Macrophages have a key role in shaping the tumour microenvironment (TME), tumour immunity and response to immunotherapy, which makes them an important target for cancer treatment
. However, ...modulating macrophages has proved extremely difficult, as we still lack a complete understanding of the molecular and functional diversity of the tumour macrophage compartment. Macrophages arise from two distinct lineages. Tissue-resident macrophages self-renew locally, independent of adult haematopoiesis
, whereas short-lived monocyte-derived macrophages arise from adult haematopoietic stem cells, and accumulate mostly in inflamed lesions
. How these macrophage lineages contribute to the TME and cancer progression remains unclear. To explore the diversity of the macrophage compartment in human non-small cell lung carcinoma (NSCLC) lesions, here we performed single-cell RNA sequencing of tumour-associated leukocytes. We identified distinct populations of macrophages that were enriched in human and mouse lung tumours. Using lineage tracing, we discovered that these macrophage populations differ in origin and have a distinct temporal and spatial distribution in the TME. Tissue-resident macrophages accumulate close to tumour cells early during tumour formation to promote epithelial-mesenchymal transition and invasiveness in tumour cells, and they also induce a potent regulatory T cell response that protects tumour cells from adaptive immunity. Depletion of tissue-resident macrophages reduced the numbers and altered the phenotype of regulatory T cells, promoted the accumulation of CD8
T cells and reduced tumour invasiveness and growth. During tumour growth, tissue-resident macrophages became redistributed at the periphery of the TME, which becomes dominated by monocyte-derived macrophages in both mouse and human NSCLC. This study identifies the contribution of tissue-resident macrophages to early lung cancer and establishes them as a target for the prevention and treatment of early lung cancer lesions.
Maxwell's equations are invariant under both duality rotations and conformal transformations. Recently Bandos, Lechner, Sorokin, and Townsend have found a nonlinear generalisation of electrodynamics ...which possesses both of these symmetries. We couple this theory to General Relativity and explore self-gravitating configurations with a clear physical interpretation. We find charged black holes and exact gravitational waves. The black hole geometry is Reissner-Nordström, however, the non-linearity parameter acts as a screening factor allowing extremal configurations where the mass of the black hole is smaller than its charge. Furthermore, we also discuss the phenomenon of birefringence and determine the optical metrics associated to the propagation of photons.
Pumpkin pulp is the main waste generated by pumpkin seed growers. This agro‐industrial waste is a valuable source of bioactive compounds, especially carotenoids (β‐carotene, α‐carotene, and lutein), ...which exhibit a broad spectrum of health‐promoting effects. In this study, vegetable oils (canola, corn, and soybean oil) were used as green solvent alternatives to conventional organic solvents for carotenoid extraction from dried pumpkin pulp (DPP) waste. The highest carotenoid extraction yield (CEY) was obtained with canola oil, at a 1:10 DPP/oil ratio. Response surface methodology (RSM) was used to optimize the extraction process parameters (temperature, time, and stirring rate) through a Box‐Behnken design (BBD) maximizing CEY in canola oil. The extraction temperature and stirring rate were found to have a significant linear and quadratic effect, respectively, on CEY. Optimum conditions were achieved at 21.8 min, 250 rpm, and 60°C. Under these optimized conditions, the estimated value for CEY was 378.1 µg β‐carotene equivalents/g of DPP, corresponding to 61.6% of the total carotenoid content present in the DPP. In contrast, the observed experimental value was 373.2 µg β‐carotene equivalents/g of DPP (61.2%). The experimental value was very close to the estimated value, which verifies the model's adequacy and fit. This study shows an alternative method to extract carotenoids from DPP with canola oil, obtaining an oil naturally enriched with carotenoids that could be used as a potential functional ingredient in the development of food, cosmetics, and medicinal products.
Practical Application
Pumpkin by‐products are a potential carotenoid source. Vegetable oil can be used as an alternative solvent for carotenoid extraction from pumpkin residues to obtain an enriched carotenoid oil that can be used to formulate food products.
Abstract
Mutations in the lamin A/C gene (LMNA) cause an autosomal dominant inherited form of dilated cardiomyopathy associated with cardiac conduction disease (hereafter referred to as LMNA ...cardiomyopathy). Compared with other forms of dilated cardiomyopathy, mutations in LMNA are responsible for a more aggressive clinical course owing to a high rate of malignant ventricular arrhythmias. Gap junctions are intercellular channels that allow direct communication between neighboring cells, which are involved in electrical impulse propagation and coordinated contraction of the heart. For gap junctions to properly control electrical synchronization in the heart, connexin-based hemichannels must be correctly targeted to intercalated discs, Cx43 being the major connexin in the working myocytes. We here showed an altered distribution of Cx43 in a mouse model of LMNA cardiomyopathy. However, little is known on the molecular mechanisms of Cx43 remodeling in pathological context. We now show that microtubule cytoskeleton alteration and decreased acetylation of α-tubulin lead to remodeling of Cx43 in LMNA cardiomyopathy, which alters the correct communication between cardiomyocytes, ultimately leading to electrical conduction disturbances. Preventing or reversing this process could offer a strategy to repair damaged heart. Stabilization of microtubule cytoskeleton using Paclitaxel improved intraventricular conduction defects. These results indicate that microtubule cytoskeleton contributes to the pathogenesis of LMNA cardiomyopathy and that drugs stabilizing the microtubule may be beneficial for patients.
