From Synapses to Circuits, Astrocytes Regulate Behavior

Astrocytes are non-neuronal cells that regulate synapses, neuronal circuits, and behavior. Astrocytes ensheath neuronal synapses to form the tripartite synapse where astrocytes influence synapse formation, function, and plasticity. Beyond the synapse, recent research has revealed that astrocyte influences on the nervous system extend to the modulation of neuronal circuitry and behavior. Here we review recent findings on the active role of astrocytes in behavioral modulation with a focus on in vivo studies, primarily in mice. Using tools to acutely manipulate astrocytes, such as optogenetics or chemogenetics, studies reviewed here have demonstrated a causal role for astrocytes in sleep, memory, sensorimotor behaviors, feeding, fear, anxiety, and cognitive processes like attention and behavioral flexibility. Current tools and future directions for astrocyte-specific manipulation, including methods for probing astrocyte heterogeneity, are discussed. Understanding the contribution of astrocytes to neuronal circuit activity and organismal behavior will be critical toward understanding how nervous system function gives rise to behavior.

Regulation of spatially restricted gene expression: linking RNA localization and phase separation

Subcellular restriction of gene expression is crucial to the functioning of a wide variety of cell types. The cellular machinery driving spatially restricted gene expression has been studied for many years, but recent advances have highlighted novel mechanisms by which cells can generate subcellular microenvironments with specialized gene expression profiles. Particularly intriguing are recent findings that phase separation plays a role in certain RNA localization pathways. The burgeoning field of phase separation has revolutionized how we view cellular compartmentalization, revealing that, in addition to membrane-bound organelles, phase-separated cytoplasmic microenvironments — termed biomolecular condensates — are compositionally and functionally distinct from the surrounding cytoplasm, without the need for a lipid membrane. The coupling of phase separation and RNA localization allows for precise subcellular targeting, robust translational repression and dynamic recruitment of accessory proteins. Despite the growing interest in the intersection between RNA localization and phase separation, it remains to be seen how exactly components of the localization machinery, particularly motor proteins, are able to associate with these biomolecular condensates. Further studies of the formation, function, and transport of biomolecular condensates promise to provide a new mechanistic understanding of how cells restrict gene expression at a subcellular level.

Developmental mechanisms of sex differences: from cells to organisms

ABSTRACT Male-female differences in many developmental mechanisms lead to the formation of two morphologically and physiologically distinct sexes. Although this is expected for traits with prominent differences between the sexes, such as the gonads, sex-specific processes also contribute to traits without obvious male-female differences, such as the intestine. Here, we review sex differences in developmental mechanisms that operate at several levels of biological complexity – molecular, cellular, organ and organismal – and discuss how these differences influence organ formation, function and whole-body physiology. Together, the examples we highlight show that one simple way to gain a more accurate and comprehensive understanding of animal development is to include both sexes.

On the Formation of the New Construction “ta bu xiang ma” of Polysemy Isomorphism and Its Usage in Discourse

The paper takes “ta bu xiang ma2” as the research object, and analyzes its formation, function, and application in discourse. The study results indicate that “ta bu xiang ma2” is a new and fillable construction that expresses the meaning of the domain of knowing and uttering. The structure has the functions of subjectivity, exclamation, anticipation and illocutionary. The formation mechanism is metaphor, and the motivation is the widespread use of network language and people’s psychology of seeking novelty and differences. “Ta bu xiang ma2” has strong spoken language style and is used in interactive and evaluative contexts. It can be used as both trigger and response sentences, and it has similarities and differences with its related formats.

Barrier islands of the central Georgia coast: Formation, function, and future

ABSTRACT Georgia’s coastline is composed of a series of short, wide, mixed-energy (tide-dominated) barrier islands, each backed by extensive marsh, topped with mobile dunes, and flanked by deep inlets. Many of the islands, particularly those along the southern Georgia coast, consist of Pleistocene cores surrounded by mobile deposits that attached during the Holocene sea-level transgression. Positioned within the head of the funnel-shaped South Atlantic Bight, tidal ranges here commonly reach ~2–3 m. As a result, inlets are numerous and the back-barrier environment hosts nearly 400,000 acres of salt marsh. Today, many of the barriers are transgressive, and hard structures such as revetments and groins are becoming increasingly more common to stabilize shorelines along the four developed islands. This field guide presents evidence of island formation, modern ecologic function, and likely future changes for three island groups: (1) Blackbeard, Cabretta, and Sapelo Islands; (2) Sea Island and St. Simons Island; and (3) Jekyll Island. The field trip provides evidence of the Pleistocene-age island cores, the natural southward migration of the mobile Holocene-age sandy shorelines, and the impacts of storm erosion and hard structures built to combat that erosion. This field guide serves as the static, print companion to an online virtual field trip (https://storymaps.arcgis.com/stories/0aa3fd921cc4458da0a19a928e5fa87c).

