G protein-coupled receptors (GPCRs) play a crucial role as membrane receptors, facilitating the communication of eukaryotic species with their environment and regulating cellular and organ interactions. Consequently, GPCRs hold immense potential in contributing to adaptation to ecological niches and responding to environmental shifts. Comparative analyses of vertebrate genomes reveal patterns of GPCR gene loss, expansion, and signatures of selection. Integrating these genomic data with insights from functional analyses of gene variants enables the interpretation of genotype-phenotype correlations. This review underscores the involvement of GPCRs in adaptive processes, presenting numerous examples of how alterations in GPCR functionality influence vertebrate physiology or, conversely, how environmental changes impact GPCR functions. The findings demonstrate that modifications in GPCR function contribute to adapting to aquatic, arid, and nocturnal habitats, influencing camouflage strategies, and specializing in particular dietary preferences. Furthermore, the adaptability of GPCR functions provides an effective mechanism in facilitating past, recent, or ongoing adaptations in animal domestication and human evolution and should be considered in therapeutic strategies and drug development.

Myosin II is a molecular motor that converts chemical energy derived from ATP hydrolysis into mechanical work. Myosin II isoforms are responsible for muscle contraction and a range of cell functions relying on the development of force and motion. When the motor attaches to actin, ATP is hydrolyzed and inorganic phosphate (P) and ADP are released from its active site. These reactions are coordinated with changes in the structure of myosin, promoting the so-called "power stroke" that causes the sliding of actin filaments. The general features of the myosin-actin interactions are well accepted, but there are critical issues that remain poorly understood, mostly due to technological limitations. In recent years, there has been a significant advance in structural, biochemical, and mechanical methods that have advanced the field considerably. New modeling approaches have also allowed researchers to understand actomyosin interactions at different levels of analysis. This paper reviews recent studies looking into the interaction between myosin II and actin filaments, which leads to power stroke and force generation. It reviews studies conducted with single myosin molecules, myosins working in filaments, muscle sarcomeres, myofibrils, and fibers. It also reviews the mathematical models that have been used to understand the mechanics of myosin II in approaches focusing on single molecules to ensembles. Finally, it includes brief sections on translational aspects, how changes in the myosin motor by mutations and/or posttranslational modifications may cause detrimental effects in diseases and aging, among other conditions, and how myosin II has become an emerging drug target.

Syncope is a symptom in which transient loss of consciousness occurs as a consequence of a self-limited, spontaneously terminating period of cerebral hypoperfusion. Many circulatory disturbances (e.g. brady- or tachyarrhythmias, reflex cardioinhibition-vasodepression-hypotension) may trigger a syncope or near-syncope episode, and identifying the cause(s) is often challenging. Some syncope may involve multiple etiologies operating in concert, whereas in other cases multiple syncope events may be due to various differing causes at different times. In this communication, we address the current understanding of the principal contributors to syncope pathophysiology including examination of the manner in which concepts evolved, an overview of factors that constitute consciousness and loss of consciousness, and aspects of neurovascular control and communication that are impacted by cerebral hypoperfusion leading to syncope. Emphasis focuses on ) current understanding of the way transient systemic hypotension impacts brain blood flow and brain function; ) the complexity and temporal sequence of vascular, humoral, and cardiac factors that may accompany the most common causes of syncope; ) the range of circumstances and disease states that may lead to syncope; and ) clinical features associated with syncope and in particular the reflex syncope syndromes.

Parenting behavior comprises a variety of adult-infant and adult-adult interactions across multiple timescales. The state transition from nonparent to parent requires an extensive reorganization of individual priorities and physiology and is facilitated by combinatorial hormone action on specific cell types that are integrated throughout interconnected and brainwide neuronal circuits. In this review, we take a comprehensive approach to integrate historical and current literature on each of these topics across multiple species, with a focus on rodents. New and emerging molecular, circuit-based, and computational technologies have recently been used to address outstanding gaps in our current framework of knowledge on infant-directed behavior. This work is raising fundamental questions about the interplay between instinctive and learned components of parenting and the mutual regulation of affiliative versus agonistic infant-directed behaviors in health and disease. Whenever possible, we point to how these technologies have helped gain novel insights and opened new avenues of research into the neurobiology of parenting. We hope this review will serve as an introduction for those new to the field, a comprehensive resource for those already studying parenting, and a guidepost for designing future studies.

