Fine particulate matter (PM2.5) association with peripheral artery disease admissions in northeastern United States

Background: Current evidence, on the association of PM_2.5 and peripheral artery disease (PAD) is very sparse. Methods: We use novel PM_2.5 prediction models to investigate associations between chronic and acute PM_2.5 exposures and hospital PAD admissions across the northeast USA. Poisson regression analysis was preformed where daily admission counts in each zip code are regressed against both chronic and acute PM_2.5 exposure, temperature, socio-economic characteristics and time to control for seasonal patterns. Results: Positive significant associations were observed between both chronic and acute exposure to PM_2.5 and PAD hospitalizations. Every 10-μg/m³ increase in acute PM_2.5 exposure was associated with a 0.26 % increase in admissions (CI = 0.08 – 0.45 %) and every 10-μg/m³ increase in chronic PM _2.5 exposure was associated with a 4.4 % increase in admissions (CI = 3.50 – 5.35 %). Conclusions: The study supports the hypothesis that acute and chronic exposure to PM_2.5 can increase the risk of PAD.     

Long-term PM2.5 exposure before diagnosis is associated with worse outcome in breast cancer

Breast Cancer Research and Treatment - Many patients seek breast reconstruction following mastectomy. Debate exists regarding the best reconstructive option. The authors evaluate outcomes comparing...     

Insights into myosin regulatory and essential light chains: a focus on their roles in cardiac and skeletal muscle function,development and disease

Journal of Muscle Research and Cell Motility - The activity of cardiac and skeletal muscles depends upon the ATP-coupled actin–myosin interactions to execute the power stroke and muscle...     

Muscarinic Modulation of Intrinsic Burst Firing in Rat Hippocampal Neurons

Intracellular recordings in rat hippocampal slices were used to examine how exogenous and endogenous cholinergic agonists modulate the firing pattern of intrinsically burst-firing pyramidal cells. About 24% of CA1 pyramidal cells generated all-or-none, high-frequency bursts of fast action potentials in response to intracellular injection of long positive current pulses. Application of carbachol (5 μM) converted burst firing in these neurons into regular trains of independent spikes. Acetylcholine (5 μM) exerted a similar effect, provided acetylcholine esterase activity was blocked with neostigmine (2 μM). Atropine (1 μM) reversed this cholinergic effect, indicating its mediation by muscarinic receptors. Cholinergic agonists also caused mild neuronal depolarization but the block of intrinsic burst firing was independent of this effect. Repetitive stimulation of cholinergic fibres in the presence of neostigmine (2 μM) evoked a slow cholinergic excitatory postsynaptic potential (EPSP) lasting about a minute. During the slow EPSP, burst firing could not be evoked by depolarizing pulses and the neurons fired in regular mode. These effects were prevented by pretreatment with atropine (1 μM). Exogenously applied cholinergic agonists and endogenously released acetylcholine also reduced spike frequency accommodation and suppressed the long-duration afterhyperpolarization in burst-firing pyramidal cells in an atropine-sensitive manner. A membrane-permeable cAMP analogue (8-bromo-cAMP; 1 mM) also reduced frequency accommodation and blocked the long-duration afterhyperpolarization, but did not affect intrinsic burst firing at all. Taken together, the data show that muscarinic receptor stimulation transforms the stereotyped, phasic response of burst-firing neurons into stimulus-graded, tonic discharge.     

Placental trophoblast syncytialization potentiates macropinocytosis via mTOR signaling to adapt to reduced amino acid supply

During pregnancy, the appropriate allocation of nutrients between the mother and the fetus is dominated by maternal–fetal interactions, which is primarily governed by the placenta. The syncytiotrophoblast (STB) lining at the outer surface of the placental villi is directly bathed in maternal blood and controls feto–maternal exchange. The STB is the largest multinucleated cell type in the human body, and is formed through syncytialization of the mononucleated cytotrophoblast. However, the physiological advantage of forming such an extensively multinucleated cellular structure remains poorly understood. Here, we discover that the STB uniquely adapts to nutrient stress by inducing the macropinocytosis machinery through repression of mammalian target of rapamycin (mTOR) signaling. In primary human trophoblasts and in trophoblast cell lines, differentiation toward a syncytium triggers macropinocytosis, which is greatly enhanced during amino acid shortage, induced by inhibiting mTOR signaling. Moreover, inhibiting mTOR in pregnant mice markedly stimulates macropinocytosis in the syncytium. Blocking macropinocytosis worsens the phenotypes of fetal growth restriction caused by mTOR-inhibition. Consistently, placentas derived from fetal growth restriction patients display: 1) Repressed mTOR signaling, 2) increased syncytialization, and 3) enhanced macropinocytosis. Together, our findings suggest that the unique ability of STB to undergo macropinocytosis serves as an essential adaptation to the cellular nutrient status, and support fetal survival and growth under nutrient deprivation.

During pregnancy, the health of the mother and the fetus is dominated by the appropriate allocation of nutrients between the two individuals. Maternal–fetal material exchange predominantly depends on the placenta, which is responsible for transferring the bulk of nutrients between maternal and fetal circulations. The placenta plays a critical role in sensing fetal nutritional demands, modulating maternal supply, and adapting its nutrient transport capacity. Limited maternal nutrient availability can lead to adaptive changes in the placental endocrine function, which is thought to attenuate the potential conflict between fetal growth demands and maternal health (1).Fetal growth restriction (FGR) represents a pregnancy complication whereby the fetus fails to attain its genetically determined growth potential due to insufficient delivery of maternal nutrition, especially amino acids, by the placenta (1–3). Annually, ∼30 million newborns, mainly in developing countries, suffer from FGR (4), which leads to increased perinatal morbidity and mortality and multiple lifelong health problems (5). The mechanisms deployed by the placenta to compensate nutrient-deprivation injury and support fetal survival remain unknown.At the outermost surface of the placenta, the syncytial layer lines the placental villi, with a continuous surface measuring 12 to 14 m² at term (6). This layer is directly bathed in maternal blood, and thus positioned to regulate feto–maternal exchanges of gases, nutrients, and waste. The syncytial layer comprises the multinucleated syncytiotrophoblast (STB), the largest multinucleated epithelial surface in the body, which is formed through fusion of the mononucleated cytotrophoblast (CTB). Yet, the physiological advantages of forming such an extensive multinucleated cellular structure and the regulatory mechanisms underlying this process remain to be explored.Macropinocytosis constitutes a specialized route for cellular nutrient uptake from the fluid phase. It is functional in certain cell types, including immature dendritic cells, macrophages, podocytes, and tumor cells (7–10). The process involves the formation of large vesicles of 0.2 to 5 μm in diameter at the sites of membrane ruffling (11). Macropinocytosis promotes the uptake of fluid phase-derived molecules by at least 10-fold (12), especially with respect to internalization of large-sized molecules (>70 kDa) (7). In tumor cells, deprivation of amino acid supply inhibits mammalian target of rapamycin (mTOR) and enhances macropinocytosis and lysosomal catabolism of extracellular proteins to sustain cell survival and growth (13, 14), indicating macropinocytosis as an efficient way to attenuate nutrient shortage in the high-demanding cells.Based on the above evidence, we hypothesized that trophoblasts, particularly STB, may utilize macropinocytosis to facilitate nutrient absorption from the maternal environment, thereby negotiating fetal demands in the face of diminished maternal supply. We tested our hypothesis by using cultures of primary human trophoblast (PHT) cells, human trophoblast cell lines, and rapamycin-treated pregnant mice, and demonstrated the physiological significance of macropinocytosis in STB to adapt to maternal undernutrition stress during pregnancy.