Proangiogenic contribution of adiponectin toward mammary tumor growth in vivo

PURPOSE: Adipocytes represent one of the most abundant constituents of the mammary gland. They are essential for mammary tumor growth and survival. Metabolically, one of the more important fat-derived factors (“adipokines”) is adiponectin (APN). Serum concentrations of APN negatively correlate with body mass index and insulin resistance. To explore the association of APN with breast cancer and tumor angiogenesis, we took an in vivo approach aiming to study its role in the mouse mammary tumor virus (MMTV)-polyoma middle T antigen (PyMT) mammary tumor model. EXPERIMENTAL DESIGN: We compared the rates of tumor growth in MMTV-PyMT mice in wild-type and APN-null backgrounds. RESULTS: Histology and micro-positron emission tomography imaging show that the rate of tumor growth is significantly reduced in the absence of APN at early stages. PyMT/APN knockout mice exhibit a reduction in their angiogenic profile resulting in nutrient deprivation of the tumors and tumor-associated cell death. Surprisingly, in more advanced malignant stages of the disease, tumor growth develops more aggressively in mice lacking APN, giving rise to a larger tumor burden, an increase in the mobilization of circulating endothelial progenitor cells, and a gene expression fingerprint indicative of more aggressive tumor cells. CONCLUSIONS: These observations highlight a novel important contribution of APN in mammary tumor development and angiogenesis, indicating that APN has potent angio-mimetic properties in tumor vascularization. However, in tumors deprived of APN, this antiangiogenic stress results in an adaptive response that fuels tumor growth through mobilization of circulating endothelial progenitor cells and the development of mechanisms enabling massive cell proliferation despite a chronically hypoxic micro-environment

Adipocyte mesenchymal transition contributes to mammary tumor progression

Obesity is associated with increased cancer incidence and progression. However, the relationship between adiposity and cancer remains poorly understood at the mechanistic level. Here, we report that adipocytes from tumor-invasive mammary fat undergo de-differentiation to fibroblast-like precursor cells during tumor progression and integrate into the tumor microenvironment. Single-cell sequencing reveals that these de-differentiated adipocytes lose their original identities and transform into multiple cell types, including myofibroblast- and macrophage-like cells, with their characteristic features involved in immune response, inflammation, and extracellular matrix remodeling. The de-differentiated cells are metabolically distinct from tumor-associated fibroblasts but exhibit comparable effects on tumor cell proliferation. Inducing de-differentiation by Xbp1s overexpression promotes tumor progression despite lower adiposity. In contrast, promoting lipid-storage capacity in adipocytes through MitoNEET overexpression curbs tumor growth despite greater adiposity. Collectively, the metabolic interplay between tumor cells and adipocytes induces adipocyte mesenchymal transition and contributes to reconfigure the stroma into a more tumor-friendly microenvironment

Uridine and its role in metabolic diseases, tumors, and neurodegenerative diseases

Uridine is a pyrimidine nucleoside found in plasma and cerebrospinal fluid with a concentration higher than the other nucleosides. As a simple metabolite, uridine plays a pivotal role in various biological processes. In addition to nucleic acid synthesis, uridine is critical to glycogen synthesis through the formation of uridine diphosphate glucose in which promotes the production of UDP-GlcNAc in the hexosamine biosynthetic pathway and supplies UDP-GlcNAc for O-GlcNAcylation. This process can regulate protein modification and affect its function. Moreover, Uridine has an effect on body temperature and circadian rhythms, which can regulate the metabolic rate and the expression of metabolic genes. Abnormal levels of blood uridine have been found in people with diabetes and obesity, suggesting a link of uridine dysregulation and metabolic disorders. At present, the role of uridine in glucose metabolism and lipid metabolism is controversial, and the mechanism is not clear, but it shows the trend of long-term damage and short-term benefit. Therefore, maintaining uridine homeostasis is essential for maintaining basic functions and normal metabolism. This article summarizes the latest findings about the metabolic effects of uridine and the potential of uridine metabolism as therapeutic target in treatment of metabolic disorders