The human brain possesses neural networks and mechanisms enabling the representation of numbers, basic arithmetic operations, and mathematical reasoning. Without the ability to represent numerical quantity and perform calculations, our scientifically and technically advanced culture would not exist. However, the origins of numerical abilities are grounded in an intuitive understanding of quantity deeply rooted in biology. Nevertheless, more advanced symbolic arithmetic skills require a cultural background with formal mathematical education. In the past two decades, cognitive neuroscience has seen significant progress in understanding the workings of the calculating brain through various methods and model systems. This review begins by exploring the mental and neuronal representations of nonsymbolic numerical quantity and then progresses to symbolic representations acquired in childhood. During arithmetic operations (addition, subtraction, multiplication, and division), these representations are processed and transformed according to arithmetic rules and principles, leveraging different mental strategies and types of arithmetic knowledge that can be dissociated in the brain. Although it was once believed that number processing and calculation originated from the language faculty, it is now evident that mathematical and linguistic abilities are primarily processed independently in the brain. Understanding how the healthy brain processes numerical information is crucial for gaining insights into debilitating numerical disorders, including acquired conditions like acalculia and learning-related calculation disorders such as developmental dyscalculia.

In 1996, we published a review article (Marder E, Calabrese RL. 76: 687-717, 1996) describing the state of knowledge about the structure and function of the central pattern-generating circuits important for producing rhythmic behaviors. Although many of the core questions persist, much has changed since 1996. Here, we focus on newer studies that reveal ambiguities that complicate understanding circuit dynamics, despite the enormous technical advances of the recent past. In particular, we highlight recent studies of animal-to-animal variability and our understanding that circuit rhythmicity may be supported by multiple state-dependent mechanisms within the same animal and that robustness and resilience in the face of perturbation may depend critically on the presence of modulators and degenerate circuit mechanisms. Additionally, we highlight the use of computational models to ask whether there are generalizable principles about circuit motifs that can be found across rhythmic motor systems in different animal species.

Lipids represent the most abundant molecular type in the brain, with a fat content of ∼60% of the dry brain weight in humans. Despite this fact, little attention has been paid to circumscribe the dynamic role of lipids in brain function and disease. Membrane lipids such as cholesterol, phosphoinositide, sphingolipids, arachidonic acid, and endocannabinoids finely regulate both synaptic receptors and ion channels that ensure critical neural functions. After a brief introduction on brain lipids and their respective properties, we review here their role in regulating synaptic function and ion channel activity, action potential propagation, neuronal development, and functional plasticity and their contribution in the development of neurological and neuropsychiatric diseases. We also provide possible directions for future research on lipid function in brain plasticity and diseases.

At the simplest level, neurons are structured to integrate synaptic input and perform computational transforms on that input, converting it into an action potential (AP) code. This process-converting synaptic input into AP output-typically occurs in a specialized region of axon termed the axon initial segment (AIS). The AIS, as its name implies, is often contained to the first section of axon abutted to the soma and is home to a dizzying array of ion channels, attendant scaffolding proteins, intracellular organelles, extracellular proteins, and, in some cases, synapses. The AIS serves multiple roles as the final arbiter for determining if inputs are sufficient to evoke APs, as a gatekeeper that physically separates the somatodendritic domain from the axon proper, and as a regulator of overall neuronal excitability, dynamically tuning its size to best suit the needs of parent neurons. These complex roles have received considerable attention from experimentalists and theoreticians alike. Here, we review recent advances in our understanding of the AIS and its role in neuronal integration and polarity in health and disease.

