Human aging is associated with an increased frequency of somatic mutations in hematopoietic cells. Several of these recurrent mutations, including those in the gene encoding the epigenetic modifier ...enzyme TET2, promote expansion of the mutant blood cells. This clonal hematopoiesis correlates with an increased risk of atherosclerotic cardiovascular disease. We studied the effects of the expansion of Tet2-mutant cells in atherosclerosis-prone, low-density lipoprotein receptor–deficient (Ldlr
–/–) mice. We found that partial bone marrow reconstitution with TET2-deficient cells was sufficient for their clonal expansion and led to a marked increase in atherosclerotic plaque size. TET2-deficient macrophages exhibited an increase in NLRP3 inflammasome–mediated interleukin-1β secretion. An NLRP3 inhibitor showed greater atheroprotective activity in chimeric mice reconstituted with TET2-deficient cells than in nonchimeric mice. These results support the hypothesis that somatic TET2 mutations in blood cells play a causal role in atherosclerosis.
Outcomes of bariatric surgery, while frequently impressive, are not universal and vary between patients and across surgical procedures. Between 20% and 30% of patients experience suboptimal weight ...loss or significant weight regain within the first few postoperative years. The reasons for this are not fully understood, but likely involve both physiologic processes, behavioral factors, and psychological characteristics. Evidence suggests that preoperative psychosocial status and functioning can contribute to suboptimal weight losses and/or postoperative psychosocial distress. Much of this work has focused on the presence of recognized psychiatric diagnoses and with particular emphasis on mood disorders as well as binge eating disorder. Several studies have suggested that the presence of preoperative psychopathology is associated with suboptimal weight losses, postoperative complications, and less positive psychosocial outcomes. Contemporary psychological theory suggests that it may be shared features across diagnoses, rather than a discrete diagnosis, that better characterizes psychopathology. Mood and substance use disorders as well as binge eating disorder, share common features of impulsivity, although clinicians and researchers often use complementary, yet different terms, such as emotional dysregulation or disinhibition (i.e., loss of control over eating, as applied to food intake), to describe the phenomenon. Impulse control is a central factor in eating behavior and extreme obesity. It also may contribute to the experience of suboptimal outcomes after bariatric surgery, including smaller than expected weight loss and psychosocial distress. This paper reviews the literature in these areas of research and articulates a direction for future studies of these complex relationships among persons with extreme obesity.
M2 macrophages in the tumor microenvironment are important drivers of cancer metastasis. Exosomes play a critical role in the crosstalk between different cells by delivering microRNAs or other ...cargos. Whether exosomes derived from pro-tumorigenic M2 macrophages (M2-Exos) could modulate the metastatic behavior of renal cell carcinoma (RCC) is unclear. This study found that M2-Exos promotes migration and invasion in RCC cells. Inhibiting miR-21-5p in M2-Exos significantly reversed their pro-metastatic effects on RCC cells in vitro and in the avian embryo chorioallantoic membrane in vivo tumor model. We further found that the pro-metastatic mechanism of miR-21-5p in M2-Exos is by targeting PTEN-3'UTR to regulate PTEN/Akt signaling. Taken together, our results demonstrate that M2-Exos carries miR-21-5p promote metastatic features of RCC cells through PTEN/Akt signaling. Reversing this could serve as a novel approach to control RCC metastasis.
Biramous appendages are a common feature among modern marine arthropods that evolved deep in arthropod phylogeny. The branched appendage of Cambrian arthropods has long been considered as the ancient ...biramous limb, sparking numerous investigations on its origin and evolution. Here, we report a new arthropod,
gen. et sp. nov., from the Lower Cambrian (Stage 3, 520 Ma) Chengjiang biota of Yunnan, China, with unique trunk appendages formed of lateral anomalocaridid-type flaps and ventral subconical endopods. These appendages represent an intermediate stage of biramous limb evolution, i.e. from 'two pairs of flap appendages' in radiodonts to 'flap + endopod' in
, to 'exopod + endopod' in the rest of carapace-bearing arthropods that populate the basal region of the upper-stem lineage arthropods (deuteropods). The new species occupies a phylogenetic position at the first node closer to deuteropods than to radiodonts, and therefore pinpoints the earliest occurrence of the endopod within Deuteropoda. The primitive endopod is weakly sclerotized, and has unspecialized segments without endites or claw. The findings might support previous claims that the outer branch of the biramous limb of fossil marine arthropods, such as trilobites, is not a true exopod, but is instead a modified exite. This article is part of the theme issue 'The impact of Chinese palaeontology on evolutionary research'.