An Improved Density Peak Clustering Algorithm for Multi-Density Data

Density peak clustering is the latest classic density-based clustering algorithm, which can directly find the cluster center without iteration. The algorithm needs to determine a unique parameter, so the selection of parameters is particularly important. However, for multi-density data, when one parameter cannot satisfy all data, clustering often cannot achieve good results. Moreover, the subjective selection of cluster centers through decision diagrams is often not very convincing, and there are also certain errors. In view of the above problems, in order to achieve better clustering of multi-density data, this paper improves the density peak clustering algorithm. Aiming at the selection of parameter dc, the K-nearest neighbor idea is used to sort the neighbor distance of each data, draw a line graph of the K-nearest neighbor distance, and find the global bifurcation point to divide the data with different densities. Aiming at the selection of cluster centers, the local density and distance of each data point in each data division is found, a γ map is drawn, the average value of the γ height difference is calculated, and through two screenings the largest discontinuity point is found to automatically determine the cluster center and the number of cluster centers. The divided datasets are clustered by the DPC algorithm, and then the clustering results are perfected and integrated by using the cluster fusion rules. Finally, a variety of experiments are designed from various perspectives on various artificial simulated datasets and UCI real datasets, which demonstrate the superiority of the F-DPC algorithm in terms of clustering effect, clustering quality, and number of samples

A new yeast PUF family protein, Puf6p, represses ASH1 mRNA translation and is required for its localization

In yeast Saccharomyces cerevisiae, Ash1p, a protein determinant for mating-type switching, is segregated within the daughter cell nucleus to establish asymmetry of HO expression. The accumulation of Ash1p results from ASH1 mRNA that is sorted as a ribonucleoprotein particle (mRNP or locasome) to the distal tip of the bud where translation occurs. To study the mechanism regulating ASH1 mRNA translation, we isolated the ASH1 locasome and characterized the associated proteins by MALDI-TOF. One of these proteins was Puf6p, a new member of the PUF family of highly conserved RNA-binding proteins such as Pumilio in Drosophila, responsible for translational repression, usually to effect asymmetric expression. Puf6p-bound PUF consensus sequences in the 3′UTR of ASH1 mRNA and repressed the translation of ASH1 mRNA both in vivo and in vitro. In the puf6Δ strain, asymmetric localization of both Ash1p and ASH1 mRNA were significantly reduced. We propose that Puf6p is a protein that functions in the translational control of ASH1 mRNA, and this translational inhibition is necessary before localization can proceed

Ventilation and air conditioning system of deep-buried subway station in sub-tropical climates: Energy-saving strategies

Subway systems are rapidly developing, and their energy consumption is considerably growing. The ventilation and air conditioning system in the subway station is the key energy-consuming system. It consumes a large amount of energy every day to provide a comfortable environment for passengers, and it has therefore received increasingly more attention from researchers worldwide. In this work, the variation law of the ventilation and air conditioning system of a subway station is analyzed from three aspects (energy consumption, load, and temperature) based on field test data, and the problems existing in the operation and management of the system are analyzed. For example, the results show that the total load of fresh air in the station was as high as 34-37%, and about 30 min was required to adjust the indoor temperature to a stable state. In addition, three general models and seven energy-saving strategies are put forward, and their energy saving potentials are estimated. After optimization, the ventilation and air conditioning system is found to reduce energy consumption by more than 30%. Not only are common problems that exist in the actual operation of the subway station ventilation and air conditioning system found in this research, but valuable measured data is also provided for the theoretical research of the thermal environment of the subway and the design of environmental control systems

Subduction Evolution Controlled Himalayan Orogenesis: Implications from 3-D Subduction Modeling

Himalayan orogenesis remains enigmatic in terms of Tibetan Plateau geodynamics originating from the Cenozoic India–Eurasian continental collision. India underthrusts below Tibet to the Yarlung–Tsangpo suture, which has been identified as the northernmost boundary for underplating. However, the way in which the historical evolution of continental subduction induces plateau uplift and the way it controls the variation in uplift between outboard and inboard areas is still unclear. To interpret the evolutionary mechanisms involved in the Himalayan growth history, we constructed different 3-D dynamic models at important stages to address these questions related to the formation of the Himalayas on the basis of paleoenthalpy evidence encoded in fossil leaves from recently documented assemblages in southern Tibet. The results show that (1) the effect of crustal thickening was the predominant factor in the early evolution from the Paleocene to the early Eocene, which resulted in a moderate growth rate. (2) The consecutive slab break-off eastward from the western syntaxis and the associated slab rebound significantly accelerated orogenesis from the late Eocene to the Oligocene. The upwelling asthenospheric flow was a key control of increasing crustal buoyancy, which resulted in the fastest growth of the Himalayas during the early Miocene. (3) Thereafter, the gradually enhanced monsoon and surface erosion during accompanying the increasing mountain height resulted in a slowdown of the orogenic rate, which counterbalanced the buoyant force produced by asthenospheric flow driving continuous Himalayan growth