The rockefeller university

A survey of nearly two hundred reports shows that rapid estrogenic actions can be detected across a range of kinds of estrogens, a range of doses, on a wide range of tissue, cell and ion channel types. Striking is the fact that preparations of estrogenic agents that do not permeate the cell membrane almost always mimic the actions of the estrogenic agents that do permeate the membrane. All kinds of estrogens, ranging from natural ones, through receptor modulators, endocrine disruptors, phytoestrogens, agonists, and antagonists to novel G-1 and SIX, have been reported to be effective. For actions on specific types of ion channels, the possibility of opposing actions, in different cases, is the rule, not the exception. With this variety there is no single, specific action mechanism for estrogens per se, although in some cases estrogens can act directly or via some signaling pathways to affect ion channels. We infer that estrogens can bind a large number of substrates/receptors at the membrane surface. As against the variety of subsequent routes of action, this initial step of the estrogen's binding action is the key. (C) 2016 Elsevier Inc. All rights reserved.

Epoxyeicosatrienoic acid (EET) contributes to browning of white adipose stem cells to ameliorate obesity/diabetes and insulin resistance. In the current study, we show that EET altered preadipocyte function, enhanced peroxisome proliferation-activated receptor gamma coactivator alpha (PGC-1 alpha) expression, and increased mitochondrial function in the 3T3-L1 preadipocyte subjected to adipogenesis. Cells treated with EET resulted in an increase, P < 0.05, in PGC-1 alpha and a decrease in mitochondria-derived ROS (MitoSox), P < 0.05. The EET increase in heme oxygenase-1 (HO-1) levels is dependent on activation of PGC-1 alpha as cells deficient in PGC-1 alpha (PGC-1 alpha knockout adipocyte cell) have an impaired ability to express HO-1, P < 0.02. Additionally, adipocytes treated with EET exhibited an increase in mitochondrial superoxide dismutase (SOD) in a PGC-1 alpha-dependent manner, P < 0.05. The increase in PGC-1 alpha was associated with an increase in beta-catenin, P < 0.05, adiponectin expression, P < 0.05, and lipid accumulation, P < 0.02. EET decreased heme levels and mitochondria-derived ROS (MitoSox), P < 0.05, compared to adipocytes that were untreated. EET also decreased mesoderm-specific transcript (MEST) mRNA and protein levels (P < 0.05). Adipocyte secretion of EET act in an autocrine/ paracrine manner to increase PGC-1 alpha is required for activation of HO-1 expression. This is the first study to dissect the mechanism by which the antiadipogenic and anti-inflammatory lipid, EET, induces the PGC-1 alpha signaling cascade and reprograms the adipocyte phenotype by regulating mitochondrial function and HO-1 expression, leading to an increase in healthy, that is, small, adipocytes and a decrease in adipocyte enlargement and terminal differentiation. This is manifested by an increase in mitochondrial function and an increase in the canonical Wnt signaling cascade during adipocyte proliferation and terminal differentiation.

Objective: To assess effectiveness of preimplantation genetic screening (PGS) in fresh IVF cycles. Design: Reanalysis of retrospective US national data. Setting: Not applicable. Patient(s): A total of 5,471 fresh autologous IVF cycles with PGS and 97,069 cycles without PGS, reported in 2011-2012 to the Centers for Disease Control and Prevention. Intervention(s): Not applicable. Main Outcome Measure(s): Cycles that reached ET, miscarriage rates, live birth rates per cycle and per transfer. Result(s): More PGS than non-PGS cycles reached ET (64.2% vs. 62.3%), suggesting favorable patient selection bias for patients using PGS. Nevertheless, live births rates per cycle start (25.2% vs. 28.8%) and per ET (39.3% vs. 46.2%) were significantly better in non-PGS cycles, whereas miscarriage rates were similar (13.7% vs. 13.9%). With a maternal age > 37 years significantly more cycles in the PGS group reached ET (53.1% vs. 41.9%), suggesting a significant selection bias for more favorable patients in the PGS population. This bias rather than the PGS procedure may partially explain the observed improved live birth rate per cycle (17.7% vs. 12.7%) and lower miscarriage rate (16.8% vs. 26.0%) in the older PGS group. Conclusion(s): Overall, PGS decreased chances of live birth in association with IVF. National improvements in live birth and miscarriage rates reported with PGS in older women are likely the consequence of favorable patient selection biases. (C) 2016 by American Society for Reproductive Medicine.