Glucose homeostasis is mainly under the control of the pancreatic islet hormones insulin and glucagon, which, respectively, stimulate glucose uptake and utilization by liver, fat, and muscle and glucose production by the liver. The balance between the secretions of these hormones is under the control of blood glucose concentrations. Indeed, pancreatic islet β-cells and α-cells can sense variations in glycemia and respond by an appropriate secretory response. However, the secretory activity of these cells is also under multiple additional metabolic, hormonal, and neuronal signals that combine to ensure the perfect control of glycemia over a lifetime. The central nervous system (CNS), which has an almost absolute requirement for glucose as a source of metabolic energy and thus a vital interest in ensuring that glycemic levels never fall below ∼5 mM, is equipped with populations of neurons responsive to changes in glucose concentrations. These neurons control pancreatic islet cell secretion activity in multiple ways: through both branches of the autonomic nervous system, through the hypothalamic-pituitary-adrenal axis, and by secreting vasopressin (AVP) in the blood at the level of the posterior pituitary. Here, we present the autonomic innervation of the pancreatic islets; the mechanisms of neuron activation by a rise or a fall in glucose concentration; how current viral tracing, chemogenetic, and optogenetic techniques allow integration of specific glucose sensing neurons in defined neuronal circuits that control endocrine pancreas function; and, finally, how genetic screens in mice can untangle the diversity of the hypothalamic mechanisms controlling the response to hypoglycemia.

Coenzyme Q (CoQ), also known as ubiquinone, comprises a benzoquinone head group and a long isoprenoid side chain. It is thus extremely hydrophobic and resides in membranes. It is best known for its complex function as an electron transporter in the mitochondrial electron transport chain (ETC) but is also required for several other crucial cellular processes. In fact, CoQ appears to be central to the entire redox balance of the cell. Remarkably, its structure and therefore its properties have not changed from bacteria to vertebrates. In metazoans, it is synthesized in all cells and is found in most, and maybe all, biological membranes. CoQ is also known as a nutritional supplement, mostly because of its involvement with antioxidant defenses. However, whether there is any health benefit from oral consumption of CoQ is not well established. Here we review the function of CoQ as a redox-active molecule in the ETC and other enzymatic systems, its role as a prooxidant in reactive oxygen species generation, and its separate involvement in antioxidant mechanisms. We also review CoQ biosynthesis, which is particularly complex because of its extreme hydrophobicity, as well as the biological consequences of primary and secondary CoQ deficiency, including in human patients. Primary CoQ deficiency is a rare inborn condition due to mutation in CoQ biosynthetic genes. Secondary CoQ deficiency is much more common, as it accompanies a variety of pathological conditions, including mitochondrial disorders as well as aging. In this context, we discuss the importance, but also the great difficulty, of alleviating CoQ deficiency by CoQ supplementation.

A canonical view of the primary physiological function of myoglobin (Mb) is that it is an oxygen (O) storage protein supporting mitochondrial oxidative phosphorylation, especially as the tissue O partial pressure (Po) drops and Mb off-loads O. Besides O storage/transport, recent findings support functions for Mb in lipid trafficking and sequestration, interacting with cellular glycolytic metabolites such as lactate (LAC) and pyruvate (PYR), and "ectopic" expression in some types of cancer cells and in brown adipose tissue (BAT). Data from Mb knockout (Mb) mice and biochemical models suggest additional metabolic roles for Mb, especially regulation of nitric oxide (NO) pools, modulation of BAT bioenergetics, thermogenesis, and lipid storage phenotypes. From these and other findings in the literature over many decades, Mb's function is not confined to delivering O in support of oxidative phosphorylation but may serve as an O sensor that modulates intracellular Po- and NO-responsive molecular signaling pathways. This paradigm reflects a fundamental change in how oxidative metabolism and cell regulation are viewed in Mb-expressing cells such as skeletal muscle, heart, brown adipocytes, and select cancer cells. Here, we review historic and emerging views related to the physiological roles for Mb and present working models illustrating the possible importance of interactions between Mb, gases, and small-molecule metabolites in regulation of cell signaling and bioenergetics.

