocrine circuits influence the stomach's function. We also discuss how NRs contribute to pathological conditions like precancerous lesions and cancer. Additionally, we summarize known agonists, antagonists, and coregulatory proteins, highlighting potential therapeutic targets. Understanding NR roles could pave the way for a better understanding of dietary and environmental toxin exposure and also lead to innovative treatments for gastric disorders, including gastritis, gastric intestinal metaplasia, and gastric cancer.
The alpha rhythm, first identified by Hans Berger 100 years ago, is the dominant noninvasive electrophysiological signature of the healthy human brain in the awake state. For decades, it was believed that the alpha rhythm reflected rest or idling; however, this perspective changed in the 2000s when researchers found that alpha oscillations increase with cognitive demands. This discovery led to a paradigm shift, demonstrating that alpha oscillations reflect the functional inhibition of brain regions that are not needed for a specific task, thereby directing information to task-specific areas. We have reviewed the physiological mechanisms involved in generating alpha oscillations, which have informed computational models explaining how these oscillations emerge within physiologically realistic networks. At the behavioral level, alpha oscillations are strongly modulated across nearly all cognitive paradigms tested in humans, reflecting the allocation of computational resources within the active brain network. Research in individuals with attention-related issues has highlighted their impaired ability to modulate alpha oscillations, which is associated with performance deficits. Therefore, further exploration of alpha oscillations has the potential to uncover causal mechanisms underlying attention problems, such as those related to attention deficit hyperactivity disorder (ADHD) and aging. Finally, advancements in technology are opening new avenues for characterizing alpha oscillations in ecologically valid settings and across the lifespan. This progress sets the stage for exploring the role of alpha oscillations in cognitive development and their functioning in natural environments.
The human genome harbors millions of noncoding sequence variants. Genome-wide association studies (GWAS) have identified thousands of robust associations linking noncoding variants to human physiological traits and complex diseases. Integrative approaches, including expression quantitative trait locus mapping, epigenomic profiling, and precise genome editing in trait-relevant cell types, enable the identification of effector genes and underlying regulatory mechanisms, such as long-range chromatin interactions, that mediate the effects of noncoding variants. Investigations of blood pressure (BP)-associated noncoding sequence variants have uncovered previously unrecognized roles of genes in BP regulation, reinforced the human genetic relevance of established BP regulatory pathways, and elucidated specific regulatory mechanisms by which noncoding variants influence gene expression and BP. Studies of orthologous noncoding genomic regions in animal models corresponding to human genomic regions harboring BP-associated variants have demonstrated substantial effects on BP, suggesting that the phenotypic impact of noncoding sequence variants may be large within human subgroups. Continued expansion of functional studies of trait-associated noncoding sequence variants, together with advances in mapping molecular quantitative trait loci and epigenomic landscapes, will provide novel insights directly relevant to human biology and disease and essential for understanding humans as molecular systems.
