LKB1 Regulates Vascular Macrophage Functions in Atherosclerosis

Liver kinase B1 (LKB1) is known to shape the regulation of macrophage function by participating in multiple processes including cell metabolism, growth, and polarization. However, whether LKB1 also affects the functional plasticity of macrophages in atherosclerosis has not attracted much attention. Abnormal macrophage function is a pathophysiological hallmark of atherosclerosis, characterized by the formation of foam cells and the maintenance of vascular inflammation. Mounting evidence supports that LKB1 plays a vital role in the regulation of macrophage function in atherosclerosis, including affecting lipid metabolism reprogramming, inflammation, endoplasmic reticulum stress, and autophagy in macrophages. Thus, decreased expression of LKB1 in atherosclerosis aggravates vascular injury by inducing excessive lipid deposition in macrophages and the formation of foam cells. To systematically understand the role and potential mechanism of LKB1 in regulating macrophage functions in atherosclerosis, this review summarizes the relevant data in this regard, hoping to provide new ideas for the prevention and treatment of atherosclerosis.

Sensory Circuit Remodeling and Movement Recovery After Spinal Cord Injury

Restoring sensory circuit function after spinal cord injury (SCI) is essential for recovery of movement, yet current interventions predominantly target motor pathways. Integrated cortical sensorimotor networks, disrupted by SCI, are critical for perceiving, shaping, and executing movement. Corticocortical connections between primary sensory (S1) and motor (M1) cortices are critical loci of functional plasticity in response to learning and injury. Following SCI, in the motor cortex, corticocortical circuits undergo dynamic remodeling; however, it remains unknown how rehabilitation shapes the plasticity of S1-M1 networks or how these changes may impact recovery of movement.

Minor Alterations in Core Promoter Element Positioning Reveal Functional Plasticity of a Bacterial Transcription Factor

Transcription regulation is a key process in all living organisms, involving a myriad of transcription factors. In E. coli , the regulator of the iron-sulfur cluster biogenesis pathway, IscR, acts as a global transcription factor, activating the transcription of some pathways and repressing others.

A Multi-Modal Toolkit for Studying Neutrophils in Cancer and Beyond

As key effector cells of the innate immune response, neutrophils are rapidly deployed to sites of inflammation where they deliver a payload of potent effector mechanisms that are essential for host defense against pathogens as well as tissue homeostasis. In addition, neutrophils are central contributors to the pathogenesis of a vast spectrum of inflammatory, degenerative, and neoplastic diseases. As our understanding of neutrophils in health and disease continually expands, so too does our appreciation of their complex and dynamic nature in vivo; from development, maturation, and trafficking to cellular heterogeneity and functional plasticity. Therefore, contemporary neutrophil research relies on multiple complementary methodologies to perform integrated analysis of neutrophil phenotypic heterogeneity, organ- and stimulus-specific trafficking mechanisms, as well as tailored effector functions in vivo. This review discusses established and emerging technologies used to study neutrophils, with a focus on in vivo imaging in animal models, as well as next-generation ex vivo model systems to study mechanisms of neutrophil function. Furthermore, we discuss how high-dimensional single-cell analysis technologies are driving a renaissance in neutrophil biology by redefining our understanding of neutrophil development, heterogeneity, and functional plasticity. Finally, we discuss innovative applications and emerging opportunities to integrate these high-dimensional, multi-modal techniques to deepen our understanding of neutrophils in cancer research and beyond.

Tiam1-mediated synaptic plasticity drives comorbid depressive symptoms in chronic pain

Chronic pain and depression are frequently comorbid and ketamine has emerged as a potentially promising therapy. But the molecular mechanisms underlying comorbid depressive symptoms in chronic pain and ketamine antidepressant effects remain elusive. Here, we show that Tiam1 orchestrates synaptic structural and functional remodeling in anterior cingulate cortex (ACC) neurons via actin cytoskeleton reorganization and synaptic NMDAR stabilization. This Tiam1-coordinated synaptic plasticity underpins ACC hyperactivity and drives chronic pain-induced depressive-like behaviors. Ketamine induces sustained antidepressant effects in chronic pain by blocking Tiam1-mediated synaptic structural and functional plasticity in ACC neurons. Our results reveal Tiam1 as a key factor in the pathophysiology of chronic pain-induced depression and in the sustained antidepressant effects of ketamine in ACC neurons.

Mechanisms of functional plasticity in subcortical visual areas

Visual plasticity is classically considered to occur essentially in the primary and secondarycortical areas. Subcortical visual areas such as the dorsal lateral geniculate nucleus (dLGN)or the superior colliculus (SC) have long been held as basic structures responsible for a stableand defined function. In this model, the dLGN was considered as a relay of visual informationtravelling from the retina to cortical areas and the SC as a sensory integrator orienting bodymovements towards visual targets. However, recent findings suggest that both dLGN and SCneurons express functional plasticity, adding unexplored layers of complexity to theirpreviously attributed functions. The existence of neuronal plasticity at the level of visualsubcortical areas redefines our approach of the visual system. The aim of this paper istherefore to review the cellular and molecular mechanisms for activity-dependent plasticity ofsynaptic transmission and of cellular properties in subcortical visual areas.

Tumor-Derived Extracellular Vesicles: A Means of Co-opting Macrophage Polarization in the Tumor Microenvironment

Extracellular vesicles (EVs) are a heterogeneous population of membrane-bound parcels of bioactive proteins, nucleic acids, and lipids released from almost all cell types. The diversity of cargo packaged into EVs proffer the induction of an array of effects on recipient cells. EVs released from tumor cells have emerged as a vital means of communication and immune modulation within the tumor microenvironment (TME). Macrophages are an important contributor to the TME with seemingly paradoxical roles promoting either pro- or anti-tumoral immune function depending on their activated phenotypes. Here, we discuss the influence of tumor-derived extracellular vesicles on the functional plasticity of macrophages in tumor progression.

Determinants of Ligand Specificity and Functional Plasticity in Type I Interferon Signaling

The Type I Interferon family of cytokines all act through the same cell surface receptor and induce phosphorylation of the same subset of response regulators of the STAT family. Despite their shared receptor, different Type I Interferons have different functions during immune response to infection. In particular, they differ in the potency of their induced anti-viral and anti-proliferative responses in target cells. It remains not fully understood how these functional differences can arise in a ligand-specific manner both at the level of STAT phosphorylation and the downstream function. We use a minimal computational model of Type I Interferon signaling, focusing on Interferon-α and Interferon-β. We validate the model with quantitative experimental data to identify the key determinants of specificity and functional plasticity in Type I Interferon signaling. We investigate different mechanisms of signal discrimination, and how multiple system components such as binding affinity, receptor expression levels and their variability, receptor internalization, short-term negative feedback by SOCS1 protein, and differential receptor expression play together to ensure ligand specificity on the level of STAT phosphorylation. Based on these results, we propose phenomenological functional mappings from STAT activation to downstream anti-viral and anti-proliferative activity to investigate differential signal processing steps downstream of STAT phosphorylation. We find that the negative feedback by the protein USP18, which enhances differences in signaling between Interferons via ligand-dependent refractoriness, can give rise to functional plasticity in Interferon-α and Interferon-β signaling, and explore other factors that control functional plasticity. Beyond Type I Interferon signaling, our results have a broad applicability to questions of signaling specificity and functional plasticity in signaling systems with multiple ligands acting through a bottleneck of a small number of shared receptors.