Mouse models are the benchmark tests for in vivo cancer studies. However, cost, time, and ethical considerations have led to calls for alternative in vivo cancer models. The chicken chorioallantoic ...membrane (CAM) model provides an inexpensive, rapid alternative that permits direct visualization of tumor development and is suitable for in vivo imaging. As such, we sought to develop an optimized protocol for engrafting gynecological and urological tumors into this model, which we present here. Approximately 7 days postfertilization, the air cell is moved to the vascularized side of the egg, where an opening is created in the shell. Tumors from murine and human cell lines and primary tissues can then be engrafted. These are typically seeded in a mixture of extracellular matrix and medium to avoid cellular dispersal and provide nutrient support until the cells recruit a vascular supply. Tumors may then grow for up to an additional 14 days prior to the eggs hatching. By implanting cells stably transduced with firefly luciferase, bioluminescence imaging can be used for the sensitive detection of tumor growth on the membrane and cancer cell spread throughout the embryo. This model can potentially be used to study tumorigenicity, invasion, metastasis, and therapeutic effectiveness. The chicken CAM model requires significantly less time and financial resources compared to traditional murine models. Because the eggs are immunocompromised and immune tolerant, tissues from any organism can potentially be implanted without costly transgenic animals (e.g., mice) required for implantation of human tissues. However, many of the advantages of this model could potentially also be limitations, including the short tumor generation time and immunocompromised/immune tolerant status. Additionally, although all tumor types presented here engraft in the chicken chorioallantoic membrane model, they do so with varying degrees of tumor growth.
Abstract Hypertension remains a leading cause of cardiovascular and kidney diseases. Failure to control blood pressure with ≥ 3 medications or control requiring ≥ 4 medications is classified as ...resistant hypertension (rHTN) and new therapies are needed to reduce the resulting increased risk of morbidity and mortality. Here, we report genetic evidence that relaxin family peptide receptor 2 (RXFP2) is associated with rHTN in men, but not in women. This study shows that adrenal gland gene expression of RXFP2 is increased in men with hypertension and the RXFP2 natural ligand, INSL3, increases adrenal steroidogenesis and corticosteroid secretion in human adrenal cells. To address the hypothesis that RXFP2 activation is an important mechanism in rHTN, we discovered and characterized small molecule and monoclonal antibody (mAb) blockers of RXFP2. The novel chemical entities and mAbs show potent, selective inhibition of RXFP2 and reduce aldosterone and cortisol synthesis and release. The RXFP2 mAbs have suitable rat pharmacokinetic profiles to evaluate the role of RXFP2 in the development and maintenance of rHTN. Overall, we identified RXFP2 activity as a potential new mechanism in rHTN and discovered RXFP2 antagonists for the future interrogation of RXFP2 in cardiovascular and renal diseases.
Environmental factors play an important role in the development and exacerbation of allergic rhinitis (AR) in childhood. Indoor air pollution, such as house dust mites and secondhand smoke, can ...significantly increase the onset of AR, while pet dander may affect the exacerbation of AR symptoms in children. Furthermore, traffic related air pollution and pollen are outdoor air pollutants that can affect immune competency and airway responsiveness, increasing the risk of AR in children. Climate change has increased AR in children, as growth patterns of allergenic species have changed, resulting in longer pollen seasons. More extreme and frequent weather events also contribute to the deterioration of indoor air quality due to climate change. Additionally, viruses provoke respiratory tract infections, worsening the symptoms of AR, while viral infections alter the immune system. Although viruses and pollution influence development and exacerbation of AR, a variety of treatment and prevention options are available for AR patients. The protective influence of vegetation (greenness) is heavily associated with air pollution mitigation, relieving AR exacerbations, while the use of air filters can reduce allergic triggers. Oral antihistamines and intranasal corticosteroids are common pharmacotherapy for AR symptoms. In this review, we discuss the environmental risk factors for AR and summarize treatment strategies for preventing and managing AR in children.
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