Decreased progesterone receptor isoform expression in luteal phase fallopian tube epithelium and high-grade serous carcinoma

We previously reported that BRCA1/2-mutated fallopian tube epithelium (FTE) collected during the luteal phase exhibits gene expression profiles more closely resembling that of high-grade serous carcinoma (HGSC) specimens than FTE collected during the follicular phase or from control patients. Since the luteal phase is characterised by high levels of progesterone, we determined whether the expression of progesterone receptor (PR) and PR-responsive genes was altered in FTE obtained from BRCA mutation carriers during the luteal phase of the menstrual cycle. RT-qPCR confirmed a decreased expression of PR mRNA in FTE during the luteal phase relative to follicular phase, in both BRCA1/2 mutation carriers and control patients. Immunohistochemistry using isoform-specific antibodies confirmed a low level of both PR-A and PR-B in HGSC and a lower level of staining in FTE samples obtained during the luteal phase compared with the follicular phase. No significant difference in PR-A or PR-B staining was found based on patient BRCA mutation status. Analysis of our previously reported gene expression profiles based upon known PR-A- and PR-B-specific target genes did not partition samples by BRCA mutation status, indicating that overall FTE PR response is not altered in BRCA mutation carriers. HGSC samples grouped separately from other samples, consistent with the observed loss of PR expression. These findings indicate no overall difference in PR signalling in FTE as a function of BRCA mutation status. Thus, the molecular similarity of BRCA1/2-mutated luteal phase FTE and HGSC likely results from an altered response to luteal phase factors other than progesterone

Advanced Glycation End Products Acutely Impair Ca2+ Signaling in Bovine Aortic Endothelial Cells

Post-translational modification of proteins in diabetes, including formation of advanced glycation end products (AGEs) are believed to contribute to vascular dysfunction and disease. Impaired function of the endothelium is an early indicator of vascular dysfunction in diabetes and as many endothelial cell processes are dependent upon intracellular [Ca2+] and Ca2+ signalling, the aim of this study was to examine the acute effects of AGEs on Ca2+ signalling in bovine aortic endothelial cells (BAEC). Ca2+ signalling was studied using the fluorescent indicator dye Fura2-AM. AGEs were generated by incubating bovine serum albumin with 0 - 250 mM glucose or glucose-6-phosphate for 0 to 120 days at 37ºC. Under all conditions, the main AGE species generated was carboxymethyl lysine (CML) as assayed using both GC-MS and HPLC. In Ca2+-replete solution, exposure of BAEC to AGEs for 5 min caused an elevation in basal [Ca2+] and attenuated the increase in intracellular [Ca2+] caused by ATP (100 µM). In the absence of extracellular Ca2+, exposure of BAEC to AGEs for 5 min caused an elevation in basal [Ca2+] and attenuated subsequent intracellular Ca2+ release caused by ATP, thapsigargin (0.1 µM) and ionomycin (3 µM), but AGEs did not affect extracellular Ca2+ entry induced by the re-addition of Ca2+ to the bathing solution in the presence of any of these agents. The anti-oxidant α-lipoic acid (2 µM) and NAD(P)H oxidase inhibitors apocynin (500 µM) and diphenyleneiodonium (DPI, 1 µM) abolished these effects of AGEs on BAECs, as did the IP3 receptor antagonist xestospongin C (1 µM). In summary, AGEs caused an acute depletion of Ca2+ from the intracellular store in BAECs, such that the Ca2+ signal stimulated by the subsequent application other agents acting upon this store is reduced. The mechanism may involve generation of ROS from NAD(P)H oxidase and possible activation of the IP3 receptor

Association between Serum Lycopene and Lung Cancer Mortality: An 18-Year Follow-up Study of a National Cohort

Background: Lycopene is a carotenoid found in some fruits and vegetables that is responsible for the red pigment in tomatoes and tomato products. While many studies have shown a link between lycopene and protection against the initiation and/or progression of lung cancer, data on its effect on lung cancer survivability is limited. Objective: The primary objective of this study was to see if there was a link between lycopene levels in the blood and lung cancer mortality. A secondary goal was to see if dietary factors influence lycopene levels in the blood. Materials and Methods: A retrospective cohort study of 14,358 adults who took part in Phase II of the National Health and Nutrition Examination Survey III was carried out (1991- 1994). This dataset served as the baseline for a 15-year (1991-2006) follow-up study, which was correlated with the National Death Index database. The Cox Proportional Hazards Regression Model was used to calculate the HR for all-cause and cancer-related deaths for individuals with high, moderate, and low serum lycopene levels. Results: The unadjusted hazard ratio (HR) of deaths associated with low serum lycopene levels (25 percent cutoff) was 1.67 (95 percent CI=1.24-2.23) and 1.00, respectively (ref). After controlling for multiple risk factors such as age and gender, the HR for lung cancer fatalities was 1.45 (95% CI=1.08-1.96) for low serum levels (25 percent cutoff) with a reference value of 1.00. For low vs. high serum lycopene levels, the adjusted HR for lung cancer death using 3-level categorization (and adjusted for fruits and vegetables) was 1.67 (95 percent CI=1.03-2.71). In addition, the adjusted HR for lung cancer death using 3-level categorization (and unadjusted for fruits and vegetables) was 1.68 (95 percent CI=1.04-2.72) for low serum lycopene levels vs. high serum lycopene levels. Conclusions: The results suggest that high serum lycopene levels may reduce the risk of dying from lung cancer. Furthermore, lycopene may not only reduce the risk of lung cancer development but may also improve survival among lung cancer patients. More research is needed to understand the physiological mechanisms underlying this association