Depending on cell type, environmental inputs, and disease, the cells in the human body can have widely different sizes. In recent years, it has become clear that cell size is a major regulator of cell function. However, we are only beginning to understand how the optimization of cell function determines a given cell's optimal size. Here, we review currently known size control strategies of eukaryotic cells and the intricate link of cell size to intracellular biomolecular scaling, organelle homeostasis, and cell cycle progression. We detail the cell size-dependent regulation of early development and the impact of cell size on cell differentiation. Given the importance of cell size for normal cellular physiology, cell size control must account for changing environmental conditions. We describe how cells sense environmental stimuli, such as nutrient availability, and accordingly adapt their size by regulating cell growth and cell cycle progression. Moreover, we discuss the correlation of pathological states with misregulation of cell size and how for a long time this was considered a downstream consequence of cellular dysfunction. We review newer studies that reveal a reversed causality, with misregulated cell size leading to pathophysiological phenotypes such as senescence and aging. In summary, we highlight the important roles of cell size in cellular function and dysfunction, which could have major implications for both diagnostics and treatment in the clinic.

Representing severe morbidity and mortality globally, respiratory infections associated with chronic respiratory diseases, including complicated pneumonia, asthma, interstitial lung disease, and chronic obstructive pulmonary disease, are a major public health concern. Lung health and the prevention of pulmonary disease rely on the mechanisms of airway surface fluid secretion, mucociliary clearance, and adequate immune response to eradicate inhaled pathogens and particulate matter from the environment. The antimicrobial proteins and peptides contribute to maintaining an antimicrobial milieu in human lungs to eliminate pathogens and prevent them from causing pulmonary diseases. The predominant antimicrobial molecules of the lung environment include human α- and β-defensins and cathelicidins, among numerous other host defense molecules with antimicrobial and antibiofilm activity such as PLUNC (palate, lung, and nasal epithelium clone) family proteins, elafin, collectins, lactoferrin, lysozymes, mucins, secretory leukocyte proteinase inhibitor, surfactant proteins SP-A and SP-D, and RNases. It has been demonstrated that changes in antimicrobial molecule expression levels are associated with regulating inflammation, potentiating exacerbations, pathological changes, and modifications in chronic lung disease severity. Antimicrobial molecules also display roles in both anticancer and tumorigenic effects. Lung antimicrobial proteins and peptides are promising alternative therapeutics for treating and preventing multidrug-resistant bacterial infections and anticancer therapies.

This review addresses oxidative stress and redox signaling in the pancreas under physiological conditions as well as in acute pancreatitis, chronic pancreatitis, pancreatic cancer, and diabetes. Physiological redox homeodynamics is maintained mainly by NRF2/KEAP1, NF-κB, protein tyrosine phosphatases, peroxisome proliferator-activated receptor-γ co-activator 1α (PGC1α), and normal autophagy. Depletion of reduced glutathione in the pancreas is a hallmark of acute pancreatitis and is initially accompanied by disulfide stress, which is characterized by protein cysteinylation without increased glutathione oxidation. A cross-talk between oxidative stress, MAPKs, and NF-κB amplifies the inflammatory cascade, acting PP2A and PGC1α as key redox regulatory nodes. In acute pancreatitis, nitration of cystathionine-β synthase causes blockade of the trans-sulfuration pathway leading to increased homocysteine levels, whereas p53 triggers necroptosis in the pancreas through downregulation of sulfiredoxin, PGC1α, and peroxiredoxin 3. Chronic pancreatitis exhibits oxidative distress mediated by NADPH oxidase 1 and/or CYP2E1, which promotes cell death, fibrosis, and inflammation. Oxidative stress cooperates with mutant KRAS to initiate and promote pancreatic adenocarcinoma. Mutant KRAS increases mitochondrial ROS, which trigger acinar-to-ductal metaplasia and progression to PanIN. ROS are maintained at sufficient level to promote cell proliferation, whilst avoiding cell death or senescence through formation of NADPH and GSH, and activation of NRF-2, HIF-1/2α, and CREB. Redox signalling also plays a fundamental role in differentiation, proliferation, and insulin secretion of β-cells. However, ROS overproduction promotes β-cell dysfunction and apoptosis in type 1 and type 2 diabetes.

