Notes

In a situation document of childish parkinsonism-dystonia-2 caused by homozygous mutation inside the SLC18A2 gene.
Proteoglycans are now well regarded as key facilitators of cell biology. Although a majority of their interactions and functions are attributed to the decorating glycosaminoglycan chains, there is a growing appreciation for the roles of the proteoglycan core protein and for considering proteoglycans as replete protein-glycan conjugates. This appreciation, seeded by early work in proteoglycan biology, is now being advanced and exalted by modern approaches in chemical glycobiology. In this review, we discuss up-and-coming methods to unearth the fine-scale architecture of proteoglycans that modulate their functions and interactions. Saracatinib Crucial to these efforts is the production of chemically defined materials, including semisynthetic proteoglycans and the in situ capture of interacting proteins. Together, the integration of chemical biology approaches promises to expedite the dissection of the structural heterogeneity of proteoglycans and deliver refined insight into their functions.Local acidification is a common feature of many disease processes such as inflammation, infarction, or solid tumor growth. Acidic pH is not merely a sequela of disease but contributes to recruitment and regulation of immune cells, modifies metabolism of parenchymal, immune and tumor cells, modulates fibrosis, vascular permeability, oxygen availability, and consumption, invasiveness of tumor cells, and impacts on cell survival. Thus, multiple pH-sensing mechanisms must exist in cells involved in these processes. These pH sensors play important roles in normal physiology and pathophysiology, and hence might be attractive targets for pharmacological interventions. Among the pH-sensing mechanisms, OGR1 (GPR68), GPR4 (GPR4), and TDAG8 (GPR65) have emerged as important molecules. These G protein-coupled receptors are widely expressed, upregulated in inflammation and tumors, sense changes in extracellular pH in the range between pH 8 and 6, and are involved in modulating key processes in inflammation, tumor biology, and fibrosis. This review discusses key features of these receptors and highlights important disease states and pathways affected by their activity.Sickle cell disease (SCD) is an autosomal recessive genetic disorder that affects ∼100,000 Americans and millions of people worldwide. Erythrocyte sickling, vaso-occlusion, sterile inflammation, and hemolysis are the major pathophysiological pathways leading to liver injury in SCD. Although hepatic dysfunction affects up to 10%-40% of patients with SCD, therapeutic approaches to prevent liver injury in SCD are not known, and the molecular mechanisms promoting progressive liver injury in SCD remain poorly understood. Animal models have been beneficial in bridging the gap between preclinical and translational research in SCD. Recent advances in methodology have allowed the development of several humanized animal models to address various aspects of SCD-related liver diseases. This review provides an overview of current knowledge of the molecular mechanisms and potential therapeutic options of SCD-associated liver dysfunction using the Townes mouse model.The growing recognition of abundance of oscillating functions in biological systems has motivated this brief overview, which narrows down on the microvasculature. Specifically, it encompasses self-sustained oscillations of blood flow, hematocrit, and viscosity at bifurcations; blood flow effects on the oscillations of endothelial glycocalyx, mechanotransduction, and its termination to prime endothelial cells for the subsequent mechanical signaling event; oscillating affinity of hyaluronan-CD44 binding domain; spontaneous contractility of actomyosin complexes in the cortical actin web and its effects on the tension of the plasma membrane; reversible effects of sirtuin-1 on endothelial glycocalyx; and effects of plasma membrane tension on endo- and exocytosis. Some potential interactions between those oscillators, and their coupling, are discussed together with their transition into chaotic movements. Future in-depth understanding of the oscillatory activities in the microvasculature could serve as a guide to its chronotherapy under pathological conditions.Gene mutations in the extracellular matrix protein fibrillin-1 cause connective tissue disorders including Marfan syndrome (MFS) with clinical symptoms in the cardiovascular, skeletal, and ocular systems. Patients with MFS also exhibit alterations in adipose tissues, which in some individuals leads to lipodystrophy, whereas in others to obesity. We have recently demonstrated that fibrillin-1 regulates adipose tissue homeostasis. Here, we examined how fibrillin-1 abnormality affects metabolic adaptation to different diets. We used two MFS mouse models hypomorph mice develop a fatty liver phenotype, likely mediated by a baseline increased endoplasmic reticulum stress. In contrast, female MFS mice were protected from the consequence of HFD.Neurohormonal signaling and mitochondrial dynamism are seemingly distinct processes that are almost ubiquitous among multicellular organisms. Both of these processes are regulated by GTPases, and disturbances in either can provoke disease. Here, inconspicuous pathophysiological connectivity between neurohormonal signaling and mitochondrial dynamism is reviewed in the context of cardiac and neurological syndromes. For both processes, greater understanding of basic mechanisms has evoked a reversal of conventional pathophysiological concepts. Thus, neurohormonal systems induced in, and previously thought to be critical for, cardiac functioning in heart failure are now pharmaceutically interrupted as modern standard of