An exploration of grip force regulation with a low-impedance myoelectric prosthesis featuring referred haptic feedback

Abstract Background Haptic display technologies are well suited to relay proprioceptive, force, and contact cues from a prosthetic terminal device back to the residual limb and thereby reduce reliance on visual feedback. The ease with which an amputee interprets these haptic cues, however, likely depends on whether their dynamic signal behavior corresponds to expected behaviors—behaviors consonant with a natural limb coupled to the environment. A highly geared motor in a terminal device along with the associated high back-drive impedance influences dynamic interactions with the environment, creating effects not encountered with a natural limb. Here we explore grasp and lift performance with a backdrivable (low backdrive impedance) terminal device placed under proportional myoelectric position control that features referred haptic feedback. Methods We fabricated a back-drivable terminal device that could be used by amputees and non-amputees alike and drove aperture (or grip force, when a stiff object was in its grasp) in proportion to a myoelectric signal drawn from a single muscle site in the forearm. In randomly ordered trials, we assessed the performance of N=10 participants (7 non-amputee, 3 amputee) attempting to grasp and lift an object using the terminal device under three feedback conditions (no feedback, vibrotactile feedback, and joint torque feedback), and two object weights that were indiscernible by vision. Results Both non-amputee and amputee participants scaled their grip force according to the object weight. Our results showed only minor differences in grip force, grip/load force coordination, and slip as a function of sensory feedback condition, though the grip force at the point of lift-off for the heavier object was significantly greater for amputee participants in the presence of joint torque feedback. An examination of grip/load force phase plots revealed that our amputee participants used larger safety margins and demonstrated less coordination than our non-amputee participants. Conclusions Our results suggest that a backdrivable terminal device may hold advantages over non-backdrivable devices by allowing grip/load force coordination consistent with behaviors observed in the natural limb. Likewise, the inconclusive effect of referred haptic feedback on grasp and lift performance suggests the need for additional testing that includes adequate training for participants.http://deepblue.lib.umich.edu/bitstream/2027.42/116041/1/12984_2015_Article_98.pd

Developing a Novel Platform for Characterizing Thermoelectric Materials for Uncooled Detectors for Land Imaging Applications

Thermal land imaging (imaging at ~8-14 micron optical wavelength) is an essential tool for understanding and managing terrestrial freshwater resources. Current thermal imaging instruments employ low temperature detectors, which require cryocoolers. Consequently, cost-saving reductions in size, weight, and power can be achieved by employing uncooled detectors. One uncooled detector concept, which NASA is pursuing, is a thermopile detector with sub-micron thick doped-Si thermoelectric materials. In order to characterize the thermoelectric properties of the doped silicon, we designed and optimized a novel apparatus. This simple apparatus measures the Seebeck coefficient with thermally isolated stages and LABVIEW automation. We optimized thermal stability using PID tuning and optimized the thermal contact between the thin film samples and stages using electrically conductive springs. Utilizing our apparatus, we measured the Seebeck coefficient of 0.45 micron thick phosphorus-doped single crystal Si samples bonded to alumina substrates. Using these Seebeck coefficient measurements and four-wire electrical resistivity measurements, we determined the relationship between the thermoelectric figure of merit and dopant concentration. These characterization results for doped-Si will guide our thermopile detector design to provide an optimal and competitive detector alternative for future thermal imaging instruments

EVLA Observations Constrain the Environment and Progenitor System of Type Ia Supernova 2011fe

We report unique EVLA observations of SN 2011fe representing the most sensitive radio study of a Type Ia supernova to date. Our data place direct constraints on the density of the surrounding medium at radii ~10^15-10^16 cm, implying an upper limit on the mass loss rate from the progenitor system of Mdot <~ 6 x 10^-10 Msol/yr (assuming a wind speed of 100 km/s), or expansion into a uniform medium with density n_CSM <~ 6 cm^-3. Drawing from the observed properties of non-conservative mass transfer among accreting white dwarfs, we use these limits on the density of the immediate environs to exclude a phase space of possible progenitors systems for SN 2011fe. We rule out a symbiotic progenitor system and also a system characterized by high accretion rate onto the white dwarf that is expected to give rise to optically-thick accretion winds. Assuming that a small fraction, 1%, of the mass accreted is lost from the progenitor system, we also eliminate much of the potential progenitor parameter space for white dwarfs hosting recurrent novae or undergoing stable nuclear burning. Therefore, we rule out the most popular single degenerate progenitor models for SN 2011fe, leaving a limited phase space inhabited by some double degenerate systems and exotic progenitor scenarios.Comment: Accepted to Ap

Prophylactic methylprednisolone to reduce inflammation and improve outcomes from one lung ventilation in children: a randomized clinical trial.