The purpose of this review is to describe the immune function of the liver, guiding the reader from the homeostatic tolerogenic status to the aberrant activation demonstrated in chronic liver disease. An extensive description of the pathways behind the inflammatory modulation of the healthy liver will be provided focusing on the complex immune cell network residing within the liver. The limit of tolerance will be presented in the context of organ transplantation, seizing the limits of homeostatic mechanisms that fail in accepting the graft, progressing eventually toward rejection. The triggers and mechanisms behind chronic activation in metabolic liver conditions and viral hepatitis will be discussed. The last session will be dedicated to one of the greatest paradoxes for a tolerogenic organ, developing autoimmunity. Through the description of the three most common autoimmune liver disease, the autoimmune reaction against hepatocytes and biliary epithelial cells will be dissected.

In the past decade, evidence for numerous roles of copper (Cu) in mammalian physiology has grown exponentially. The discoveries of Cu involvement in cell signaling, autophagy, cell motility, differentiation, and regulated cell death (cuproptosis) have markedly extended the list of already known functions of Cu, such as a cofactor of essential metabolic enzymes, a protein structural component, and a regulator of protein trafficking. Novel and unexpected functions of Cu transporting proteins and enzymes have been identified, and new disorders of Cu homeostasis have been described. Significant progress has been made in the mechanistic studies of two classic disorders of Cu metabolism, Menkes disease and Wilson disease, which paved ways to novel approaches to their treatment. Discovery of cuproptosis and the role of Cu in cells metastatic growth have markedly increased interest in targeting Cu homeostatic pathways to treat cancer. In this review, we summarize the established concepts in the field of mammalian Cu physiology, and discuss how new discoveries of the past decade expand and modify these concepts. The roles of Cu in brain metabolism, in cells' functional speciation and a recently discovered regulated cell death have attracted significant attention and are highlighted in this review.

3', 5'-cyclic adenosine monophosphate (cAMP) mediates the effects of sympathetic stimulation on the rate and strength of cardiac contraction. Beyond this pivotal role, in cardiac myocytes cAMP also orchestrates a diverse array of reactions to various stimuli. To ensure specificity of response, the cAMP signaling pathway is intricately organized into multiple, spatially confined, subcellular domains, each governing a distinct cellular function. In this review, we describe the molecular components of the cAMP signalling pathway, how they organized are inside the intracellular space and how they achieve exquisite regulation of signalling within nanometer-size domains. We delineate the key experimental findings that lead to the current model of compartmentalised cAMP signaling and we offer an overview of our present understanding of how cAMP nanodomains are structured and regulated within cardiac myocytes. Furthermore, we discuss how compartmentalized cAMP signaling is affected in cardiac disease and consider the potential therapeutic opportunities arising from understanding such organization. By exploiting the nuances of compartmentalized cAMP signaling, novel and more effective therapeutic strategies for managing cardiac conditions may emerge. Finally, we highlight the unresolved questions and hurdles that must be addressed to translate these insights into interventions that may benefit patients.

Effective data management is crucial for scientific integrity and reproducibility, a cornerstone of scientific progress. Well-organized and well-documented data enable validation and building on results. Data management encompasses activities including organization, documentation, storage, sharing, and preservation. Robust data management establishes credibility, fostering trust within the scientific community and benefiting researchers' careers. In experimental biomedicine, comprehensive data management is vital due to the typically intricate protocols, extensive metadata, and large datasets. Low-throughput experiments, in particular, require careful management to address variations and errors in protocols and raw data quality. Transparent and accountable research practices rely on accurate documentation of procedures, data collection, and analysis methods. Proper data management ensures long-term preservation and accessibility of valuable datasets. Well-managed data can be revisited, contributing to cumulative knowledge and potential new discoveries. Publicly funded research has an added responsibility for transparency, resource allocation, and avoiding redundancy. Meeting funding agency expectations increasingly requires rigorous methodologies, adherence to standards, comprehensive documentation, and widespread sharing of data, code, and other auxiliary resources. This review provides critical insights into raw and processed data, metadata, high-throughput versus low-throughput datasets, a common language for documentation, experimental and reporting guidelines, efficient data management systems, sharing practices, and relevant repositories. We systematically present available resources and optimal practices for wide use by experimental biomedical researchers.