care. And, mitochondrial abnormalities in neuropathies that were originally attributed to an imbalance between mitochondrial fusion and fission are increasingly recognized as an interruption of axonal mitochondrial transport. The data are presented in a historical context to provide insight into how scientific thought has evolved and to foster an appreciation for how seemingly different areas of investigation can converge. Finally, some theoretical notions are presented to explain how different molecular and functional defects can evoke tissue-specific disease.One in three persons will develop cancer in their lifetime (Siegel RL, Miller KD, Fuchs HE, Jemal A. CA Cancer J Clin 71 7-33, 2021) and the majority of these patients will die from the spread of cancer throughout their body-a process known as metastasis. Metastasis is strongly regulated by the tumor microenvironment (TME) comprising cellular and noncellular components. In this review, we will focus on the role of neutrophils regulating the extracellular matrix (ECM), enabling ECM remodeling and cancer progression. In particular, we highlight the role of neutrophil-secreted proteases (NSP) and how these promote metastasis.Hypokalemic periodic paralysis (HypoPP) is a channelopathy of skeletal muscle caused by missense mutations in the voltage sensor domains (usually at an arginine of the S4 segment) of the CaV1.1 calcium channel or of the NaV1.4 sodium channel. The primary clinical manifestation is recurrent attacks of weakness, resulting from impaired excitability of anomalously depolarized fibers containing leaky mutant channels. Although the ictal loss of fiber excitability is sufficient to explain the acute episodes of weakness, a deleterious change in voltage sensor function for CaV1.1 mutant channels may also compromise excitation-contraction coupling (EC-coupling). We used the low-affinity Ca2+ indicator Oregon Green 488 BAPTA-5N (OGB-5N) to assess voltage-dependent Ca2+-release as a measure of EC-coupling for our knock-in mutant mouse models of HypoPP. The peak ΔF/F0 in fibers isolated from CaV1.1-R528H mice was about two-thirds of the amplitude observed in WT mice; whereas in HypoPP fibers from NaV1.4-R669H mice the ΔF/F0 was indistinguishable from WT. No difference in the voltage dependence of ΔF/F0 from WT was observed for fibers from either HypoPP mouse model. Because late-onset permanent muscle weakness is more severe for CaV1.1-associated HypoPP than for NaV1.4, we propose that the reduced Ca2+-release for CaV1.1-R528H mutant channels may increase the susceptibility to fixed myopathic weakness. In contrast, the episodes of transient weakness are similar for CaV1.1- and NaV1.4-associated HypoPP, consistent with the notion that acute attacks of weakness are primarily caused by leaky channels and are not a consequence of reduced Ca2+-release.One of the main components of the extracellular matrix (ECM) of blood vessels is hyaluronic acid or hyaluronan (HA). It is a ubiquitous polysaccharide belonging to the family of glycosaminoglycans, but, differently from other proteoglycan-associated glycosaminoglycans, it is synthesized on the plasma membrane by a family of three HA synthases (HAS). HA can be released as a free polymer in the extracellular space or remain associated with the plasma membrane in the pericellular space via HAS or HA-binding proteins. Several cell surface proteins can interact with HA working as HA receptors, like CD44, RHAMM, and LYVE-1. In physiological conditions, HA is localized in the glycocalyx and the adventitia where it is responsible for the loose and hydrated vascular structure favoring flexibility and allowing the stretching of vessels in response to mechanical forces. During atherogenesis, ECM undergoes dramatic alterations that have a crucial role in lipoprotein retention and in triggering multiple signaling cascades that induce the cells to exit from their quiescent status. HA becomes highly present in the media and neointima favoring smooth muscle cells dedifferentiation, migration, and proliferation that strongly contribute to vessel wall thickening. Furthermore, HA is able to modulate immune cell recruitment both within the vessel wall and on the endothelial cell layer. This review is focused on deeply analyzing the effects of HA on vascular cell behavior.The extracellular matrix is an intricate and essential network of proteins and nonproteinaceous components that provide a conducive microenvironment for cells to regulate cell function, differentiation, and survival. Fibronectin is one key component in the extracellular matrix that participates in determining cell fate and function crucial for normal vertebrate development. Fibronectin undergoes time-dependent expression patterns during stem cell differentiation, providing a unique stem cell niche. Mutations in fibronectin have been recently identified to cause a rare form of skeletal dysplasia with scoliosis and abnormal growth plates. Even though fibronectin has been extensively analyzed in developmental processes, the functional role and importance of this protein and its various isoforms in skeletal development remain less understood. This review attempts to provide a concise and critical overview of the role of fibronectin isoforms in cartilage and bone physiology and associated pathologies. This will facilitate a better understanding of the possible mechanisms through which fibronectin exerts its regulatory role on cellular differentiation during skeletal development. The review discusses the consequences of mutations in fibronectin leading to corner fracture type spondylometaphyseal dysplasia and presents a new outlook toward matrix-mediated molecular pathways in relation to therapeutic and clinical relevance.
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