Factors constraining the structure of food webs can be investigated by comparing classes of ecosystems. We find that pelagic ecosystems, those based on one-celled primary producers, have longer food chains than terrestrial ecosystems. Yet pelagic ecosystems have lower primary productivity, contrary to the hypothesis that greater energy flows permit higher trophic levels. We hypothesize that longer food chain length in pelagic ecosystems, compared with terrestrial ecosystems, is associated with smaller pelagic animal body size permitting more rapid trophic energy transfer. Assuming negative allometric dependence of biomass production rate on body mass at each trophic level, the lowest three pelagic animal trophic levels are estimated to add biomass more rapidly than their terrestrial counterparts by factors of 12, 4.8, and 2.6. Pelagic animals consequently transport primary production to a fifth trophic level 50-190 times more rapidly than animals in terrestrial webs. This difference overcomes the approximately fivefold slower pelagic basal productivity, energetically explaining longer pelagic food chains. In addition, ectotherms, dominant at lower pelagic animal trophic levels, have high metabolic efficiency, also favoring higher rates of trophic energy transfer in pelagic ecosystems. These two animal trophic flow mechanisms imply longer pelagic food chains, reestablishing an important role for energetics in food web structure.

The United States Immunodeficiency Network (USIDNET) patient registry was used to characterize the presentation, genetics, phenotypes, and treatment of patients with Hyper IgM Syndrome (HIGM). The USIDNET Registry was queried for HIGM patient data collected from October 1992 to July 2015. Data fields included demographics, criteria for diagnosis, pedigree analysis, mutations, clinical features, treatment and transplant records, laboratory findings, and mortality. Fifty-two physicians entered data from 145 patients of ages 2 months to 62 years (median 12 years); 131 were males. Using patients' age at last entry, data from 2072 patient years are included. Mutations were recorded for 85 subjects; 82 were in CD40LG. Eighteen subjects had non-X-linked HIGM. 40 % had a normal serum IgM and 15 %, normal IgA. Infections were reported for 91 %, with pulmonary, ear, and sinus infections being the most common. 42 % had Pneumocystis jirovecii pneumonia; 6 % had Cryptosporidium. 41 % had neutropenia. 78 % experienced non-infectious complications: chronic diarrhea (n = 22), aphthous ulcers (n = 28), and neoplasms (n = 8) including colon cancer, adrenal adenoma, liver adenocarcinoma, pancreatic carcinoid, acute myeloid leukemia, hepatoma, and, in a female with an autosomal dominant gain of function mutation in PIK3CD, an ovarian dysgerminoma. Thirteen patients had a hematopoietic marrow or stem cell transplant; three had solid organ transplants. Thirteen were known to have died (median age = 14 years). Analysis of the USIDNET Registry provides data on the common clinical features of this rare syndrome, and in contrast with previously published data, demonstrates longer survival times and reduced gastrointestinal manifestations.