BACKGROUND: One lung ventilation (OLV) results in inflammatory and mechanical injury, leading to intraoperative and postoperative complications in children. No interventions have been studied in children to minimize such injury. OBJECTIVE: We hypothesized that a single 2-mg·kg(-1) dose of methylprednisolone given 45-60 min prior to lung collapse would minimize injury from OLV and improve physiological stability. METHODS: Twenty-eight children scheduled to undergo OLV were randomly assigned to receive 2 mg·kg(-1) methylprednisolone (MP) or normal saline (placebo group) prior to OLV. Anesthetic management was standardized, and data were collected for physiological stability (bronchospasm, respiratory resistance, and compliance). Plasma was assayed for inflammatory markers related to lung injury at timed intervals related to administration of methylprednisolone. RESULTS: Three children in the placebo group experienced clinically significant intraoperative and postoperative respiratory complications. Respiratory resistance was lower (P = 0.04) in the methylprednisolone group. Pro-inflammatory cytokine IL-6 was lower (P = 0.01), and anti-inflammatory cytokine IL-10 was higher (P = 0.001) in the methylprednisolone group. Tryptase, measured before and after OLV, was lower (P = 0.03) in the methylprednisolone group while increased levels of tryptase were seen in placebo group after OLV (did not achieve significance). There were no side effects observed that could be attributed to methylprednisolone in this study. CONCLUSIONS: Methylprednisolone at 2 mg·kg(-1) given as a single dose prior to OLV provides physiological stability to children undergoing OLV. In addition, methylprednisolone results in lower pro-inflammatory markers and higher anti-inflammatory markers in the children\u27s plasma

The Glial Regenerative Response to Central Nervous System Injury Is Enabled by Pros-Notch and Pros-NFκB Feedback

Organisms are structurally robust, as cells accommodate changes preserving structural integrity and function. The molecular mechanisms underlying structural robustness and plasticity are poorly understood, but can be investigated by probing how cells respond to injury. Injury to the CNS induces proliferation of enwrapping glia, leading to axonal re-enwrapment and partial functional recovery. This glial regenerative response is found across species, and may reflect a common underlying genetic mechanism. Here, we show that injury to the Drosophila larval CNS induces glial proliferation, and we uncover a gene network controlling this response. It consists of the mutual maintenance between the cell cycle inhibitor Prospero (Pros) and the cell cycle activators Notch and NFκB. Together they maintain glia in the brink of dividing, they enable glial proliferation following injury, and subsequently they exert negative feedback on cell division restoring cell cycle arrest. Pros also promotes glial differentiation, resolving vacuolization, enabling debris clearance and axonal enwrapment. Disruption of this gene network prevents repair and induces tumourigenesis. Using wound area measurements across genotypes and time-lapse recordings we show that when glial proliferation and glial differentiation are abolished, both the size of the glial wound and neuropile vacuolization increase. When glial proliferation and differentiation are enabled, glial wound size decreases and injury-induced apoptosis and vacuolization are prevented. The uncovered gene network promotes regeneration of the glial lesion and neuropile repair. In the unharmed animal, it is most likely a homeostatic mechanism for structural robustness. This gene network may be of relevance to mammalian glia to promote repair upon CNS injury or disease

Faktor-Faktor Yang Mempengaruhi Motivasi Para Investor Pada Keputusan Pembelian Residensial Properti Di Yogyakarta

Penelitian ini dilakukan untuk mengetahui pengaruh faktorlokasi, keuangan, fitur rumah, lingkungan sekitar terhadap motivasi konsumen terhadap pembelian residensial properti di Yogyakarta. Teori yang digunakan pada penelitian ini adalah teori investasi dari Sharpe et al 2006, teori motivasi konsumen dari buku Kotler 2016 dan teori pendukung lainnya. Pada penelitian ini disebarkan sebanyak 150 kuesioner. Penelitian ini menggunakan alat analisis regresi linear berganda dengan program SPSS 19for windows. Hasil penelitian ini didapatkan faktorlokasi, keuangan, fitur rumah, lingkungan sekitar berpengaruh positif terhadap motivasi konsumen terhadap pembelian residensial properti di Yogyakarta