Abstract
Hyper-activation of extracellular signal-regulated kinase (ERK) 1/2 contributes to heart dysfunction in cardiomyopathy caused by mutations in the lamin A/C gene (LMNA cardiomyopathy). The ...mechanism of how this affects cardiac function is unknown. We show that active phosphorylated ERK1/2 directly binds to and catalyzes the phosphorylation of the actin depolymerizing factor cofilin-1 on Thr25. Cofilin-1 becomes active and disassembles actin filaments in a large array of cellular and animal models of LMNA cardiomyopathy. In vivo expression of cofilin-1, phosphorylated on Thr25 by endogenous ERK1/2 signaling, leads to alterations in left ventricular function and cardiac actin. These results demonstrate a novel role for cofilin-1 on actin dynamics in cardiac muscle and provide a rationale on how increased ERK1/2 signaling leads to LMNA cardiomyopathy.
Emery-Dreifuss muscular dystrophy (EDMD) is a genetic condition characterized by early contractures, skeletal muscle weakness, and cardiomyopathy. During the last 20 years, various genetic approaches ...led to the identification of causal genes of EDMD and related disorders, all encoding nuclear envelope proteins. By their respective localization either at the inner nuclear membrane or the outer nuclear membrane, these proteins interact with each other and establish a connection between the nucleus and the cytoskeleton. Beside this physical link, these proteins are also involved in mechanotransduction, responding to environmental cues, such as increased tension of the cytoskeleton, by the activation or repression of specific sets of genes. This ability of cells to adapt to environmental conditions is altered in EDMD. Increased knowledge on the pathophysiology of EDMD has led to the development of drug or gene therapies that have been tested on mouse models. This review proposed an overview of the functions played by the different proteins involved in EDMD and related disorders and the current therapeutic approaches tested so far.
Husk tomato (Physalis ixocarpa Brot. var. Rendidora) waste was evaluated as a source of specialized pectin, and pectin extracted from this waste was characterized physicochemically. Fruit was ...blanched for 10 or 15 min and extracted in 0.1 N HCl for 15 to 25 min. Extracted pectin was subjected to physicochemical analysis. For all extraction conditions, the percentage of anhydrogalacturonic acid exceeded 60%, indicating that husk tomato was a good source of pectin. The degree of esterification of pectin molecules was 63% to 91%. The amount of extracted pectin decreased with increasing extraction time. The apparent viscosity of husk tomato pectin showed the characteristic behavior of pseudoplastic fluids. Neutral sugars were identified, and the amounts of 6 sugars (fucose, rhamnose, arabinose, galactose, glucose, and xylose) were quantified. Sugars identified in husk tomato pectin and present in the Rhamnogalacturonan I region, arabinose, galactose, and rhamnose suggest a highly branched structure, which will influence its future applications. Molecular weight values were 542 to 699 kDa, exceeding molecular weight values reported for commercial citrus pectins from 134 to 480 kDa. The extraction process significantly (P < 0.05) influenced the physicochemical properties of pectin. Up to 19.8% from the total amount of pectin in the husk tomato was extracted by 10 min of blanching and 20 min of a more heat treatment. Our findings indicate that husk tomato can be a good alternative source of pectin having highly distinctive physicochemical characteristics.
Altered bone morphogenetic protein (BMP) signaling is associated with many musculoskeletal diseases. However, it remains unknown whether BMP dysfunction has direct contribution to debilitating pain ...reported in many of these disorders. Here, we identified a novel neuropathic pain phenotype in patients with fibrodysplasia ossificans progressiva (FOP), a rare autosomal-dominant musculoskeletal disorder characterized by progressive heterotopic ossification. Ninety-seven percent of these patients carry an R206H gain-of-function point mutation in the BMP type I receptor ACVR1 (ACVR1 R206H ), which causes neofunction to Activin A and constitutively activates signaling through phosphorylated SMAD1/5/8. Although patients with FOP can harbor pathological lesions in the peripheral and central nervous system, their etiology and clinical impact are unclear. Quantitative sensory testing of patients with FOP revealed significant heat and mechanical pain hypersensitivity. Although there was no major effect of ACVR1 R206H on differentiation and maturation of nociceptive sensory neurons (iSNs) derived from FOP induced pluripotent stem cells, both intracellular and extracellular electrophysiology analyses of the ACVR1 R206H iSNs displayed ACVR1-dependent hyperexcitability, a hallmark of neuropathic pain. Consistent with this phenotype, we recorded enhanced responses of ACVR1 R206H iSNs to TRPV1 and TRPA1 agonists. Thus, activated ACVR1 signaling can modulate pain processing in humans and may represent a potential target for pain management in FOP and related BMP pathway diseases.
Abstract
Cardiomyopathy caused by lamin A/C gene (LMNA) mutations (hereafter referred as LMNA cardiomyopathy) is an anatomic and pathologic condition associated with muscle and electrical dysfunction ...of the heart, often leading to heart failure-related disability. There is currently no specific therapy available for patients that target the molecular pathophysiology of LMNA cardiomyopathy. Recent studies suggested that nicotinamide adenine dinucleotide (NAD+) cellular content could be a critical determinant for heart function. Biosynthesis of NAD+ from vitamin B3 (known as salvage pathways) is the primary source of NAD+. We showed here that NAD+ salvage pathway was altered in the heart of mouse and human carrying LMNA mutation, leading to an alteration of one of NAD+ co-substrate enzymes, PARP-1. Oral administration of nicotinamide riboside, a natural NAD+ precursor and a pyridine-nucleoside form of vitamin B3, leads to a marked improvement of the NAD+ cellular content, an increase of PARylation of cardiac proteins and an improvement of left ventricular structure and function in a model of LMNA cardiomyopathy. Collectively, our results provide mechanistic and therapeutic insights into dilated cardiomyopathy caused by LMNA mutations.
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