Despite the extensive use of doxycycline in tetracycline-inducible rodent models, little is known regarding its stability in feed or water or the most effective route or dose. We assessed the concentrations of doxycycline in reverse-osmosis-purified (RO; pH 6.0) and acidified RO (pH 2.6) water in untinted or green-tinted bottles. Doxycycline remained stable in all groups for 7 d and in acidified water in untinted bottles for 14 d. Fungal growth occurred in nonacidified water in tinted and untinted bottles by 12 and 14 d, respectively, and in tinted bottles containing acidified water on day 14, but not in untinted bottles with acidified water. Doxycycline concentrations were also assessed before and at various points after the pelleting of feed from 2 vendors. Each batch was divided for storage at 4 degrees C, at room temperature, or within ventilated mouse isolator cages and then sampled monthly for 6 mo. Drying caused the greatest decline in doxycycline concentration, whereas.-irradiation plus shipping and storage condition had minimal effect. Two mouse lines with tetracycline-inducible promoters received 25, 150, or 467 mu g/mL or 2 mg/mL doxycycline in water and 200 or 625 ppm in feed before analysis of GFP expression. GFP was expressed in Rosa-rtTA2 mice at 150 mu g/mL, whereas Cags-rtTA3 mice required 25 mu g/mL. These studies indicate that 1) doxycycline-compounded feed can be handled in the same manner as standard rodent feed, 2) tinted water bottles are not necessary for maintaining drug concentrations, and 3) concentrations lower than those used typically may be effective in lines with tetracycline-inducible promoters.

Whether beta(1) integrin ectodomains visit conformational states similarly to beta(2) and beta(3) integrins has not been characterized. Furthermore, despite a wealth of activating and inhibitory antibodies to beta(1) integrins, the conformational states that these antibodies stabilize, and the relation of these conformations to function, remain incompletely characterized. Using negative-stain electron microscopy, we show that the integrin alpha(5)beta(1) ectodomain adopts extended-closed and extended-open conformations as well as a bent conformation. Antibodies SNAKA51, 8E3, N29, and 9EG7 bind to different domains in the alpha(5) or beta(1) legs, activate, and stabilize extended ectodomain conformations. Antibodies 12G10 and HUTS-4 bind to the beta(1) beta I domain and hybrid domains, respectively, activate, and stabilize the open headpiece conformation. Antibody TS2/16 binds a similar epitope as 12G10, activates, and appears to stabilize an open beta I domain conformation without requiring extension or hybrid domain swing-out. mAb13 and SG/19 bind to the beta I domain and beta I-hybrid domain interface, respectively, inhibit, and stabilize the closed conformation of the headpiece. The effects of the antibodies on cell adhesion to fibronectin substrates suggest that the extended-open conformation of alpha(5)beta(1) is adhesive and that the extended-closed and bent-closed conformations are nonadhesive. The functional effects and binding sites of antibodies and fibronectin were consistent with their ability in binding to alpha(5)beta(1) on cell surfaces to cross-enhance or inhibit one another by competitive or noncompetitive (allosteric) mechanisms.

It is well established that danger information can be transmitted by ants through relatively small distances, provoking either a state of alarm when they move away from potentially dangerous stimulus, or charge toward it aggressively. There is almost no knowledge if danger information can be transmitted along large distances. In this paper, we abduct leaf cutting ants of the species Atta insularis while they forage in their natural environment at a certain point of the foraging line, so ants make a "U" turn to escape from the danger zone and go back to the nest. Our results strongly suggest that those ants do not transmit "danger information" to other nestmates marching towards the abduction area. The individualistic behavior of the ants returning from the danger zone results in a depression of the foraging activity due to the systematic sacrifice of non-informed individuals.

In vesicular transport pathways, membrane proteins and lipids are internalized, externalized or transported within cells, not by bulk diffusion of single molecules, but embedded in the membrane of small vesicles or thin tubules. The formation of these 'transport carriers' follows sequential events: membrane bending, fission from the donor compartment, transport and eventually fusion with the acceptor membrane. A similar sequence is involved during the internalization of drug or gene carriers inside cells. These membrane-shaping events are generally mediated by proteins binding to membranes. The mechanisms behind these biological processes are actively studied both in the context of cell biology and biophysics. Bin/amphiphysin/Rvs (BAR) domain proteins are ideally suited for illustrating how simple soft matter principles can account for membrane deformation by proteins. We review here some experimental methods and corresponding theoretical models to measure how these proteins affect the mechanics and the shape of membranes. In more detail, we show how an experimental method employing optical tweezers to pull a tube from a giant vesicle may give important quantitative insights into the mechanism by which proteins sense and generate membrane curvature and the mechanism of membrane scission. This article is part of the themed issue 'Soft interfacial materials: from fundamentals to formulation'.