High Endothelial Venules: A Vascular Perspective on Tertiary Lymphoid Structures in Cancer

High endothelial venules (HEVs) are specialized postcapillary venules composed of cuboidal blood endothelial cells that express high levels of sulfated sialomucins to bind L-Selectin/CD62L on lymphocytes, thereby facilitating their transmigration from the blood into the lymph nodes (LN) and other secondary lymphoid organs (SLO). HEVs have also been identified in human and murine tumors in predominantly CD3+T cell-enriched areas with fewer CD20+B-cell aggregates that are reminiscent of tertiary lymphoid-like structures (TLS). While HEV/TLS areas in human tumors are predominantly associated with increased survival, tumoral HEVs (TU-HEV) in mice have shown to foster lymphocyte-enriched immune centers and boost an immune response combined with different immunotherapies. Here, we discuss the current insight into TU-HEV formation, function, and regulation in tumors and elaborate on the functional implication, opportunities, and challenges of TU-HEV formation for cancer immunotherapy.

Differences in human placental mesenchymal stromal cells may impair vascular function in FGR

Placentae from pregnancies with fetal growth restriction (FGR) exhibit poor oxygen and nutrient exchange, in part due to impaired placental vascular development. Placental mesenchymal stromal cells (pMSCs) reside in a perivascular niche, where they may influence blood vessel formation/ function. However, the role of pMSCs in vascular dysfunction in FGR is unclear. To elucidate the mechanisms by which pMSCs may impact placental vascularisation we compared the transcriptomes of human pMSCs isolated from FGR (<5th centile) (n=7) and gestation-matched control placentae (n=9) using Affymetrix microarrays. At the transcriptome level there were no statistically significant differences between normal and FGR pMSCs, however several genes linked to vascular function exhibited notable fold changes, and thus the dataset was used as a hypothesis-generating tool for possible dysfunction in FGR. Genes/proteins of interest were followed up by real-time PCR and by immunohistochemistry. Gene expression of ADAMTS1 and FBLN2 (fibulin-2) were significantly upregulated, whilst HAS2 (hyaluronan synthase-2) was significantly downregulated, in pMSCs from FGR placentae (n=8) relative to controls (n=7, p<0.05 for all). At the protein level, significant differences in the level of fibulin-2 and hyaluronan synthase-2, but not ADAMTS1 were confirmed between pMSCs from FGR and control pregnancies by western blot. All three proteins demonstrated perivascular expression in third-trimester placentae. Fibulin-2 maintains vessel elasticity, and its increased expression in FGR pMSCs could help explain the increased distensibility of FGR blood vessels. ADAMTS1 and hyaluronan synthase-2 regulate angiogenesis, and their differential expression by FGR pMSCs may contribute to the impaired angiogenesis in these placentae.

Myofibroblasts: Function, Formation, and Scope of Molecular Therapies for Skin Fibrosis

Myofibroblasts are contractile, α-smooth muscle actin-positive cells with multiple roles in pathophysiological processes. Myofibroblasts mediate wound contractions, but their persistent presence in tissues is central to driving fibrosis, making them attractive cell targets for the development of therapeutic treatments. However, due to shared cellular markers with several other phenotypes, the specific targeting of myofibroblasts has long presented a scientific and clinical challenge. In recent years, myofibroblasts have drawn much attention among scientific research communities from multiple disciplines and specialisations. As further research uncovers the characterisations of myofibroblast formation, function, and regulation, the realisation of novel interventional routes for myofibroblasts within pathologies has emerged. The research community is approaching the means to finally target these cells, to prevent fibrosis, accelerate scarless wound healing, and attenuate associated disease-processes in clinical settings. This comprehensive review article describes the myofibroblast cell phenotype, their origins, and their diverse physiological and pathological functionality. Special attention has been given to mechanisms and molecular pathways governing myofibroblast differentiation, and updates in molecular interventions.

When form meets function: the cells and signals that shape the lymphatic vasculature during development

ABSTRACT The lymphatic vasculature is an integral component of the cardiovascular system. It is essential to maintain tissue fluid homeostasis, direct immune cell trafficking and absorb dietary lipids from the digestive tract. Major advances in our understanding of the genetic and cellular events important for constructing the lymphatic vasculature during development have recently been made. These include the identification of novel sources of lymphatic endothelial progenitor cells, the recognition of lymphatic endothelial cell specialisation and heterogeneity, and discovery of novel genes and signalling pathways underpinning developmental lymphangiogenesis. Here, we review these advances and discuss how they inform our understanding of lymphatic network formation, function and dysfunction.