The endomembrane system consists of organellar membranes in the biosynthetic pathway [endoplasmic reticulum (ER), Golgi apparatus, and secretory vesicles] as well as those in the degradative pathway (early endosomes, macropinosomes, phagosomes, autophagosomes, late endosomes, and lysosomes). These endomembrane organelles/vesicles work together to synthesize, modify, package, transport, and degrade proteins, carbohydrates, and lipids, regulating the balance between cellular anabolism and catabolism. Large ion concentration gradients exist across endomembranes: Ca gradients for most endomembrane organelles and H gradients for the acidic compartments. Ion (Na, K, H, Ca, and Cl) channels on the organellar membranes control ion flux in response to cellular cues, allowing rapid informational exchange between the cytosol and organelle lumen. Recent advances in organelle proteomics, organellar electrophysiology, and luminal and juxtaorganellar ion imaging have led to molecular identification and functional characterization of about two dozen endomembrane ion channels. For example, whereas IP3R1-3 channels mediate Ca release from the ER in response to neurotransmitter and hormone stimulation, TRPML1-3 and TMEM175 channels mediate lysosomal Ca and H release, respectively, in response to nutritional and trafficking cues. This review aims to summarize the current understanding of these endomembrane channels, with a focus on their subcellular localizations, ion permeation properties, gating mechanisms, cell biological functions, and disease relevance.

Stress resilience is the phenomenon that some people maintain their mental health despite exposure to adversity or show only temporary impairments followed by quick recovery. Resilience research attempts to unravel the factors and mechanisms that make resilience possible and to harness its insights for the development of preventative interventions in individuals at risk for acquiring stress-related dysfunctions. Biological resilience research has been lagging behind the psychological and social sciences but has seen a massive surge in recent years. At the same time, progress in this field has been hampered by methodological challenges related to finding suitable operationalizations and study designs, replicating findings, and modeling resilience in animals. We embed a review of behavioral, neuroimaging, neurobiological, and systems biological findings in adults in a critical methods discussion. We find preliminary evidence that hippocampus-based pattern separation and prefrontal-based cognitive control functions protect against the development of pathological fears in the aftermath of singular, event-type stressors [as found in fear-related disorders, including simpler forms of posttraumatic stress disorder (PTSD)] by facilitating the perception of safety. Reward system-based pursuit and savoring of positive reinforcers appear to protect against the development of more generalized dysfunctions of the anxious-depressive spectrum resulting from more severe or longer-lasting stressors (as in depression, generalized or comorbid anxiety, or severe PTSD). Links between preserved functioning of these neural systems under stress and neuroplasticity, immunoregulation, gut microbiome composition, and integrity of the gut barrier and the blood-brain barrier are beginning to emerge. On this basis, avenues for biological interventions are pointed out.

The collective efforts of scientists over multiple decades have led to advancements in molecular and cellular biology-based technologies including genetic engineering and animal cloning that are now being harnessed to enhance the suitability of pig organs for xenotransplantation into humans. Using organs sourced from pigs with multiple gene deletions and human transgene insertions, investigators have overcome formidable immunological and physiological barriers in pig-to-nonhuman primate (NHP) xenotransplantation and achieved prolonged pig xenograft survival. These studies informed the design of Revivicor's (Revivicor Inc, Blacksburg, VA) genetically engineered pigs with 10 genetic modifications (10 GE) (including the inactivation of 4 endogenous porcine genes and insertion of 6 human transgenes), whose hearts and kidneys have now been studied in preclinical human xenotransplantation models with brain-dead recipients. Additionally, the first two clinical cases of pig-to-human heart xenotransplantation were recently performed with hearts from this 10 GE pig at the University of Maryland. Although this review focuses on xenotransplantation of hearts and kidneys, multiple organs, tissues, and cell types from genetically engineered pigs will provide much-needed therapeutic interventions in the future.